TW201422254A - Composition for immediate and extended release - Google Patents

Composition for immediate and extended release Download PDF

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Publication number
TW201422254A
TW201422254A TW102140886A TW102140886A TW201422254A TW 201422254 A TW201422254 A TW 201422254A TW 102140886 A TW102140886 A TW 102140886A TW 102140886 A TW102140886 A TW 102140886A TW 201422254 A TW201422254 A TW 201422254A
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pharmaceutical composition
active ingredient
tolterodine
composition according
drug
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TW102140886A
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Chinese (zh)
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Varinder Ahuja
Rajan Verma
Umesh Vinayakrao Barabde
Arne Hagsten
Kristin Wannerberger
Rambabu Boorugu
Amol Vilasrao Somwanshi
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Ferring Bv
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A61K38/095—Oxytocins; Vasopressins; Related peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5089—Processes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

The subject invention relates to fast dissolving pharmaceutical compositions comprising an active ingredient for immediate release and further comprising a controlled release dosage form comprising an active ingredient for controlled release.

Description

用於速釋及延釋的組成物 Composition for immediate release and extended release 發明領域 Field of invention

本發明係有關一種包含活性成分之快速溶解藥學組成物，以用於速釋，且更包含含有活性成分之控制釋放劑量形式，以用於控制釋放，並有關於其製造方法，及其在治療與預防哺乳類動物，特別是人類之疾病上的用途。 The present invention relates to a fast-dissolving pharmaceutical composition comprising an active ingredient for immediate release, and further comprising a controlled release dosage form containing the active ingredient for controlled release, and related to its method of manufacture, and its treatment And the use of prevention of diseases in mammals, especially humans.

發明背景 Background of the invention

經設計以在口腔中速釋活性成分之快速溶解之藥學劑量形式，為已習知，並可用於輸送廣泛範圍的藥物(Critical Reviews in Therapeutic Drug Carrier Systems,21(6)：433-475(2004)；Seager H.(1998),J.Phar.Pharmacol 50：375-382；Bandari et al.(January 2008),Asian Journal of Pharmaceutics 2-11)。 Pharmaceutical dosage forms designed to rapidly release active ingredients in the oral cavity are well known and can be used to deliver a wide range of drugs ( Critical Reviews in Therapeutic Drug Carrier Systems, 21(6): 433-475 (2004) Seager H. (1998), J. Phar. Pharmacol 50: 375-382; Bandari et al. (January 2008), Asian Journal of Pharmaceutics 2-11 ).

在快速溶解的劑量形式中，藥物可被物理地捕捉在由例如甘露糖醇及魚明膠(EP 1 501 534；EP 1 165 053)、改質澱粉(US 6,509,040)、與胺基酸結合之聚三葡萄糖(pullulan)(EP 1 803 446)、與山梨糖醇結合之麥芽糖糊精(maltodextrin)(US 2004/0228919)、左聚糖(levan)(WO 2011/120904)或菊糖(inulin)(WO 2011/120903)等載劑材料所組成的基質(matrix)中。在製備該快速溶解之藥劑形式方面，該藥物之溶液、懸浮液或分散液及載劑材料，可被填裝至泡殼空腔內、冷凍，之後凍乾。 In a rapidly dissolving dosage form, the drug can be physically captured in a combination of, for example, mannitol and fish gelatin ( EP 1 501 534; EP 1 165 053 ), modified starch ( US 6,509,040 ), in combination with an amino acid. Pullulan ( EP 1 803 446 ), sorbitol-conjugated maltodextrin ( US 2004/0228919 ), levan ( WO 2011/120904 ) or inulin (inulin) WO 2011/120903 ) in a matrix composed of a carrier material. In preparing the rapidly dissolving pharmaceutical form, the solution, suspension or dispersion of the drug and the carrier material can be filled into the blister cavity, frozen, and then lyophilized.

欲以受控方式釋放的含有活性成分之控制釋放丸粒亦為本領域所習知，並如US 6,911,217、US 2009/0192228、EP 1 781 275及WO 2007/029087所描述。該些控制釋放珠粒典型上用於醫藥業的藥物(硬明膠)膠囊內，以作為口服投藥及可以廣泛種類的方法製備，例如分層法、擠出滾圓法(extrusion spheronization)、粒化法、熱熔擠出法、噴霧乾燥法及類似方法。 Controlled release pellets containing the active ingredient to be released in a controlled manner are also known in the art and are described in US 6,911,217 , US 2009/0192228 , EP 1 781 275 and WO 2007/029087 . These controlled release beads are typically used in pharmaceutical (hard gelatin) capsules for the pharmaceutical industry for oral administration and can be prepared in a wide variety of ways, such as layering, extrusion spheronization, granulation. , hot melt extrusion, spray drying and the like.

某些疾病與病症需要以造成速釋的方式投予一藥物，且以造成延釋的方式投予另一藥物。若該二種藥物能以單一劑量單元投藥，包括以速釋方式釋放一藥物且以延釋方式釋放另一藥物，這當然會有優勢。 Certain diseases and conditions require administration of a drug in a manner that results in immediate release and administration of another drug in a manner that causes a delayed release. It would certainly be advantageous if the two drugs could be administered in a single dosage unit, including releasing one drug in an immediate release and releasing another drug in a delayed release.

發明概要 Summary of invention

本發明現在提供一種配方，其不僅包含被基質捕捉的用於速釋之第一藥物，還額外包含捕捉在基質內的另一劑量形式，該另一劑量形式為包含第二藥物之延釋珠粒，以用於延釋。 The present invention now provides a formulation comprising not only a first drug for immediate release captured by a matrix, but additionally another dosage form captured within the matrix, the other dosage form being a delayed release bead comprising a second drug Granules for extended release.

此，本發明提供一種包含凍乾、熔融型、快速溶解或崩解(disintegrating)配方的單一劑量單元藥學結合產物，其包含用於速釋(IR)之第一活性成分，其中該快速溶 解配方進一步包含含有第二藥學上活性成分的延釋(ER)丸粒，其以受控方式被釋放。該延釋丸粒被物理地捕捉或包埋在該快速溶解配方之基質中。 Thus, the present invention provides a single dosage unit pharmaceutical binding product comprising a lyophilized, melted, fast dissolving or disintegrating formulation comprising a first active ingredient for immediate release (IR), wherein the rapid dissolution The formulation further comprises a delayed release (ER) pellet containing a second pharmaceutically active ingredient that is released in a controlled manner. The extended release pellets are physically captured or embedded in a matrix of the fast dissolving formulation.

該快速溶解口服藥學組成物典型上為口服冷凍乾燥物(lyophilizates)(亦命名為口服崩解錠劑或口服溶解錠劑)，其包含用於速釋(IR)之第一活性成分，及進一步包含含有第二藥學上活性成分的延釋(ER)丸粒，其以受控方式被釋放。 The fast-dissolving oral pharmaceutical composition is typically an oral lyophilizates (also known as oral disintegrating lozenges or oral dissolving lozenges) comprising a first active ingredient for immediate release (IR), and further A delayed release (ER) pellet containing a second pharmaceutically active ingredient is included which is released in a controlled manner.

該延釋丸粒可藉由本領域習知之方法配製，例如分層、擠出滾圓、粒化、熱熔擠出、噴霧乾燥及類似方法。 The extended release pellets can be formulated by methods known in the art, such as delamination, extrusion spheronization, granulation, hot melt extrusion, spray drying, and the like.

已經發現，本發明之組成物，其中快速溶解配方內含有丸粒，可達成許多意外的及有益的技術效果：˙該第一與第二藥物(活性成分)之穩定釋放曲線，亦即釋放曲線類似於、大致上相同於或相同於僅於IR配方中包含該第一藥物，及僅於ER配方中包含該第二藥物之個別組成物所觀察到之曲線；˙相較於不含丸粒之組成物，相對高的抗張強度(亦即，在三點彎曲試驗中破碎一錠劑所需之力量)；˙組成物之總重量為藥學上可接受，及就消費者的觀點而言可接受；˙小於30秒的快速崩解/溶解時間；以及˙組成物可藉由凍乾製備，對於丸粒的延釋曲線僅有些微、大致上不會，或不會產生影響。 It has been found that the compositions of the present invention, wherein the fast dissolving formulation contains pellets, can achieve a number of unexpected and beneficial technical effects: 稳定 a stable release profile of the first and second drug (active ingredient), i.e., a release profile a curve similar to, substantially identical to, or identical to the inclusion of the first drug only in the IR formulation, and only the individual composition comprising the second drug in the ER formulation; a composition having a relatively high tensile strength (i.e., the force required to break a tablet in a three-point bending test); the total weight of the bismuth composition is pharmaceutically acceptable, and from the consumer's point of view Acceptable; 快速 rapid disintegration/dissolution time of less than 30 seconds; and bismuth composition can be prepared by lyophilization, with only slight, substantially no, or no effect on the delayed release profile of the pellet.

該相對高的抗張強度容許，其中包括，易於自其 容器(典型上為泡殼包裝)移去該組成物，而不會崩解及不會有在指間使該劑量形式損毀的風險。本發明之單位劑量形式可典型上以類似於傳統的壓縮錠劑方式操作，其僅在與水性液體或口腔內唾液接觸時發生崩解。 The relatively high tensile strength allows, among other things, The container (typically a blister pack) removes the composition without disintegration and without the risk of damaging the dosage form between the fingers. The unit dosage form of the present invention can typically be operated in a manner similar to conventional compressed tabletes which disintegrate only upon contact with aqueous liquids or oral saliva.

儘管具有此抗張強度，本發明組成物當與水性介質或與唾液接觸時迅速地崩解，特別是當以口服投藥時該組成物迅速地崩解。 Despite this tensile strength, the composition of the present invention rapidly disintegrates when contacted with an aqueous medium or with saliva, particularly when the composition is rapidly disintegrated when administered orally.

本發明之藥學組成物可，例如在冷凍乾燥方法中，藉由從一在溶液中包含第一活性成分、基質形成劑及控制釋放珠粒(其亦包含額外的第二活性成分)的液體製備物中，昇華該溶劑(例如，水)而獲得。依據一實施例，將單位劑量數量之該液體製備物導入凹陷及隨後進行昇華，因此獲得(在昇華之後)呈單位劑量形式之藥學組成物，其包含二種活性成分，一者用於速釋及一者用於控制釋放。該凹陷可以是開放式泡殼包裝之凹陷，及在昇華步驟後(及因此在該組成物於凹陷內形成固體單位劑量形式之後)，將密封薄膜或箔放在該凹陷上，以形成密封的泡殼包裝。 The pharmaceutical composition of the present invention can be prepared, for example, in a freeze-drying process by preparing a liquid comprising a first active ingredient, a matrix forming agent, and a controlled release bead (which also contains an additional second active ingredient) in solution. Obtained by sublimating the solvent (for example, water). According to one embodiment, a unit dose amount of the liquid preparation is introduced into a depression and subsequently sublimed, thereby obtaining (after sublimation) a pharmaceutical composition in unit dosage form comprising two active ingredients, one for immediate release And one is used to control the release. The depression may be a depression of an open blister package, and after the sublimation step (and thus after the composition forms a solid unit dosage form within the depression), a sealing film or foil is placed over the depression to form a sealed Buffer packaging.

特別是，本發明係有關包含開放式基質網狀物之藥學組成物，其包含第一藥學上活性成分；一或多種基質形成劑；及含有第二藥學上活性成分之控制釋放珠粒。 In particular, the invention relates to a pharmaceutical composition comprising an open matrix network comprising a first pharmaceutically active ingredient; one or more matrix forming agents; and a controlled release bead comprising a second pharmaceutically active ingredient.

本發明係進一步有關製備藥學組成物之方法，其包含從液體製備物中昇華溶劑，該液體製備物包含第一藥學上活性成分、一或多種基質形成劑、含有第二藥學上活性成分之控制釋放丸粒，以及溶劑。 The invention further relates to a method of preparing a pharmaceutical composition comprising sublimating a solvent from a liquid preparation, the liquid preparation comprising a first pharmaceutically active ingredient, one or more matrix forming agents, and a control comprising a second pharmaceutically active ingredient Release the pellets, as well as the solvent.

本發明亦有關用於製備藥學組成物之方法，其步驟包含：(a)製備一包含第一活性成分、含有第二活性成分之控制釋放珠粒、一或多種基質形成劑，及溶劑之混合物；(b)冷凍該溶液；(c)從該經冷凍之溶液中昇華該溶劑，其中因此獲得之藥學組成物在與標準水性介質接觸後，於30秒內崩解。 The invention also relates to a process for the preparation of a pharmaceutical composition, the process comprising: (a) preparing a mixture comprising a first active ingredient, a controlled release bead comprising a second active ingredient, one or more matrix forming agents, and a solvent mixture (b) freezing the solution; (c) sublimating the solvent from the frozen solution, wherein the pharmaceutical composition thus obtained disintegrates within 30 seconds after contact with a standard aqueous medium.

本發明係有關一種用於治療有其需求個體之膀胱過動症(overactive bladder)、夜尿症(nocturia)或其結合病症之方法，其包含投予該個體一治療有效量之組成物，其中該第二活性成分為抗毒蕈鹼化合物(antimuscarinic compound)。 The present invention relates to a method for treating overactive bladder, nocturia or a combination thereof for treating a subject in need thereof, comprising administering to the individual a therapeutically effective amount of a composition, wherein the The second active ingredient is an antimuscarinic compound.

本發明係有關一種用於治療有其需求個體之良性攝護腺肥大症(benign prostatic hyperplasia)之方法，其包含投予該個體一治療有效量之組成物，其中該第二活性成分為選擇性α-阻斷劑。 The present invention relates to a method for treating benign prostatic hyperplasia in a subject in need thereof, comprising administering to the individual a therapeutically effective amount of a composition, wherein the second active ingredient is selective Alpha-blocker.

1‧‧‧核心 1‧‧‧ core

2‧‧‧任擇的內部封合塗層 2‧‧‧Optional internal seal coating

3‧‧‧內部含藥層 3‧‧‧ Internal drug layer

4‧‧‧任擇的外部封合塗層 4‧‧‧Optional external seal coating

5‧‧‧外部膜層 5‧‧‧External film

6‧‧‧任擇的額外之聚合物層 6‧‧‧Optional additional polymer layer

圖1a係圖示包含凍乾、熔融型、快速溶解配方之本發明單劑量單位藥學結合產物，其包含用於速釋之第一活性成分，其中該快速溶解配方進一步包含含有第二藥學上活性成分之延釋丸粒，其以可控方式被釋放。 Figure 1a is a diagram showing a single dose unit pharmaceutical binding product of the invention comprising a lyophilized, melted, fast dissolving formulation comprising a first active ingredient for immediate release, wherein the fast dissolving formulation further comprises a second pharmaceutically active ingredient A delayed release pellet of the ingredient that is released in a controlled manner.

圖1b係圖示用於本發明之延釋丸粒或珠粒，包 含： Figure 1b is a diagram showing the extended release pellets or beads used in the present invention, Contains:

- 1：核心 - 1: Core

- 2：任擇的內部封合塗層 - 2: Optional internal seal coating

- 3：內部含藥層 - 3: Internal drug layer

- 4：任擇的外部封合塗層 - 4: Optional external seal coating

- 5：外部膜層及 - 5: External film layer and

- 6：任擇的額外之聚合物層。 - 6: Optional additional polymer layer.

圖1c係圖示用於本發明之延釋丸粒或珠粒，及包含含有藥物、賦形劑及任擇的控制釋放聚合物之核心。該核心可任擇地以控制釋放聚合物塗佈。 Figure 1c is a diagram showing the extended release pellets or beads for use in the present invention, and comprising a core comprising a drug, an excipient, and optionally a controlled release polymer. The core can optionally be coated with a controlled release polymer.

圖2係得舒妥XL(Detrusitol® XL)及托特羅定(tolterodine)ER珠粒(顆粒)，及依據範例1之冷凍乾燥物的溶解曲線比較圖，其於pH 6.8之磷酸鹽緩衝液中，以美國藥典(USP)裝置1(籃式法)之100rpm進行。 Figure 2 is a comparison of the dissolution curves of Detrusitol ® XL and tolterodine ER beads (granules) and the lyophilized product according to Example 1, which is a phosphate buffer at pH 6.8. The procedure was carried out at 100 rpm of the United States Pharmacopoeia (USP) device 1 (basket method).

圖3係範例2之劑量形式之第一活性成分(去氨加壓素(desmopressin))及第二活性成分(托特羅定)之釋放的比較圖，其於pH 6.8之磷酸鹽緩衝液中，以USP裝置2(槳法)之50rpm用於去氨加壓素，及以USP裝置1(籃式法)之100rpm用於托特羅定。 Figure 3 is a comparison of the release of the first active ingredient (desmopressin) and the second active ingredient (tolterodine) in the dosage form of Example 2 in phosphate buffer pH 6.8. It was used for desmopressin at 50 rpm of USP device 2 (paddle method) and tolterodine at 100 rpm of USP device 1 (basket method).

圖4係範例3之劑量形式之第一活性成分(去氨加壓素)及第二活性成分(托特羅定)之釋放的比較圖，其於pH 6.8之磷酸鹽緩衝液中以USP裝置2(槳法)之50rpm用於去氨加壓素，及以USP裝置1(籃式法)之100rpm用於托特羅定。 Figure 4 is a comparison of the release of the first active ingredient (desmopressin) and the second active ingredient (tolterodine) in the dosage form of Example 3, in a phosphate buffer of pH 6.8 as a USP device 50 rpm of 2 (paddle method) was used for desmopressin, and 100 rpm of USP apparatus 1 (basket method) was used for tolterodine.

圖5係範例4之劑量形式之第一活性成分(去氨加壓素)及第二活性成分(托特羅定)之釋放的比較圖，其於pH 6.8之磷酸鹽緩衝液中以USP裝置2(槳法)之50rpm用於去氨加壓素，及以USP裝置1(籃式法)之100rpm用於托特羅定。 Figure 5 is a comparison of the release of the first active ingredient (desmopressin) and the second active ingredient (tolterodine) in the dosage form of Example 4, in a phosphate buffer of pH 6.8 as a USP device 50 rpm of 2 (paddle method) was used for desmopressin, and 100 rpm of USP apparatus 1 (basket method) was used for tolterodine.

圖6係範例5之劑量形式之第一活性成分(去氨加壓素)及第二活性成分(托特羅定)之釋放的比較圖，其於pH 6.8之磷酸鹽緩衝液中以USP裝置2(槳法)之50rpm用於去氨加壓素，及以USP裝置1(籃式法)之100rpm用於托特羅定。 Figure 6 is a comparison of the release of the first active ingredient (desmopressin) and the second active ingredient (tolterodine) in the dosage form of Example 5, in a phosphate buffer of pH 6.8 as a USP device 50 rpm of 2 (paddle method) was used for desmopressin, and 100 rpm of USP apparatus 1 (basket method) was used for tolterodine.

圖7係得舒妥及托特羅定ER珠粒(顆粒)及依據範例6之冷凍乾燥物的溶解曲線比較圖，其於pH 6.8之磷酸鹽緩衝液以美國藥典(USP)裝置1(籃式法)之100rpm進行。 Figure 7 is a comparison of the dissolution profiles of the sulphon and tolterodine ER beads (granules) and the lyophilized product according to Example 6, which is in the United States Pharmacopoeia (USP) device 1 (basket) at pH 6.8 phosphate buffer. The method was carried out at 100 rpm.

圖8係得舒妥及托特羅定ER珠粒(顆粒)及依據範例7之冷凍乾燥物的溶解曲線比較圖，其於pH 6.8之磷酸鹽緩衝液以美國藥典(USP)裝置1(籃式法)之100rpm進行。 Figure 8 is a graph comparing the dissolution curves of the sulphon and tolterodine ER beads (granules) and the lyophilized product according to Example 7, which is in the United States Pharmacopoeia (USP) device 1 (basket) at pH 6.8 phosphate buffer. The method was carried out at 100 rpm.

圖9係得舒妥及托特羅定ER珠粒(顆粒)及依據範例8之冷凍乾燥物的溶解曲線比較圖，其於pH 6.8之磷酸鹽緩衝液以美國藥典(USP)裝置1(籃式法)之100rpm進行。 Figure 9 is a comparison of the dissolution profiles of the sulphon and tolterodine ER beads (granules) and the lyophilized product according to Example 8, which is in the United States Pharmacopoeia (USP) device 1 (basket) at pH 6.8 phosphate buffer. The method was carried out at 100 rpm.

圖10係範例9之劑量形式之第一活性成分(去氨加壓素)及第二活性成分(托特羅定)之釋放的比較圖，其於pH 6.8之磷酸鹽緩衝液中以USP裝置2(槳法)之50rpm用於去氨加壓素，及以USP裝置1(籃式法)之100rpm用於托特羅定。 Figure 10 is a comparison of the release of the first active ingredient (desmopressin) and the second active ingredient (tolterodine) in the dosage form of Example 9, which is in USP apparatus in phosphate buffer pH 6.8. 50 rpm of 2 (paddle method) was used for desmopressin, and 100 rpm of USP apparatus 1 (basket method) was used for tolterodine.

圖11係範例10之劑量形式之第一活性成分(去氨加壓素)及第二活性成分(托特羅定)之釋放的比較圖，其於pH 6.8之磷酸鹽緩衝液中以USP裝置2(槳法)之50rpm用於去氨加壓素，及以USP裝置1(籃式法)之100rpm用於托特羅定。 Figure 11 is a comparison of the release of the first active ingredient (desmopressin) and the second active ingredient (tolterodine) in the dosage form of Example 10, in a phosphate buffer of pH 6.8 as a USP device 50 rpm of 2 (paddle method) was used for desmopressin, and 100 rpm of USP apparatus 1 (basket method) was used for tolterodine.

圖12係範例11之劑量形式之第一活性成分(去氨加壓素)及第二活性成分(托特羅定)之釋放的比較圖，其於pH 6.8之磷酸鹽緩衝液中以USP裝置2(槳法)之50rpm用於去氨加壓素，及以USP裝置1(籃式法)之100rpm用於托特羅定。 Figure 12 is a comparison of the release of the first active ingredient (desmopressin) and the second active ingredient (tolterodine) in the dosage form of Example 11 in a phosphate buffer of pH 6.8 as a USP device 50 rpm of 2 (paddle method) was used for desmopressin, and 100 rpm of USP apparatus 1 (basket method) was used for tolterodine.

圖13係範例12之劑量形式之第一活性成分(去氨加壓素)及第二活性成分(托特羅定)之釋放的比較圖，其於pH 6.8之磷酸鹽緩衝液中以USP裝置2(槳法)之50rpm用於去氨加壓素，及以USP裝置1(籃式法)之100rpm用於托特羅定。 Figure 13 is a comparison of the release of the first active ingredient (desmopressin) and the second active ingredient (tolterodine) in the dosage form of Example 12, in a phosphate buffer of pH 6.8 as a USP device 50 rpm of 2 (paddle method) was used for desmopressin, and 100 rpm of USP apparatus 1 (basket method) was used for tolterodine.

圖14係範例13之劑量形式之第一活性成分(去氨加壓素)及第二活性成分(托特羅定)之釋放的比較圖，其於pH 6.8之磷酸鹽緩衝液中以USP裝置2(槳法)之50rpm用於去氨加壓素，及以USP裝置1(籃式法)之100rpm用於托特羅定。 Figure 14 is a comparison of the release of the first active ingredient (desmopressin) and the second active ingredient (tolterodine) in the dosage form of Example 13, which is in USP apparatus in phosphate buffer pH 6.8. 50 rpm of 2 (paddle method) was used for desmopressin, and 100 rpm of USP apparatus 1 (basket method) was used for tolterodine.

圖15係範例14之劑量形式之第一活性成分(去氨加壓素)及第二活性成分(托特羅定)之釋放的比較圖，其於pH 6.8之磷酸鹽緩衝液中以USP裝置2(槳法)之50rpm用於去氨加壓素，及以USP裝置1(籃式法)之100rpm用於托特羅定。 Figure 15 is a comparison of the release of the first active ingredient (desmopressin) and the second active ingredient (tolterodine) in the dosage form of Example 14, which is in USP apparatus in phosphate buffer pH 6.8. 50 rpm of 2 (paddle method) was used for desmopressin, and 100 rpm of USP apparatus 1 (basket method) was used for tolterodine.

較佳實施例之詳細說明 Detailed description of the preferred embodiment

本發明之目的係提供一劑量形式，其包含二種活性成分，其中一者以立即方式釋放，及另一者以受控方式釋放。 It is an object of the present invention to provide a dosage form comprising two active ingredients, one of which is released in an immediate manner and the other in a controlled manner.

本發明現在提供一種包含二種藥物(活性成分)之新穎的口內崩散型劑量形式。該藥物之一者係以立即方式釋放，另一者以受控方式釋放。該劑量形式為快速溶解之劑量形式，例如但不限於，熔融狀或冷凍乾燥單元。以受控方式釋放之藥物係包含於丸粒(珠粒)之內，之後包含於該快速溶解配方之內。儘管有丸粒存在於該快速溶解之劑量形式之內，該組成物穩定，整體組成物之重量為藥學上可接受，及就消費者的觀點而言可接受，及該快速溶解之劑量形式之口中溶解時間仍然相當快速。 The present invention now provides a novel intra-oral collapse dosage form comprising two drugs (active ingredients). One of the drugs is released in an immediate manner and the other is released in a controlled manner. The dosage form is a rapidly dissolving dosage form such as, but not limited to, a molten or freeze dried unit. The drug released in a controlled manner is contained within the pellet (beads) and is then included in the fast dissolving formulation. While the pellet is present in the rapidly dissolving dosage form, the composition is stable, the weight of the overall composition is pharmaceutically acceptable, and acceptable from the consumer's point of view, and the rapidly dissolving dosage form The dissolution time in the mouth is still quite fast.

術語“藥物”、“活性成分”或“藥學上活性成分”在此可互換使用。 The terms "drug", "active ingredient" or "pharmaceutically active ingredient" are used interchangeably herein.

術語“藥學組成物”及“組成物”在此可互換使用以意指本發明之藥學組成物。 The terms "pharmaceutical composition" and "composition" are used interchangeably herein to mean a pharmaceutical composition of the invention.

術語“控制釋放丸粒”或“丸粒”或“控制釋放珠粒”或“珠粒”或“控制釋放顆粒”或“顆粒”在此可互換使用。 The terms "controlled release pellets" or "pellets" or "controlled release beads" or "beads" or "controlled release particles" or "particles" are used interchangeably herein.

控制釋放珠粒可藉由本領域習知之數種方法製造，例如分層法、擠出滾圓法、粒化法、熱熔擠出法、噴霧乾燥法等，其中該第二活性成分係以釋放控制劑進行混合及/或塗佈。 Controlled release beads can be made by several methods known in the art, such as layering, extrusion spheronization, granulation, hot melt extrusion, spray drying, etc., wherein the second active component is controlled by release. The agent is mixed and/or coated.

當以分層法製造控制釋放珠粒時，該控制釋放珠粒典型上含有選自於水溶性核心、水不溶性核心，及水可膨脹性核心之藥學上非活性核心1，並以內部含藥層3及外部膜層5塗佈，以控制藥物從該內部層釋放。 When the controlled release bead is produced in a layered process, the controlled release bead typically contains a pharmaceutically inactive core 1 selected from the group consisting of a water soluble core, a water insoluble core, and a water swellable core, and is internally contained. Layer 3 and outer film layer 5 are coated to control the release of the drug from the inner layer.

一些控制釋放珠粒的惰性核心1與內部含藥層3之間，亦包含由選自於實質上水不溶性聚合物及實質上水溶性聚合物之聚合物製成的“封合塗層”2。 Some of the inert core 1 and the inner drug-containing layer 3 which control the release of the beads also comprise a "sealing coating" made of a polymer selected from the group consisting of substantially water-insoluble polymers and substantially water-soluble polymers. .

一些控制釋放珠粒的內部含藥層3與外部膜層5之間，亦包含由選自於實質上水不溶性聚合物及實質上水溶性聚合物之聚合物製成的“封合塗層”4。 Between the inner drug-containing layer 3 and the outer film layer 5, which control the release of the beads, a "sealing coating" made of a polymer selected from the group consisting of substantially water-insoluble polymers and substantially water-soluble polymers is also included. 4.

該控制釋放珠粒之外部膜層5上可進一步含有額外的聚合物層6。 The outer film layer 5 of the controlled release bead may further comprise an additional polymer layer 6.

本發明之目的係提供控制釋放珠粒，其中藥物釋放曲線不會明顯被冷凍乾燥影響，因此這些珠粒可包含於本發明之經冷凍乾燥劑量形式中而使用。 It is an object of the present invention to provide controlled release beads wherein the drug release profile is not significantly affected by lyophilization, and thus these beads can be included in the lyophilized dosage form of the present invention.

該核心係典型上以水溶性、水不溶性或水可膨脹性材料製成，及可由傳統上作為核心之任何材料，或可做成珠粒或丸粒之任何其他藥學上可接受之水溶性、水不溶性或水可膨脹性材料組成。舉例而言，該核心可為蔗糖/澱粉球(糖球NF)、蔗糖晶體、玻璃或微結晶纖維素。特別是，該核心可為水溶性糖球或水可膨脹性微結晶纖維素核心。該核心可藉由將賦形劑(例如微結晶纖維素及乳糖)，例如，擠出及後續的擠出物乾燥而製成。 The core system is typically made of a water soluble, water insoluble or water swellable material, and any material that can be traditionally cored, or any other pharmaceutically acceptable water soluble, which can be made into beads or pellets. Composition of water insoluble or water swellable materials. For example, the core can be a sucrose/starch sphere (sugar sphere NF), sucrose crystals, glass or microcrystalline cellulose. In particular, the core can be a water soluble sugar sphere or a water swellable microcrystalline cellulose core. The core can be made by drying excipients such as microcrystalline cellulose and lactose, for example, by extrusion and subsequent extrudates.

位於(i)核心1與內部含藥層3之間，及/或(ii)內部 含藥層3與外部膜層5之間的選擇性封合塗層2及4中的實質上水不溶性聚合物(以控制水滲透至核心)，一般為“GI不溶性”(GI=胃腸道)，或“GI部分不溶性”成膜聚合物。該些聚合物之非侷限範例為乙基纖維素、醋酸纖維素、乙酸丁酸纖維素、聚甲基丙烯酸酯如丙烯酸乙酯/甲基丙烯酸甲酯共聚物(Eudragit® NE 30 D)，及甲基丙烯酸銨共聚物A型與B型(Eudragit® RL 30 D及RS 30 D)、聚矽氧彈性體及其二或多者之混合物。在一特定之實施例中，該內部封合塗層2之實質上水不溶性聚合物，包含乙基纖維素。偶爾，以一或多種塑化劑伴隨該聚合物使用。塑化劑之非侷限範例包括癸二酸二丁酯、丙二醇、檸檬酸三乙酯、檸檬酸三丁酯、蓖麻油(castor oil)、乙醯化單酸甘油酯、乙醯檸檬酸三乙酯、乙醯檸檬酸丁酯、鄰苯二甲酸二乙酯、鄰苯二甲酸二丁酯、三乙酸甘油酯(triacetin)、中鏈三酸甘油酯如經分餾之椰子油等。 Substantially water insoluble polymerization in the selective sealing coatings 2 and 4 between (i) the core 1 and the inner drug-containing layer 3, and/or (ii) between the inner drug-containing layer 3 and the outer film layer 5. (to control the penetration of water into the core), typically "GI insoluble" (GI = gastrointestinal), or "GI partially insoluble" film forming polymer. Non-limiting examples of such polymers are ethyl cellulose, cellulose acetate, cellulose acetate butyrate, polymethacrylates such as ethyl acrylate/methyl methacrylate copolymer (Eudragit ® NE 30 D), and Ammonium methacrylate copolymers Type A and Type B (Eudragit ® RL 30 D and RS 30 D), polyoxyxene elastomers and mixtures of two or more thereof. In a particular embodiment, the substantially water insoluble polymer of the inner seal coating 2 comprises ethylcellulose. Occasionally, one or more plasticizers are used with the polymer. Non-limiting examples of plasticizers include dibutyl sebacate, propylene glycol, triethyl citrate, tributyl citrate, castor oil, acetylated monoglyceride, ethyl citrate triacetate Ester, butyl butyl citrate, diethyl phthalate, dibutyl phthalate, triacetin, medium chain triglyceride, such as fractionated coconut oil.

選擇性封合塗層2及4之水溶性聚合物可選自於親水性聚合物如聚乙烯吡咯烷酮(PVP)、聚烷二醇如聚乙二醇、明膠、聚乙烯醇、澱粉及其衍生物、纖維素衍生物，例如羥基丙基甲基纖維素(HPMC)、羥基丙基纖維素、羧基甲基纖維素、甲基纖維素、乙基纖維素、羥基乙基纖維素、羧基乙基纖維素、羧基甲基羥基乙基纖維素、丙烯酸聚合物、聚甲基丙烯酸酯，及其二或多者之混合物。 The water-soluble polymer of the selectively encapsulated coatings 2 and 4 may be selected from hydrophilic polymers such as polyvinylpyrrolidone (PVP), polyalkylene glycols such as polyethylene glycol, gelatin, polyvinyl alcohol, starch, and derivatives thereof. , cellulose derivatives, such as hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose, carboxymethyl cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, carboxyethyl Cellulose, carboxymethylhydroxyethylcellulose, acrylic acid polymer, polymethacrylate, and mixtures of two or more thereof.

含有(第二)活性成分的內部層3，可由具有或不具有作為黏合劑之聚合物之活性成分(藥物)組成。該黏合劑 在使用時通常為親水性及可為水溶性或水不溶性。用於含有活性藥物之內部層的聚合物之非侷限範例為親水性聚合物，如聚乙烯吡咯烷酮(PVP)、聚烷二醇如聚乙二醇、明膠、聚乙烯醇、澱粉及其衍生物、纖維素衍生物如羥基丙基甲基纖維素(HPMC)、羥基丙基纖維素、羧基甲基纖維素、甲基纖維素、乙基纖維素、羥基乙基纖維素、羧基乙基纖維素、羧基甲基羥基乙基纖維素、丙烯酸聚合物、聚甲基丙烯酸酯，及其二或多者之混合物。在一特定之實施例中，該內部含藥層3包含作為黏合劑之羥基丙基甲基纖維素。在內部層中，藥物與親水性聚合物之比例通常介於1：5至10：1(w/w)之範圍內。 The inner layer 3 containing the (second) active ingredient may be composed of an active ingredient (drug) with or without a polymer as a binder. The adhesive It is usually hydrophilic when used and can be water soluble or water insoluble. Non-limiting examples of polymers for the inner layer containing the active drug are hydrophilic polymers such as polyvinylpyrrolidone (PVP), polyalkylene glycols such as polyethylene glycol, gelatin, polyvinyl alcohol, starch and derivatives thereof. , cellulose derivatives such as hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose, carboxymethyl cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, carboxyethyl cellulose , carboxymethyl hydroxyethyl cellulose, acrylic acid polymer, polymethacrylate, and a mixture of two or more thereof. In a particular embodiment, the inner drug-containing layer 3 comprises hydroxypropyl methylcellulose as a binder. In the inner layer, the ratio of drug to hydrophilic polymer is usually in the range of 1:5 to 10:1 (w/w).

用於外部膜層5以控制藥物釋放之適用聚合物，可選自於水不溶性聚合物或具有pH-依賴型溶解度之聚合物，例如，乙基纖維素、鄰苯二甲酸羥基丙基甲基纖維素、鄰苯二甲酸乙酸纖維素、偏苯三酸乙酸纖維素、聚甲基丙烯酸酯，或其混合物，任擇地與塑化劑(如該些前述者)結合。除了前述之聚合物外，該控制釋放層任擇地包含另一具有不同溶解度特徵之物質，以調節該第二藥物之通透度及釋放率。可作為修飾劑以伴隨，例如，乙基纖維素使用之示範性聚合物包括：HPMC、羥基乙基纖維素、羥基丙基纖維素、甲基纖維素、羧基甲基纖維素、聚乙二醇、聚乙烯吡咯烷酮(PVP)、聚乙烯醇、具有pH-依賴型溶解度之聚合物，例如鄰苯二甲酸乙酸纖維素，或甲基丙烯酸銨共聚物，及甲基丙烯酸共聚物，或其混合物。控制釋放層亦可 包括添加劑如蔗糖、乳糖、藥物級界面活性劑，及其二或多者之混合物。在一特定之實施例中，該外部膜層5包含羥基丙基甲基纖維素(HPMC)及乙基纖維素之組合物。 Suitable polymers for the outer membrane layer 5 to control drug release may be selected from water insoluble polymers or polymers having pH-dependent solubility, for example, ethyl cellulose, hydroxypropyl methyl phthalate Cellulose, cellulose acetate phthalate, cellulose acetate trimellitate, polymethacrylate, or mixtures thereof, optionally in combination with a plasticizer, such as those previously described. In addition to the foregoing polymers, the controlled release layer optionally includes another substance having different solubility characteristics to adjust the permeability and release rate of the second drug. Exemplary polymers that can be used as modifiers, with, for example, ethylcellulose, include: HPMC, hydroxyethylcellulose, hydroxypropylcellulose, methylcellulose, carboxymethylcellulose, polyethylene glycol , polyvinylpyrrolidone (PVP), polyvinyl alcohol, a polymer having a pH-dependent solubility, such as cellulose acetate phthalate, or an ammonium methacrylate copolymer, and a methacrylic acid copolymer, or a mixture thereof. Control release layer can also Included are additives such as sucrose, lactose, pharmaceutical grade surfactants, and mixtures of two or more thereof. In a particular embodiment, the outer film layer 5 comprises a combination of hydroxypropyl methylcellulose (HPMC) and ethylcellulose.

用於外部膜層5上之任擇的額外聚合物層6之適用聚合物，為可提供腸道及/或冷凍乾燥保護功能性者，並可選自於甲基丙烯酸共聚物、鄰苯二甲酸乙酸纖維素、乙酸丁酸纖維素、鄰苯二甲酸羥基丙基甲基纖維素、琥珀酸乙酸羥基丙基甲基纖維素、聚醋酸乙烯鄰苯二甲酸酯、偏苯三酸乙酸纖維素、羧基甲基乙基纖維素、蟲膠(shellac)、纖維素醚(例如，乙基纖維素、羥丙甲纖維素(hypromellose)、羥丙纖維素(hyprolose))、PVP、丙烯酸酯聚合物(例如，Eudragit® NE 30 D、Eudragit® RL、Eudragit® RS)及其二或多者之混合物。其可以溶液或分散液之形式塗佈於外部膜層5上。該冷凍乾燥保護功能性可為冷凍乾燥期間避免該外部膜層5溶解之選擇性需求。 Suitable polymers for the optional additional polymer layer 6 on the outer film layer 5 are those which provide intestinal and/or freeze-drying protection functionality and may be selected from methacrylic acid copolymers, phthalic acid Cellulose acetate cellulose, cellulose acetate butyrate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose succinate, polyvinyl acetate phthalate, trimellitic acid acetate fiber , carboxymethylethylcellulose, shellac, cellulose ether (eg, ethyl cellulose, hypromellose, hyprolose), PVP, acrylate polymerization (for example, Eudragit ® NE 30 D, Eudragit ® RL, Eudragit ® RS) and mixtures of two or more thereof. It can be applied to the outer film layer 5 in the form of a solution or dispersion. The freeze-drying protection functionality can be a selective requirement to avoid dissolution of the outer film layer 5 during freeze drying.

控制釋放珠粒係製備如下：a)提供實質上水溶性、水不溶性或水可膨脹性材料之核心1單元；b)任擇地施加內部封合塗層2之聚合物於該核心1上；c)施加含有(第二)活性成分之內部層3及任擇地聚合物黏合劑於核心1上或內部封合塗層2上；d)任擇地施加外部封合塗層4之聚合物於該內部層3上；e)施加外部膜層5於該內部層3上或外部封合塗層4 上，以有效控制釋放活性成分；以及f)任擇地施加額外的聚合物層6於該外部膜層5上。 The controlled release bead is prepared as follows: a) providing a core unit of a substantially water-soluble, water-insoluble or water-swellable material; b) optionally applying a polymer of the inner seal coating 2 to the core 1; c) applying an inner layer 3 containing the (second) active ingredient and optionally a polymeric binder to the core 1 or internally sealing the coating 2; d) optionally applying a polymer of the outer sealing coating 4 On the inner layer 3; e) applying an outer film layer 5 on the inner layer 3 or externally sealing the coating 4 The active component is released in an effective manner; and f) an additional polymer layer 6 is optionally applied to the outer film layer 5.

分層或塗佈操作較佳為例如在離心式塗佈機、塗佈鍋、Granurex®轉子法或流動床塗佈機，較佳為在流動床塗佈機中，藉由噴灑各層材料溶液或分散液於核心上進行。 Delamination or coating operations, for example, preferably in a centrifugal coater, pan coating, Granurex ® method or a rotor fluidized bed coater, preferably in a fluid bed coater, or by spraying a solution of layers of material The dispersion is carried out on the core.

在封合塗層及外部層的塗佈之後，珠粒可“固化”，通常是在流動床系統或盤式乾燥機系統，例如藉由加熱至溫度約30-80℃並歷時約60分鐘而達成。 After coating of the seal coat and the outer layer, the beads may be "cured", typically in a fluid bed system or a tray dryer system, for example by heating to a temperature of about 30-80 ° C for about 60 minutes. Achieved.

在一實施例中，該任擇的內部封合塗層2的含量為該最終珠粒組成物之構成量的約4%至約15%(w/w)。 In one embodiment, the optional inner seal coating 2 is present in an amount from about 4% to about 15% (w/w) of the constituents of the final bead composition.

在一實施例中，該內部含藥層3的含量為該最終珠粒組成物之構成量的約5%至約25%(w/w)。 In one embodiment, the inner drug-containing layer 3 is present in an amount from about 5% to about 25% (w/w) of the constituent amount of the final bead composition.

在一實施例中，該任擇的外部封合塗層4的含量為該最終珠粒組成物之構成量的約1%至約25%(w/w)。 In one embodiment, the optional outer seal coating 4 is present in an amount from about 1% to about 25% (w/w) of the constituents of the final bead composition.

在一實施例中，該外部膜層5的含量為該最終珠粒組成物之構成量的約25%至約55%(w/w)。 In one embodiment, the outer film layer 5 is present in an amount from about 25% to about 55% (w/w) of the constituents of the final bead composition.

在一實施例中，該任擇的額外之聚合物層6的含量為該最終珠粒組成物之構成量的約10%至約35%(w/w)。 In one embodiment, the optional additional polymeric layer 6 is present in an amount from about 10% to about 35% (w/w) of the constituents of the final bead composition.

當以熱熔擠出法取得該控制釋放丸粒時，(第二)活性成分及控制釋放賦形劑係利用習知之熱熔擠出裝置擠出。所得的擠出物經研磨及過篩以獲得所欲之部分。所欲顆粒大小之經乾燥顆粒係任擇地以控制釋放聚合物塗佈。可在適當的塗佈設備中，例如離心式塗佈機、塗佈鍋、Granurex®轉子法、流動床塗佈機及其類似設備，進行顆粒 塗佈。 When the controlled release pellets are obtained by hot melt extrusion, the (second) active ingredient and the controlled release excipient are extruded using a conventional hot melt extrusion apparatus. The resulting extrudate is ground and sieved to obtain the desired portion. The dried particles of the desired particle size are optionally coated with a controlled release polymer. In a suitable coating apparatus may be, for example, a centrifugal coater, pan coating, Granurex ® rotor method, a fluidized bed coater and the like, for coating the particles.

用於熱熔擠出法之該控制釋放賦形劑，可選自於乙基纖維素、鄰苯二甲酸羥基丙基甲基纖維素、鄰苯二甲酸乙酸纖維素、偏苯三酸乙酸纖維素、聚甲基丙烯酸酯、HPMC、羥基乙基纖維素、羥基丙基纖維素、甲基纖維素、羧基甲基纖維素、聚乙二醇、聚乙烯吡咯烷酮(PVP)、聚乙烯醇、卡波姆(carbomer)、聚乳酸-聚甘醇酸共聚物、聚氧化乙烯、硬脂酸棕櫚酸甘油酯(glyceryl palmitostearate)、山嵛酸甘油酯(glyceryl behenate)，及其二或多者之混合物，任擇地與塑化劑(如該些前述者)結合。 The controlled release excipient for hot melt extrusion may be selected from the group consisting of ethyl cellulose, hydroxypropyl methyl cellulose phthalate, cellulose acetate phthalate, and trimellitic acid acetate fiber. , polymethacrylate, HPMC, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, carboxymethyl cellulose, polyethylene glycol, polyvinylpyrrolidone (PVP), polyvinyl alcohol, card Carbomer, polylactic acid-polyglycolic acid copolymer, polyethylene oxide, glyceryl palmitostearate, glyceryl behenate, and mixtures of two or more thereof Optionally, in combination with a plasticizer, such as those previously described.

當以噴霧乾燥法取得該控制釋放珠粒時，(第二)活性成分及控制釋放聚合物係溶解或分散於介質中。此溶液或分散液係經噴霧乾燥，及所得的顆粒係任擇地經乾燥及過篩，以取得所欲之顆粒大小。 When the controlled release beads are obtained by spray drying, the (second) active ingredient and the controlled release polymer are dissolved or dispersed in the medium. The solution or dispersion is spray dried and the resulting granules are optionally dried and sieved to achieve the desired particle size.

用於噴霧乾燥法之該控制釋放聚合物可選自於例如，舉例而言，乙基纖維素、鄰苯二甲酸羥基丙基甲基纖維素、鄰苯二甲酸乙酸纖維素、偏苯三酸乙酸纖維素、聚甲基丙烯酸酯、HPMC、羥基乙基纖維素、羥基丙基纖維素、甲基纖維素、羧基甲基纖維素、聚乙二醇、聚乙烯吡咯烷酮(PVP)、聚乙烯醇及其二或多者之混合物等聚合物，任擇地與塑化劑(如該些前述者)結合。 The controlled release polymer for spray drying may be selected, for example, from ethyl cellulose, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, trimellitic acid. Cellulose acetate, polymethacrylate, HPMC, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, carboxymethyl cellulose, polyethylene glycol, polyvinylpyrrolidone (PVP), polyvinyl alcohol A polymer such as a mixture of two or more thereof, optionally in combination with a plasticizer such as those described above.

當以粒化法取得該控制釋放珠粒時，(第二)活性成分係連同賦形劑乾燥攪拌，及利用黏合劑溶液進行粒化。該顆粒係經乾燥及過篩以取得所欲之部分。所欲顆粒 大小之該經乾燥顆粒可進一步以控制釋放聚合物塗佈。或者，活性成分及控制釋放賦形劑係利用黏合劑溶液進行乾燥混合及粒化。該顆粒隨後經乾燥及過篩以取得所欲之部分。所欲顆粒大小之該經乾燥顆粒可任擇地進一步以控制釋放聚合物塗佈。 When the controlled release beads are obtained by granulation, the (second) active ingredient is dried and stirred together with the excipients, and granulated using a binder solution. The granules are dried and sieved to obtain the desired portion. Desire The dried particles of this size can be further coated with a controlled release polymer. Alternatively, the active ingredient and the controlled release vehicle are dry mixed and granulated using a binder solution. The granules are then dried and sieved to obtain the desired portion. The dried particles of the desired particle size can optionally be further coated with a controlled release polymer.

粒化方法係於製粒機，例如但不限於，快速混合製粒機、行星式攪拌機、流動床處理機、離心式製粒機，及其類似機器進行。可在適當的塗佈設備中，例如離心式塗佈機、塗佈鍋、Granurex®轉子處理機機、流動床塗佈機及其類似設備，進行顆粒塗佈。 The granulation process is carried out on a granulator such as, but not limited to, a fast mixing granulator, a planetary mixer, a fluid bed processor, a centrifugal granulator, and the like. In a suitable coating apparatus may be, for example, a centrifugal coater, pan coating, Granurex ® machine rotor processor, a fluidized bed coater and the like, for coating the particles.

用於粒化法之該控制釋放聚合物可選自於，例如，舉例而言，乙基纖維素、鄰苯二甲酸羥基丙基甲基纖維素、鄰苯二甲酸乙酸纖維素、偏苯三酸乙酸纖維素、聚甲基丙烯酸酯、HPMC、羥基乙基纖維素、羥基丙基纖維素、甲基纖維素、羧基甲基纖維素、聚乙二醇、聚乙烯吡咯烷酮(PVP)、聚乙烯醇，及其二或多者之混合物等聚合物，任擇地與塑化劑(如該些前述者)結合。 The controlled release polymer used in the granulation process may be selected, for example, from ethyl cellulose, hydroxypropyl methyl cellulose phthalate, cellulose acetate phthalate, and benzotriene. Acid cellulose acetate, polymethacrylate, HPMC, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, carboxymethyl cellulose, polyethylene glycol, polyvinylpyrrolidone (PVP), polyethylene A polymer, such as a mixture of two or more alcohols, optionally in combination with a plasticizer, such as those previously described.

當以擠出滾圓法取得控制釋放珠粒時，(第二)活性成分、填充劑及任擇地控制釋放聚合物，係在製粒機如快速混合製粒機、行星式攪拌機、流動床處理機、離心式製粒機及其類似機器中，進行乾式混合及粒化。所得的濕式物質隨後經擠出及滾圓，以形成球狀顆粒。該圓形顆粒係經乾燥及過篩，以取得所欲之部分。所欲顆粒大小之該經乾燥顆粒可任擇地進一步以控制釋放聚合物塗佈。或 者，該擠出之顆粒係經乾燥及過篩，以取得所欲之部分。所欲顆粒大小之該經乾燥顆粒可任擇地進一步以受控聚合物塗佈。在適當的塗佈設備中，例如離心式塗佈機、塗佈鍋、Granurex®轉子處理機機、流動床塗佈機及其類似設備中，進行顆粒塗佈。 When controlled release beads are obtained by extrusion spheronization, the (second) active ingredient, filler and optionally controlled release polymer are processed in a granulator such as a fast mixing granulator, a planetary mixer, a fluid bed Dry mixing and granulation in machines, centrifugal granulators and the like. The resulting wet mass is then extruded and spheronized to form spherical particles. The round particles are dried and sieved to obtain the desired portion. The dried particles of the desired particle size can optionally be further coated with a controlled release polymer. Alternatively, the extruded granules are dried and sieved to obtain the desired portion. The dried particles of the desired particle size may optionally be further coated with a controlled polymer. In a suitable coating apparatus, for example, a centrifugal coater, pan coating, Granurex ® machine rotor processor, a fluidized bed coater and the like, make the particle coating.

用於擠出滾圓法之該控制釋放聚合物可選自於例如，舉例而言，乙基纖維素、鄰苯二甲酸羥基丙基甲基纖維素、鄰苯二甲酸乙酸纖維素、偏苯三酸乙酸纖維素、聚甲基丙烯酸酯、HPMC、羥基乙基纖維素、羥基丙基纖維素、甲基纖維素、羧基甲基纖維素、聚乙二醇、聚乙烯吡咯烷酮(PVP)、聚乙烯醇及其二或多者之混合物等聚合物，任擇地與塑化劑(如該些前述者)結合。 The controlled release polymer used in the extrusion spheronization method may be selected, for example, from the group consisting of ethyl cellulose, hydroxypropyl methyl cellulose phthalate, cellulose acetate phthalate, and benzotriene. Acid cellulose acetate, polymethacrylate, HPMC, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, carboxymethyl cellulose, polyethylene glycol, polyvinylpyrrolidone (PVP), polyethylene A polymer such as an alcohol and a mixture of two or more thereof, optionally in combination with a plasticizer such as those described above.

在一實施例中，本發明使用之珠粒的延釋曲線，對於用於製備本發明藥學組成物之冷凍乾燥方法具有耐受性，亦即不會實質上受影響。 In one embodiment, the extended release profile of the beads used in the present invention is tolerant to the freeze-drying process used to prepare the pharmaceutical compositions of the present invention, i.e., is not substantially affected.

術語“基質”應被理解為代表用於活性成分之固體載劑介質。該基質包含一或多種賦形劑。形成該基質之賦形劑在此意指“基質形成劑”，及該些試劑之每一者為“基質形成劑”。 The term "matrix" is understood to mean a solid carrier medium for the active ingredient. The matrix comprises one or more excipients. An excipient that forms the matrix is herein referred to as a "matrix forming agent," and each of the agents is a "matrix forming agent."

術語“開放式基質網狀物”應被理解為包含具有分散各處之內部空隙之水溶性或水分散性載劑材料(基質形成劑)之基質。該基質在與水性介質或唾液接觸時會迅速崩解。 The term "open matrix web" is understood to include a matrix comprising a water-soluble or water-dispersible carrier material (matrix forming agent) having internal voids dispersed throughout. The matrix disintegrates rapidly upon contact with an aqueous medium or saliva.

除非另有定義，本說明書及申請專利範圍之中的 百分比係以重量百分比(wt.%或w/w)為主。 Unless otherwise defined, this specification and the scope of the patent application The percentage is based on weight percent (wt.% or w/w).

在組成物中的基質形成劑可為任何能形成水溶性或水分散性載劑材料基質之試劑。基質形成劑之非侷限範例為左聚糖(levan)、菊糖(inulin)、聚三葡萄糖(pullulan)、海藻酸鈉(sodium alginate)、魚明膠(fish gelatin)、β-極限糊精(BLD)、改質澱粉、麥芽糊精(maltodextrin)(任擇地與山梨糖醇結合)、***膠(acacia)、羥基丙基甲基纖維素及/或果膠(pectin)，及其任何組合物。在一實施例中，該基質形成劑係選自於由左聚糖、菊糖、聚三葡萄糖、***膠、麥芽糊精、HPMC、海藻酸鈉，及其組合物所組成之族群。 The matrix former in the composition can be any agent capable of forming a matrix of water soluble or water dispersible carrier material. Non-limiting examples of matrix formers are levan, inulin, pullulan, sodium alginate, fish gelatin, beta-limit dextrin (BLD). Modified starch, maltodextrin (optionally combined with sorbitol), acacia, hydroxypropylmethylcellulose and/or pectin, and any combination thereof Things. In one embodiment, the matrix forming agent is selected from the group consisting of levan, inulin, polytriglucose, gum arabic, maltodextrin, HPMC, sodium alginate, and combinations thereof.

左聚糖(亦被稱為發酵劑(leaven)、左旋聚糖(levulosan)、多聚果糖(polyfructosan)、多果糖(polyfructose)及聚果聚醣(polylevulan))為果糖C6H12O6之一聚合物。左聚糖係一果糖環之間具有β-(2->6)鍵結之多醣，其中該數目描述被連接的果糖環之碳原子及該β描述立體化學關係。左聚糖亦被描述為聚果醣(fructans)，其中D-果呋喃糖苷(D-fructofuranoside)單體單元之間的主要醣苷鍵結為β-(2->6)。該左聚糖一般而言由微生物製造及在植物中不以高分子量化合物呈現。一些具有小於100,000道耳頓之分子量的低分子量左聚糖可發生在禾草(grasses)中。 Levans (also known as leaven, levulosan, polyfructosan, polyfructose, and polylevulan) are fructose C 6 H 12 O 6 One of the polymers. A polysaccharide having a β-(2->6) linkage between the levan and a fructose ring, wherein the number describes the carbon atom of the linked fructose ring and the β describes a stereochemical relationship. Levans are also described as fructans in which the major glycosidic linkages between the D-fructofuranoside monomer units are β-(2->6). The levan is generally produced by microorganisms and is not present in plants as high molecular weight compounds. Some low molecular weight levans having a molecular weight of less than 100,000 Daltons can occur in grasses.

使用於此，“左聚糖”應被理解為包含衍生自任何來源之左聚糖，例如但不限於，印度麴菌(Aspergillus indicus)、雜色麴菌(Aspergilllus versicolor)、弱氧化醋酸菌(Acetobacter suboxydans)、無色桿菌屬(Achromobacter spp.)、放射菌屬(Actinomycenes sp.)、黏放射菌(Actinomyces viscosus)、產氣桿菌(Aerobacter aerogenes)、果聚糖產氣桿菌(Aerobacter levanicum)、薩氏麴菌(Aspergillus sydowi)、圓褐固氮菌(Azotobacter chroococcum)、多黏芽孢桿菌(Bacillus polymyxa)、地衣芽孢桿菌(Bacillus licheniformis)、浸麻芽孢桿菌(Bacillus macerans)、巨大芽孢桿菌(Bacillus megatherium)、糖化菌(Bacillus mesentericus)、枯草桿菌(Bacillus subtilis)、馬鈴薯桿菌(Bacillus vulgatus)、產左旋糖棒桿菌(Corynbacterium laevaniformans)、草生歐文氏菌(Erwinia herbicola)、氧化葡萄糖酸菌(Gluconobacter oxydans)、腸膜明串珠菌(Leuconostoc mesenteroides)、黏液牙黴菌(Odontomyces viscosus)、玻璃植物桿菌(Phytobacterium vitrosum)、桃李植物單胞菌(Phytomonas pruni)、螢光假單胞菌(Psuedomonas Fluorescens)、丁香假單胞菌(Pseudomonas Syringae)、栖李假單胞菌(Pseudomonas prunicola)、齲齒羅氏菌(Rothis dentocariosa)、基利恩沙雷氏菌(Serratia kiliensis)、牛鏈球菌(Steptococcus bovis)、變異鏈球菌(Steptococcus mutans)、嗜熱唾液鏈球菌(Steptococcus唾液rius)、野油菜黃假單胞菌(Xanthomonas campestris)、桃李黃單胞菌(Xanthomonas pruni)、運動發酵單胞菌(Zymomonas mobilis)等。在一具體之實施例中，該左聚糖係取自發酵單胞菌屬及芽孢桿菌屬。在一更具體之實施例中，該左聚糖係取自運動發酵單胞菌。 As used herein, "levans" are understood to include levans derived from any source, such as, but not limited to, Aspergillus indicus, Aspergilllus versicolor, weakly oxidized acetic acid bacteria ( Acetobacter suboxydans), Achromobacter Spp.), Actinomycenes sp., Actinomyces viscosus, Aerobacter aerogenes, Aerobacter levanicum, Aspergillus sydowi, round Azotobacter chroococcum, Bacillus polymyxa, Bacillus licheniformis, Bacillus macerans, Bacillus megatherium, Bacillus mesentericus, and hay Bacillus subtilis, Bacillus vulgatus, Corynbacterium laevaniformans, Erwinia herbicola, Gluconobacter oxydans, Leuconostoc mesenteroides , Odontomyces viscosus, Phytobacterium vitrosum, Phytomonas pruni, Psuedomonas Fluorescens, Pseudomonas Syringae, and habitat Pseudomonas prunicola, Rohes dentocariosa ), Serratia kiliensis, Steptococcus bovis, Steptococcus mutans, Streptococcus salivarius (Steptococcus saliva rius), Xanthomonas wildflower (Xanthomonas) Campestris), Xanthomonas pruni, Zymomonas mobilis, and the like. In a specific embodiment, the levan is derived from the genus Zymomonas and the genus Bacillus. In a more specific embodiment, the levan is derived from Z. mobilis.

應瞭解到，亦可使用左聚糖的衍生物(例如，描述於WO 98/03184)代替左聚糖。 It will be appreciated that derivatives of levans (e.g., as described in WO 98/03184) may also be used in place of levan.

菊糖為典型上具有一末端葡萄糖之果糖C6H12O6的聚合物。菊糖係一果糖環之間具有β-(2->1)鍵結之多醣，其中該數目描述被連接的果糖環之碳原子及該β描述立體化學關係。菊糖係由許多種類的植物產生。 Inulin is a polymer typically having a terminal glucose dextrose C 6 H 12 O 6 . The inulin has a β-(2->1) bonded polysaccharide between the fructose rings, wherein the number describes the carbon atom of the linked fructose ring and the β describes a stereochemical relationship. Inulin is produced by many types of plants.

使用於此，應可瞭解到菊糖包含衍生自任何來源之菊糖，例如但不限於，含有高濃度之菊糖的植物，包括但不限於：土木香(Elecampane)[土木香(Inula helenium)]；蒲公英(Dandelion)[西洋蒲公英(Taraxacum officinale)]；山藥(Wild Yam)[薯蕷屬(Dioscorea spp.)]；洋薑(Jerusalem artichokes)[菊芋(Helianthus tuberosus)]；菊苣(Chicory)[歐洲菊苣(Cichorium intybus)]；樹薯(Jicama)[豆薯(Pachyrhizus erosus)]；牛蒡(Burdock)[牛蒡(Arctium lappa)]；洋蔥(Onion)[洋蔥(Allium cepa)]；大蒜(Garlic)[蒜(Allium sativum)]；龍舌蘭(Agave)[龍舌蘭屬(Agave spp.)]；雪蓮薯(Yacón)[菊薯屬(Smallanthus sonchifolius spp.)]；以及北美百合(Camas)[雛百合屬(Camassia spp.)]。在一具體實施例中，該菊糖係取自菊苣(Chicory)[歐洲菊苣(Cichorium intybus)]。 As used herein, it should be understood that inulin contains inulin derived from any source, such as, but not limited to, plants containing high concentrations of inulin, including but not limited to: Elecampane [ Inula helenium ] Dandelion [ Taraxacum officinale ]; Wild Yam [ Dioscorea spp.]; Jerusalem artichokes [ Helianthus tuberosus ]; Chicory [Europe] Cichorium intybus ]; Jicama [ Pachyrhizus erosus ]; Burdock [ Arctium lappa ]; Onion [ Allium cepa ]; Garlic [Garlic] Allium sativum ]; Agave [ Agave spp.]; Yacón [ Smallanthus sonchifolius spp.]; and North American lily (Camas) Lilium ( Camassia spp.)]. In a specific embodiment, the inulin is derived from Chicory [ Cichorium intybus ].

組成物可存在一或多種基質形成劑。用於作為第二基質形成劑之醣類、醣醇類、單醣類、二醣類、三醣類、多醣類、蛋白質、胺基酸類、膠類及其類似物之非侷限範例，包括但不限於，甘露糖醇、菌藻糖、棉子糖、肌醇、 聚三葡萄糖、蔗糖、乳糖、右旋糖、丁四醇、木糖醇、乳糖醇、麥芽糖醇、異麥芽酮糖醇(isomalt)、丙胺酸、精胺酸、蘇胺酸、甘胺酸、半胱胺酸、絲胺酸、組胺酸、纈胺酸、脯胺酸、離胺酸、天門冬醯胺酸、麩醯胺酸、核糖、葡萄糖、半乳糖、果糖、麥芽糖、麥芽三糖、瓜爾膠(guar gum)、三仙膠、黃蓍膠(tragacanth gum)、矽酸鎂鋁(veegum)、微結晶纖維素、羧基甲基纖維素鈉等。 One or more matrix formers may be present in the composition. Non-limiting examples of sugars, sugar alcohols, monosaccharides, disaccharides, trisaccharides, polysaccharides, proteins, amino acids, gums and the like used as a second matrix forming agent, including But not limited to, mannitol, bacteriocin, raffinose, inositol, Polytriglucose, sucrose, lactose, dextrose, butyltetraol, xylitol, lactitol, maltitol, isomalt, alanine, arginine, threonine, glycine , cysteine, serine, histidine, valine, valine, lysine, aspartic acid, glutamic acid, ribose, glucose, galactose, fructose, maltose, malt Trisaccharide, guar gum, sanxian gum, tragacanth gum, veegum, microcrystalline cellulose, sodium carboxymethylcellulose, and the like.

一般而言，該配方之剩餘部分可為基質。因此，基質的百分比可接近100%。依據本發明，適用的第二基質形成劑之量範圍為約0至約30%。 In general, the remainder of the formulation can be a matrix. Therefore, the percentage of the matrix can approach 100%. Suitable second matrix forming agents are present in amounts ranging from about 0 to about 30% in accordance with the present invention.

在本發明之一實施例中，左聚糖為組成物中的主要基質形成劑。在另一實施例中，菊糖為主要基質形成劑。在又另一實施例中，係結合左聚糖與菊糖，以作為主要基質形成劑。 In one embodiment of the invention, the levan is the primary matrix forming agent in the composition. In another embodiment, inulin is the primary matrix forming agent. In yet another embodiment, the combination of levan and inulin is used as the primary matrix forming agent.

在另一實施例中，該組成物進一步包含甘露糖醇或棉子糖或菌藻糖或其組合物，以作為開放式基質網狀物中的第二基質形成劑。 In another embodiment, the composition further comprises mannitol or raffinose or trehalose or a combination thereof as a second matrix former in an open matrix web.

在一實施例中，左聚糖為基質形成劑，其含量為該組成物整體重量的10-50%。在另一實施例中，左聚糖之含量為該組成物整體重量的20-40%。在又另一實施例中，左聚糖之含量為該組成物整體重量的25-35%。 In one embodiment, the levan is a matrix forming agent in an amount of from 10 to 50% by weight based on the total weight of the composition. In another embodiment, the amount of levan is 20-40% of the total weight of the composition. In yet another embodiment, the amount of levan is 25-35% of the total weight of the composition.

在其他實施例中，甘露糖醇或菌藻糖或棉子糖或其組合物，係作為第二基質形成劑，其含量為該組成物整體重量的10-40%。在一實施例中，該些第二基質形成劑之 含量為該組成物整體重量的20-30%。 In other embodiments, mannitol or fucose or raffinose or a combination thereof is used as a second matrix forming agent in an amount of 10-40% by weight of the total weight of the composition. In an embodiment, the second matrix forming agents The content is 20-30% of the total weight of the composition.

因此，本發明之組成物可為包含左聚糖作為主要基質形成劑，及甘露糖醇或菌藻糖或棉子糖(或其組合物)作為第二基質形成劑，其中左聚糖之含量為10-50%(成分的全部%皆為w/w，意指出自結合的組成物之全部構成物重量的所提及之成分重量)，及該第二基質形成劑之含量為10-40%，典型上為20-30%。 Therefore, the composition of the present invention may be a drug comprising levan as a main matrix forming agent, and mannitol or fucose or raffinose (or a combination thereof) as a second matrix forming agent, wherein the content of levan It is 10-50% (all % of the components are w/w, meaning the weight of the component mentioned) from the total weight of the constituents of the combined composition, and the content of the second matrix forming agent is 10-40. %, typically 20-30%.

該第一活性成分之含量典型上可為(但非唯一)落於整體組成物的0.01-1%範圍內，典型上為落於0.02-0.2%範圍內，其取決於該活性成分之本質。該第二活性成分之含量典型上可為(但非唯一)落於整體組成物的1-50%範圍內，典型上為落於3-10%範圍內，其取決於該活性成分之本質。在一實施例中，該活性成分之含量為該組成物整體重量的約4%。在另一實施例中，該活性成分之含量為該組成物整體重量的約5%。在又另一實施例中，該活性成分之含量為該組成物整體重量的約6%。在其他實施例中，該活性成分之含量為該組成物整體重量的約7%。在又其他實施例中，該活性成分之含量為該組成物整體重量的約8%。 The amount of the first active ingredient may typically be (but not exclusively) fall within the range of from 0.01% to 1% of the total composition, typically falling within the range of from 0.02% to 0.2%, depending on the nature of the active ingredient. The amount of the second active ingredient may typically be (but not exclusively) fall within the range of from 1 to 50% of the total composition, typically falling within the range of from 3 to 10%, depending on the nature of the active ingredient. In one embodiment, the active ingredient is present in an amount of about 4% by weight of the total weight of the composition. In another embodiment, the active ingredient is present in an amount of about 5% by weight of the total weight of the composition. In yet another embodiment, the active ingredient is present in an amount of about 6% by weight of the total weight of the composition. In other embodiments, the active ingredient is present in an amount of about 7% by weight of the total composition. In still other embodiments, the active ingredient is present in an amount of about 8% by weight of the total weight of the composition.

術語“崩解”意指基質及該第一藥物之溶解或“潰散”而立即釋放，及放出或釋放該延釋之劑量形式(例如丸粒或珠粒)，因而使其開始釋放該第二藥物，其取決於水性介質之條件。在標準水性介質中的崩解典型上為小於30秒內，及更典型上為小於10秒內，或甚至小於9、8、7、6、5、4、3、2或甚至1秒。 The term "disintegration" means the immediate release of the matrix and the dissolution or "cracking" of the first drug, and the release or release of the extended dosage form (eg, pellets or beads) such that it begins to release the second The drug, which depends on the conditions of the aqueous medium. Disintegration in standard aqueous media is typically less than 30 seconds, and more typically less than 10 seconds, or even less than 9, 8, 7, 6, 5, 4, 3, 2 or even 1 second.

“崩解時間”及“溶解時間”於此可互換使用，應被理解為意指在標準水性介質中溶解或崩解本發明組成物所需的時間。 "Disintegration time" and "dissolution time" are used interchangeably herein and are understood to mean the time required to dissolve or disintegrate the compositions of the invention in a standard aqueous medium.

“口服溶解時間”使用於此應被理解為意指在口腔中溶解本發明組成物所需的時間。 "Oral dissolution time" as used herein is understood to mean the time required to dissolve the compositions of the invention in the oral cavity.

“迅速/快速崩解/溶解”使用於此應被理解為包含在30秒內(典型上為在20秒內，較佳為在10秒內，或甚至在9、8、7、6、5、4、3、2或1秒內)，本發明組成物崩解/溶解於標準水性介質中。 "Rapid/rapid disintegration/dissolution" is used herein to be understood to be included within 30 seconds (typically within 20 seconds, preferably within 10 seconds, or even at 9, 8, 7, 6, 5) Within 4, 3, 2 or 1 second, the composition of the invention disintegrates/dissolves in a standard aqueous medium.

使用於此，水性介質之範例為水或緩衝液(例如，磷酸二氫鉀、磷酸氫二鉀、磷酸氫鈉)或如Morjaria et al.(May 2004),Dissolution Technologies 12-15所描述的人工唾液。“標準水性介質”使用於此係用於確定崩解時間，其如實驗一節所定義。用於確定崩解時間之方法係描述於實驗一節。 As used herein, an example of an aqueous medium is water or a buffer (eg, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, sodium hydrogen phosphate) or artificial as described by Morjaria et al. (May 2004), Dissolution Technologies 12-15 . saliva. "Standard aqueous medium" is used herein to determine the disintegration time as defined in the experimental section. The method used to determine the disintegration time is described in the experimental section.

使用於此，唾液意指哺乳類動物(特別是人類)口腔中的唾液。 As used herein, saliva means saliva in the mouth of a mammal, particularly a human.

“抗張強度”使用於此應被理解為由三點彎曲試驗中所測量的破碎一錠劑所需之力量，其中該錠劑係進行彎曲應力(bending stress)(Mohd et al.(2002),Drug Development and Industrial Pharmacy 28(7)：809-813)。 "Tensile strength" is used herein to be understood as the force required to break a tablet as measured by a three-point bending test in which the tablet is subjected to bending stress ( Mohd et al. (2002) , Drug Development and Industrial Pharmacy 28(7): 809-813 ).

在一實施例中，本發明之藥學組成物具有在約0.05至2N/mm2之範圍內的抗張強度。在另一實施例中，本發明之藥學組成物具有在約0.05至0.3N/mm2之範圍內的抗 張強度。在另一實施例中，本發明之藥學組成物具有在約0.1至0.25N/mm2之範圍內的抗張強度。在又另一實施例中，本發明之藥學組成物具有在約0.11至0.23N/mm2之範圍內的抗張強度。 In one embodiment, the pharmaceutical compositions of the present invention have a tensile strength in the range of from about 0.05 to 2 N/mm 2 . In another embodiment, the pharmaceutical compositions of the present invention have a tensile strength in the range of from about 0.05 to 0.3 N/mm 2 . In another embodiment, the pharmaceutical compositions of the present invention have a tensile strength in the range of from about 0.1 to 0.25 N/mm 2 . In yet another embodiment, the pharmaceutical compositions of the present invention have a tensile strength in the range of from about 0.11 to 0.23 N/mm 2 .

可以設想，本發明之藥學組成物具有迅速崩解/溶解率，使得該組成物可在30秒內被溶解於標準水性介質中，典型上在10秒內。 It is contemplated that the pharmaceutical compositions of the present invention have a rapid disintegration/dissolution rate such that the composition can be dissolved in a standard aqueous medium within 30 seconds, typically within 10 seconds.

在一實施例中，本發明之藥學組成物具有在約0.05至2N/mm2之範圍內的抗張強度以及迅速崩解/溶解率，使得該組成物可在30秒內(典型上在10秒內)被溶解於標準水性介質中。 In one embodiment, the pharmaceutical composition of the present invention has a tensile strength in the range of from about 0.05 to 2 N/mm 2 and a rapid disintegration/dissolution rate such that the composition can be within 30 seconds (typically at 10) Within seconds) is dissolved in a standard aqueous medium.

在另一實施例中，本發明之藥學組成物具有在約0.05至0.3N/mm2之範圍內的抗張強度以及迅速崩解/溶解率，使得該組成物可在30秒內(典型上在10秒內)被溶解於標準水性介質中。 In another embodiment, the pharmaceutical composition of the present invention has a tensile strength in the range of from about 0.05 to 0.3 N/mm 2 and a rapid disintegration/dissolution rate such that the composition is within 30 seconds (typically Within 10 seconds) was dissolved in a standard aqueous medium.

在另一實施例中，本發明提供包含第一及第二藥學上活性成分之藥學組成物，其具有介於約0.05至2N/mm2之範圍內的抗張強度以及迅速崩解/溶解率，使得該組成物可在30秒內(典型上在10秒內)被溶解於標準水性介質中。 In another embodiment, the present invention provides a pharmaceutical composition comprising first and second pharmaceutically active ingredients having a tensile strength and a rapid disintegration/dissolution rate in the range of from about 0.05 to 2 N/mm 2 This allows the composition to be dissolved in a standard aqueous medium within 30 seconds (typically within 10 seconds).

在另一實施例中，本發明提供包含第一及第二藥學上活性成分之藥學組成物，其具有介於約0.05至0.3N/mm2之範圍內的抗張強度以及迅速崩解/溶解率，使得該組成物可在30秒內(典型上在10秒內)被溶解於標準水性介質中。 In another embodiment, the present invention provides a pharmaceutical composition comprising first and second pharmaceutically active ingredients having a tensile strength in the range of from about 0.05 to 0.3 N/mm 2 and rapid disintegration/dissolution The rate is such that the composition can be dissolved in a standard aqueous medium within 30 seconds (typically within 10 seconds).

該開放式基質網狀物能使一液體經由該些空隙進入該藥劑形式並穿透其內部。藉由水性介質(例如唾液、水等)的穿透，將該藥劑形式之內部及外部兩者的載劑材料暴露至該水性介質或唾液之作用中，藉此載劑材料之網狀物被迅速地崩解/溶解，從而釋放該第一活性成分及該控制釋放丸粒至口腔中。 The open matrix web enables a liquid to enter the form of the agent through the voids and penetrate the interior thereof. The carrier material of both the internal and external forms of the pharmaceutical form is exposed to the aqueous medium or saliva by penetration of an aqueous medium (eg, saliva, water, etc.) whereby the network of carrier material is Rapid disintegration/dissolution, thereby releasing the first active ingredient and the controlled release pellet into the oral cavity.

該開放式基質結構具有多孔性質，並可增進該藥劑形式的崩解，相較於普通的固體形狀藥學劑量形式，例如(經粒化及經壓縮)錠劑、丸劑、膠囊、栓劑及***藥栓劑(pessaries)。迅速崩解導致該基質所包含的活性成份之迅速釋放，及進一步導致該控制釋放珠粒的釋放，其被吞嚥/吸收，及其將以受控的方式釋放其活性成分。 The open matrix structure has a porous nature and can promote disintegration of the pharmaceutical form compared to conventional solid shaped pharmaceutical dosage forms such as (granulated and compressed) lozenges, pills, capsules, suppositories, and vaginal drugs. Suppositories (pessaries). Rapid disintegration results in rapid release of the active ingredient contained in the matrix, and further results in release of the controlled release bead which is swallowed/absorbed and which will release its active ingredient in a controlled manner.

用於本發明之該藥學上活性成分可為任何的藥學上活性成分，例如低分子量之化合物、胜肽、核苷酸等。 The pharmaceutically active ingredient for use in the present invention may be any pharmaceutically active ingredient such as a low molecular weight compound, a peptide, a nucleotide or the like.

該第一及第二活性成分可為彼此之間相同或不同。在一實施例中，該等彼此之間不同。 The first and second active ingredients may be the same or different from each other. In an embodiment, the ones are different from one another.

本發明之開放式基質網狀物所包含，及/或該開放式基質網狀物內所包含之該丸粒所包含的藥物(活性成分)的非侷限範例為鎭痛劑、α阻斷劑(alpha blockers)、抗過敏劑、抗氣喘藥、(過敏性鼻炎劑、慢性蕁麻疹藥(chronic uticaria))、抗發炎劑、抗酸劑(antacids)、驅蟲劑(anthelmintics)、抗心律不整劑(anti-arrhythmic agents)、抗關節炎劑(anti-arthritis)、抗菌劑、抗焦慮劑、抗凝血劑(anti-coagulants)、抗憂鬱劑、抗糖尿病藥、抗腹瀉藥 (anti-diarrheals)、抗利尿劑(anti-diuretics)、抗癲癇劑(anti-epileptics)、抗真菌劑、抗痛風劑(anti-gout)、抗高血壓藥(anti-hypertensive)、抗失禁藥(anti-incontinence)、抗失眠藥(anti-insomnia)、抗瘧疾藥(anti-malarials)、抗偏頭痛藥(anti-migraine)、抗毒蕈鹼藥(anti-muscarinic)、抗腫瘤藥(anti-neoplastic)及免疫抑制劑(immunosuppressants)、抗原蟲藥(anti-protozoal)、抗風濕藥(anti-rheumatics)、抗鼻炎藥(anti-rhinitis)、抗痙攣藥(anti-spasmatic)、抗甲狀腺藥(anti-thyroid)、抗病毒藥(antivirals)、抗焦慮藥(anxiolytics)、鎭靜藥(sedatives)、***(hypnotics)及抗精神病藥(neuroleptics)、β-阻斷劑、抗良性增生藥(anti-benign hyperplasia(BHP))、心肌收縮劑(cardiac inotropic)、皮質類固醇(corticosteroids)、止咳藥(cough suppressants)、細胞毒性劑(cytotoxics)、解充血劑(decongestants)、糖尿病性胃滯留藥(diabetic gastricstasis)、利尿劑(diuretics)、酵素(enzymes)、抗帕金森症藥(anti-parkinsonian)、胃腸藥、組織胺受體拮抗劑、***藥(infertility)、子宮內膜異位藥(endometriosis)、激素替代療法(hormone replacement therapy)、脂質調節劑(lipid regulating agents)、局部麻醉劑(local anesthetics)、神經肌肉劑(neuromuscular agents)、硝酸鹽及抗心絞痛劑(anti-anginal agents)、月經失調藥(menstrual disorders)、動暈藥(motion sickness)、抗痛素(anti-pain)、抗噁心藥(anti-nausea)、運動障礙藥(movement disorders)、營養劑(nutritional agents)、類鴉片止痛劑(opioid analgesics)、口服疫苗、蛋白質藥、胜肽及重組型藥、預防化療誘發及術後噁心及嘔吐之質子泵抑制劑、精神***症藥物、性激素及避孕藥、癲癇/驚恐症藥物、性功能障礙藥物(男性及女性)、殺精劑(spermicides)、興奮劑、排尿功能障礙藥、獸醫藥等。 Non-limiting examples of the drug (active ingredient) contained in the open matrix mesh of the present invention and/or the pellet contained in the open matrix mesh are an analgesic agent, an alpha blocker (alpha blockers), anti-allergic agents, anti-asthmatic drugs, (allergic rhinitis agents, chronic urticaria (chronic uticaria)), anti-inflammatory agents, antacids, insecticides (anthelmintics), antiarrhythmia Anti-arrhythmic agents, anti-arthritis, antibacterial agents, anti-anxiety agents, anti-coagulants, antidepressants, antidiabetics, antidiarrheals (anti-diarrheals), anti-diuretics, anti-epileptics, antifungals, anti-gout, anti-hypertensive, anti-incontinence drugs (anti-incontinence), anti-insomnia, anti-malarials, anti-migraine, anti-muscarinic, anti-tumor drugs (anti -neoplastic) and immunosuppressants, anti-protozoal, anti-rheumatics, anti-rhinitis, anti-spasmatic, anti-thyroid drugs (anti-thyroid), antivirals, anxiolytics, sedatives, hypnotics and neurotrophics, beta-blockers, anti-benign proliferative drugs ( Anti-benign hyperplasia (BHP)), cardiac inotropic, corticosteroids, cough suppressants, cytotoxics, decongestants, diabetic gastric retention drugs (Breakfast) Diabetic gastricstasis), diuretics, enzymes s), anti-parkinsonian, gastrointestinal drug, histamine receptor antagonist, infertility, endometriosis, hormone replacement therapy, Lipid regulating agents, local anesthetics, neuromuscular agents, nitrates and anti-anginal agents, menstrual disorders, motion sickness (motion) Sickness), anti-pain, anti-nausea, movement disorders, nutritional agents, opioid analgesics (opioid) Analgesics), oral vaccines, protein drugs, peptides and recombinant drugs, proton pump inhibitors for preventing chemotherapy-induced and postoperative nausea and vomiting, schizophrenia drugs, sex hormones and contraceptives, epilepsy/panic drugs, sexual dysfunction Drugs (male and female), spermicidal agents, stimulants, urinary dysfunction drugs, veterinary drugs, etc.

該些藥物之具體的非侷限範例為：α阻斷劑：坦索羅辛(Tamsulosine)。 A specific non-limiting example of such drugs is: alpha blocker: Tamsulosine.

止痛劑及抗發炎劑：阿司匹靈、阿洛普林(aloxiprin)、金諾芬(auranofin)、阿扎丙酮(azapropazone)、貝諾酯(benorylate)、二氟尼柳(diflunisal)、依託度酸(etodolac)、芬布芬(fenbufen)、菲諾洛芬鈣(fenoprofen calcium)、氟比洛芬(flurbiprofen)、布洛芬(ibuprofen)、吲哚美辛(indomethacin)、酮洛芬(ketoprofen)、甲氯滅酸(meclofenamic acid)、甲芬那酸(mefenamic acid)、萘布美酮(nabumetone)、那普洛先(naproxen)、奧沙普嗪(oxaprozin)、羥基保泰松(oxyphenbutazone)、苯丁唑酮(phenylbutazone)、吡羅昔康(piroxicam)、蘇林達克(sulindac)、乙醯胺苯酚(paracetamol)。 Analgesics and anti-inflammatory agents: aspirin, alooxiprin, auranofin, azapropazone, benorilate, diflunisal, backing Etodolac, fenbufen, fenoprofen calcium, flurbiprofen, ibuprofen, indomethacin, ketoprofen Ketoprofen), meclofenamic acid, mefenamic acid, nabumetone, naproxen, oxaprozin, hydroxybutazone ( Oxyphenbutazone), phenylbutazone, piroxicam, sulindac, paracetamol.

抗酸劑：氫氧化鋁、碳酸鎂、三矽酸鎂、水滑石(hydro滑石ite)、二甲矽油(dimethicone)。 Antacids: aluminum hydroxide, magnesium carbonate, magnesium tricaprate, hydrotalcite (ite), dimethicone.

驅蟲劑：阿苯達唑(albendazole)、羥萘芐芬寧(bephenium hydroxynaphthoate)、坎苯達唑(cambendazole)、二氯酚(dichlorophen)、依維菌素(ivermectin)、美邊達唑(mebendazole)、奧沙尼喹(oxamniquine)、奧芬噠唑 (oxfendazole)、間酚嘧啶(oxantel embonate)、吡喹酮(praziquantel)、雙羥萘酸噻嘧啶(pyrantel embonate)、噻苯咪唑(thiabendazole)。 Insect repellents: albendazole, bephenium hydroxynaphthoate, cambendazole, dichlorophen, ivermectin, mebendazole Mebendazole), oxamniquine, orphenazole (oxfendazole), oxantel embonate, praziquantel, pyrantel embonate, thiabendazole.

抗過敏劑：地氯雷他定(des loratidine)、氯雷他定(loratidine)、孟魯司特(Montelukast)、孟魯司特鈉(Montelukast sodium)、西替利臻(Cetirizin)、非索非那定(Fexofenadin)、艾巴停(Ebastine)。 Antiallergic agents: des loratidine, loratidine, Montelukast, Montelukast sodium, Cetirizin, Feno Fexofenadin, Ebastine.

抗心律不整劑：胺碘酮HCl(amiodarone HCl)、達舒平(disopyramide)、醋酸氟卡尼(f lecainide acetate)、硫酸奎尼丁(quinidine sulphate)。 Antiarrhythmic agents: amiodarone HCl, disopyramide, f lecainide acetate, quinidine sulphate.

抗菌劑：苯明青黴素(benethamine penicillin)、西諾沙星(cinoxacin)、環丙沙星HCl(ciprofloxacin HCl)、克拉黴素(clarithromycin)、克風敏(clofazimine)、氯唑西林(cloxacillin)、地美環素(demeclocycline)、多西環素(doxycycline)、紅黴素(erythromycin)、乙硫異煙胺(ethionamide)、亞胺培南(imipenem)、萘啶酮酸(nalidixic acid)、呋喃妥英(nitrofurantoin)、立復黴素(rifampicin)、史黴素(spiramycin)、苯甲醯磺胺(sulphabenzamide)、周效磺胺(sulphadoxine)、磺胺甲基嘧啶(sulphamerazine)、磺胺醋醯(sulphacetamide)、磺胺嘧啶(sulphadiazine)、磺胺異噁唑(sulphafurazole)、磺胺甲噁唑(sulphamethoxazole)、磺胺吡啶(sulphapyridine)、四環黴素(tetracycline)、甲氧芐啶(trimethoprim)。 Antibacterial agents: benethamine penicillin, cinoxacin, ciprofloxacin HCl, clarithromycin, clofazimine, cloxacillin, Demeclocycline, doxycycline, erythromycin, ethionamide, imipenem, nalidixic acid, furan Nitrofurantoin, rifampicin, spiramycin, sulphabenzamide, sulphadoxine, sulphamerazine, sulphacetamide , sulphadiazine, sulphafurazole, sulphamethoxazole, sulphapyridine, tetracycline, trimethoprim.

抗凝血劑：雙香豆素(dicoumarol)、雙嘧達莫 (dipyridamole)、新抗凝(nicoumalone)、非尼二酮(phenindione)。 Anticoagulant: dicoumarol, dipyridamole (dipyridamole), new anticoagulation (nicoumalone), phenindione.

抗憂鬱劑：阿莫沙平(amoxapine)、苯嘧吲哚(ciclazindol)、嗎普替林HCl(maprotiline HCl)、米安舍林HCl(mianserin HCl)、去甲替林HCl(nortriptyline HCl)、曲唑酮HCl(trazodone HCl)、馬來酸三甲丙咪嗪(trimipramine maleate)。 Antidepressants: amoxapine, ciclazindol, maprotiline HCl, mianserin HCl, nortriptyline HCl, Trazodone HCl, trimipramine maleate.

抗糖尿病藥：乙醯苯磺醯環己脲(acetohexamide)、氯磺丙脲(chlorpropamide)、格列本脲(glibenclamide)、格列齊特(gliclazide)、格列吡嗪(glipizide)、妥拉磺脲(tolazamide)、甲苯磺丁脲(tolbutamide)。 Antidiabetic drugs: acetohexamide, chlorpropamide, glibenclamide, gliclazide, glipizide, tola Tolazamide, tolbutamide.

抗腹瀉藥：硫酸阿托品(atropine sulphate)、磷酸可待因(codeine phosphate)、地芬諾酯-阿托品(co-phenotrope)、地芬諾新(difenoxin)、鹽酸洛哌丁胺(loperamide hydrochloride)、柳氮磺胺吡啶(suphasolazine)、美沙拉嗪(mesalazine)、奧沙拉秦(olsalazine)、皮質類固醇(corticosteroids)去氫皮質醇(prednisolone)。 Anti-diarrheal drugs: atropine sulphate, codeine phosphate, co-phenotrope, difenoxin, loperamide hydrochloride, Suphasolazine, mesalazine, olsalazine, corticosteroids, deprenisolone.

抗利尿劑：去氨加壓素、醋酸去氨加壓素。 Antidiuretic: desmopressin, desmopressin acetate.

抗癲癇劑：貝克拉(beclamide)、卡巴馬平(carbamazepine)、氯硝西泮(clonazepam)、乙妥英(ethotoin)、美索因(methoin)、甲琥胺(methsuximide)、甲苯比妥(methylphenobarbitone)、奧卡西平(oxcarbazepine)、帕臘二酮(paramethadione)、苯乙醯脲(phenacemide)、苯巴比 妥(phenobarbitone)、苯妥英(phenytoin)、苯琥胺(phensuximide)、普裡米酮(primidone)、舒噻嗪(sulthiame)、丙戊酸(valproic acid)。 Anti-epileptic agents: beclamide, carbamazepine, clonazepam, ethotoin, mesoin, methsuximide, tolazine ( Methylphenobarbitone), oxcarbazepine, paramethadione, phenacemide, phenabine   phenobarbitone, phenytoin, phensuximide, primidone, sulthiame, valproic acid.

抗真菌劑：雙性黴素(amphotericin)、硝酸布康唑(butoconazole nitrate)、克黴唑(clotrimazole)、硝酸益康唑(econazole nitrate)、氟康唑(fluconazole)、氟胞嘧啶(flucytosine)、灰黃黴素(griseofulvin)、依他康唑(itraconazole)、酮康唑(ketoconazole)、咪康唑(miconazole)、納他黴素(natamycin)、制黴菌素(nystatin)、硝酸硫康唑(sulconazole nitrate)、特比萘芬HCl(terbinafine HCl)、特康唑(terconazole)、噻康唑(tioconazole)、十一碳烯酸(undecenoic acid)。 Antifungal agents: amphotericin, butoconazole nitrate, clotrimazole, econazole nitrate, fluconazole, flucytosine , griseofulvin, itraconazole, ketoconazole, miconazole, natamycin, nystatin, thioconazole nitrate (sulconazole nitrate), terbinafine HCl, terconazole, tioconazole, undecenoic acid.

抗痛風劑：安樂普利諾(allopurinol)、丙磺舒(probenecid)、苯磺唑酮(sulphinpyrazone)。 Anti-gout agent: allopurinol, probenecid, sulphinpyrazone.

抗高血壓藥：氨氯地平(amlopidine)、比尼地平(benidipine)、達羅地平(darodipine)、迪太贊HCl(dilitazem HCl)、二氮嗪(diazoxide)、非洛地平(felodipine)、乙酸氯壓胍(guanabenz acetate)、吲哚拉明(indoramin)、伊拉地平(isradipine)、敏諾西代(minoxidil)、尼卡地平HCl(nicardipine HCl)、硝苯地平(nifedipine)、尼莫地平(nimodipine)、苯氧芐胺HCl(phenoxybenzamine HCl)、哌唑嗪HCl(prazosin HCl)、蛇根鹼(reserpine)、特拉唑嗪HCl(terazosin HCl)。 Antihypertensive drugs: amlopidine, benidipine, darodipine, dilitazem HCl, diazoxide, felodipine, acetic acid Guanabenz acetate, indoramin, isradipine, minoxidil, nicardipine HCl, nifedipine, nimodipine Nimodipine), phenoxybenzamine HCl, prazosin HCl, respine, terazosin HCl.

抗失眠藥：唑吡坦(Zolpidem)。 Anti-insomnia drugs: Zolpidem.

抗瘧疾藥：阿莫地喹(amodiaquine)、氯喹 (chloroquine)、氯丙胍HCl(chloroproguanil HCl)、鹵泛群HCl(halofantrine HCl)、美爾喹寧HCl(mefloquine HCl)、氯胍HCl(proguanil HCl)、比利美胺(pyrimethamine)，硫酸喹寧(quinine sulphate)。 Antimalarial drugs: amodiquine, chloroquine (chloroquine), chloroproguanil HCl, halofantrine HCl, mefloquine HCl, proguanil HCl, pyrimethamine, quinoxalate Ning (quinine sulphate).

抗偏頭痛藥：利扎曲坦(rizatriptan)、甲磺酸二氫麥角胺(dihydroergotamine mesylate)、酒石酸麥角胺(ergotamine tartrate)、馬來酸二甲麥角新鹼(methysergide maleate)、蘋馬來酸苯噻啶(pizotifen maleate)、琥珀酸舒馬普坦(sumatriptan succinate)、咖啡因。 Anti-migraine drugs: rizatriptan, dihydroergotamine mesylate, ergotamine tartrate, methysergide maleate, apple Pizotifen maleate, sumatriptan succinate, caffeine.

抗毒蕈鹼藥：托特羅定(tolterodin)、托特羅定酒石酸鹽、羥丁寧(oxybutinin)、阿托平(atropine)、苯海索HCl(benzhexol HCl)、比哌立登(biperiden)、愛普把嗪HCl(ethopropazine HCl)、丁溴東莨菪鹼(hyoscine butyl bromide)、莨菪鹼(hyoscyamine)、溴美噴酯(mepenzolate bromide)、奧芬那君(orphenadrine)、羥芐利明HCl(oxyphencylcimine HCl)、托吡卡胺(tropicamide)。 Antimuscarinic drugs: tolterodin, tolterodine tartrate, oxybutinin, atropine, benzisosol HCl, biperiden , ethopropazine HCl, hyoscine butyl bromide, hyoscyamine, mepenzolate bromide, orphenadrine, oxyphencylcimine HCl ), tropicamide.

抗腫瘤藥及免疫抑制劑：氨魯米特(aminoglutethimide)、安吖啶(amsacrine)、硫唑嘌呤(azathioprene)、白消安(busulphan)、氮芥苯丁酸(chlorambucil)、環孢素(cyclosporin)、達卡巴嗪(dacarbazine)、雌氮芥(estramustine)、依托泊甘(etoposide)、洛莫司汀(lomustine)、黴法蘭(melphalan)、巰嘌呤(mercaptopurine)、甲氨蝶呤(methotrexate)、絲裂黴素(mitomycin)、米托坦(mitotane)、米托蒽醌(mitozantrone)、 丙卡巴肼HCl(procarbazine HCl)、檸檬酸他莫西芬(tamoxifen citrate)、睾內酯(testolactone)。 Antineoplastic agents and immunosuppressants: aminoglutethimide, amsacrine, azathioprene, busulphan, chlorambucil, cyclosporine Cyclosporin), dacarbazine, estramustine, etoposide, lomustine, melphalan, mercaptopurine, methotrexate Methotrexate), mitomycin, mitotan, mitozantrone, Procarbazine HCl, tamoxifen citrate, testolactone.

抗原蟲藥：芐硝唑(benznidazole)、氯碘羥喹(clioquinol)、地可喹酯(decoquinate)、雙碘羥喹啉(diiodohydroxyquinoline)、糠酸二氯尼特(diloxanide furcate)、二硝托胺(dinitolmide)、呋喃唑酮(furzolidone)、甲硝唑(metronidazole)、尼莫唑(nimorazole)、硝糠腙(nitrofurazone)、奧硝唑(ornidazole)、替硝唑(tinidazole)。 Antiprotozoal drugs: benznidazole, clioquinol, decoquinate, diiodohydroxyquinoline, diloxanide furcate, dinitrazole Dinitolmide, furzolidone, metronidazole, nimorazole, nitrofurazone, ornidazole, tinidazole.

抗風濕藥：布洛芬(ibuprofen)、醋氯芬酸(aceclofenac)、阿西美辛(acemetacin)、阿扎丙酮(azapropazone)、雙氯芬酸鈉(diclofenac sodium)、二氟尼柳(diflunisal)、依託度酸(etodolac)、苯酮苯丙酸(ketoprofen)、吲哚美辛(indomethacin)、甲芬那酸(mefenamic acid)、萘普生(naproxen)、吡羅昔康(piroxicam)、阿司匹靈、貝諾酯(benorylate)、金諾芬(auranofin)、青黴胺(penicillamine)。 Anti-rheumatic drugs: ibuprofen, aceclofenac, acemetacin, azapropazone, diclofenac sodium, diflunisal, backing Etodolac, ketoprofen, indomethacin, mefenamic acid, naproxen, piroxicam, aspirin Ling, benorilate, auranofin, penicillamine.

抗鼻炎藥、抗蕁麻疹藥：西替利嗪(Cetirizin)、菲索特芬那定(fexofenadin)、依巴斯汀(ebastine)、羅拉替定(loratidin)、孟魯司特(montelukast)。 Anti-rhinitis drugs, anti-urtic drugs: Cetirizin, fexofenadin, ebastine, loratidin, montelukast.

抗痙攣藥：無水間苯三酚(phloroglucinol anhydre)。 Anticonvulsant: anhydrous phloroglucinol anhydre.

抗甲狀腺藥：卡比馬唑(carbimazole)、丙基硫脲嘧啶(propylthiouracil)。 Antithyroid drugs: carbimazole, propylthiouracil.

抗病毒藥：艾賽可威(acyclovir)、鹽酸金剛烷胺(amantadine hydrochloride)、法昔洛韋(famciclovir)、齊多夫 定(zidovadine)、地丹諾辛(didanosine)、扎西他賓(zalcitabine)、膦甲酸鈉(foscarnet sodium)。 Antiviral drugs: acyclovir, amantadine hydrochloride, famciclovir, zidov Zidovadine, didanosine, zalcitabine, foscarnet sodium.

抗焦慮藥、鎭靜藥、***及抗精神病藥：三氮二氮平(alprazolam)、異戊巴比妥(amylobarbitone)、巴比妥(barbitone)、苯他西泮(bentazepam)、溴西泮(bromazepam)、溴哌利多(bromperidol)、溴替唑侖(brotizolam)、丁巴比妥(butobarbitone)、卡溴脲(carbromal)、氯二氮平(chlordiazepoxide)、氯芬尼拉明(Chlorpheniramine)、氯美噻唑(chlormethiazole)、氯丙嗪(chlorpromazine)、氯巴佔(clobazam)、氯硝西泮(clonazepan)、氯噻西泮(clotiazepam)、氯氮平(clozapine)、二氮平(diazepam)、氟呱利多(droperidol)、炔己蟻胺(ethinamate)、氟阿尼酮(flunanisone)、氟硝西泮(fIunitrazepam)、三氟丙嗪(fluopromazine)、氟哌噻吨癸酸酯(flupenthixol decanoate)、氟非那嗪癸酸酯(fluphenazine decanoate)、氟西泮(flurazepam)、氟哌啶醇(haloperidol)、勞拉西泮(lorazepam)、氯甲西泮(lormetazepam)、美達西泮(medazepam)、美普巴邁(meprobamate)、甲喹酮(methaqualone)、咪達唑侖(midazolam)、硝西泮(nitrazepam)、奧沙西泮(oxazepam)、戊巴比妥(pentobarbitone)、羥哌氯丙嗪(perphenazine)、脫羥腎上腺素(phenylephrine)、匹莫齊特(pimozide)、普魯氯嗪(prochlorperazine)、假麻黃鹼HCl(pseudoephedrine HCL)、斯比樂(sulpride)、替馬西泮(temazepam)、硫利達嗪 (thioridazine)、***侖(triazolam)、佐匹克隆(zopiclone)。 Anxiolytics, sedatives, hypnotics and antipsychotics: alprazolam, amylobarbitone, barbitone, bentazepam, bromozepam (bromazepam), bromperidol, bromozolam, butobarbitone, carbromal, chlordiazepoxide, Chlorpheniramine , chlormethiazole, chlorpromazine, clobazam, clonazepan, clotiazepam, clozapine, diazepam ), droperidol, ethinamate, flunanisone, flunitazepam, fluopromazine, flupenthixol (flupenthixol) Decanoate), fluphenazine decanoate, flurazepam, haloperidol, lorazepam, lormetazepam, medazin Medazepam), meprobamate, methaqualone, midazolam m), nitrazepam, oxazepam, pentobarbitone, perphenazine, phenylephrine, pimozide , prochlorperazine, pseudoephedrine HCL, sulpride, temazepam, thioridazine (thioridazine), triazolam, zopiclone.

β-阻斷劑：醋丁洛爾(acebutolol)、阿普洛爾(alprenolol)、阿替洛爾atenolol)、拉貝洛爾(labetalol)、美托洛爾(metoprolol)、納多洛爾(nadolol)、氧烯洛爾(oxprenolol)、心得樂(pindolol)、普萘洛爾(propanolol)。 --blockers: acebutolol, aprenolol, atenolol (atenolol), labetalol, metoprolol, nadolol ( Nadolol), oxprenolol, pindolol, propanolol.

心肌收縮劑：氨利酮(amrinone)、毛地黃苷(digitoxin)、地谷新(digoxin)、依諾昔酮(enoximone)、毛花甙C(lanatoside C)、甲基地谷新(medigoxin)。 Myocardial contracting agents: amrinone, digitoxin, digoxin, enoximone, lanatoside C, medigoxin .

皮質類固醇：倍氯米松(beclomethasone)、倍他米松(betamethasone)、布***(budesonide)、醋酸皮質酮(cortisone acetate)、去氧米松(desoxymethasone)、***(dexamethasone)、醋酸氟氫可的松(fludrocortisone acetate)、氟尼縮松(flunisolide)、氟可龍(flucortolone)、丙酸氟替卡松(fluticasone propionate)、氫皮質酮(hydrocortisone)、甲基普立朗(methylprednisolone)、氫皮質醇(prednisolone)、普賴松(prednisone)、去炎松(triamcinolone)。 Corticosteroids: beclomethasone, betamethasone, budesonide, cortisone acetate, desoxymethasone, dexamethasone, fluorohydrogen acetate Fludrocortisone acetate, flunisolide, flucortolone, fluticasone propionate, hydrocortisone, methylprednisolone, hydrocortisol Prednisolone), prednisone, triamcinolone.

止咳藥：磷酸可待因(codeine phosphate)、右美沙芬(dexomethorphan)、癒創木酚甘油醚(guaifenesin)、福爾可定(pholcodine)、海洛英(diamorphine)、***(methadone)。 Cough suppressants: codeine phosphate, dexomethorphan, guaifenesin, pholcodine, diamorphine, methadone.

細胞毒性劑：依弗醯胺(ifosfamide)、氯氨布西(chlorambucil)、黴法蘭(melphalan)、白消安(busulphan)、細胞毒性抗體、多索柔比星(doxorubicin)、表柔比星 (epirubicin)、光神黴素(plicamycin)、博來黴素(bleomycin)、甲氨蝶呤(methotrexate)、阿糖胞苷(cytarabine)、氟達拉濱(fludarabine)、吉西他濱(gencitabine)、氟尿嘧啶(fluorouracil)、巰嘌呤(mercaptopurine)、硫鳥嘌呤(thioguanine)、長春新鹼(vincristine)、長春花鹼(vinblastine)、長春地辛(vindesine)、依託泊苷(etoposide)。 Cytotoxic agents: ifosfamide, chlorambucil, melphalan, busulphan, cytotoxic antibodies, doxorubicin, epirubicin star (epirubicin), philamycin, bleomycin, methotrexate, cytarabine, fludarabine, gecitabine, fluorouracil (fluorouracil), mercaptopurine, thioguanine, vincristine, vinblastine, vindesine, etoposide.

解充血劑：鹽酸假麻黃鹼(pseudoephedrine hydrochloride)。 Decongestant: pseudoephedrine hydrochloride.

利尿劑：乙醯唑胺(acetazolamide)、阿米洛利(amiloride)、芐氟噻嗪(bendrofluazide)、布美他尼(bumetanide)、***(chlorothiazide)、氯噻酮(chlorthalidone)、利尿酸(ethacrynic acid)、呋塞米(frusemide)、美托拉宗(metolazone)、螺甾內酯(spironolactone)、三氨蝶呤(triamterene)。 Diuretics: acetazolamide, amiloride, bendrofluazide, bumetanide, chlorothiazide, chlorthalidone, Ethacrynic acid, frosemide, metolazone, spironolactone, triamterene.

酵素：胰酶(pancreatin)、胃蛋白酶(pepsin)、脂酶(lipase)。 Enzymes: pancreatin, pepsin, lipase.

抗癲癇劑：加巴噴丁(Gabapentin)。 Antiepileptic: Gabapentin.

抗帕金森症藥：甲磺酸溴隱亭(bromocriptine mesylate)、馬來酸麥角乙脲(lysuride maleate)、司來吉蘭(selegiline)、對氟司來吉蘭(para-fluoroselegiline)、拉扎貝胺(lazabemide)、雷沙吉蘭(rasagiline)、2-BUMP[N-(2-丁基)-N-甲基炔丙胺])、M-2-PP[N-甲基-N-(2-戊基)-炔丙胺]、MDL-72145[β-(氟伸甲基)-3,4-二甲氧基-苯乙胺]、莫 非吉蘭(mofegiline)、阿樸嗎啡鹼(apomorphine)、N-丙基去甲阿樸啡(N-propylnoraporphine)、卡麥角林(cabergoline)、麥角芐酯(metergoline)、那高利特(naxagolide)、培高利特(pergolide)、吡貝地爾(piribedil)、羅平尼咯(ropinirole)、特麥角脲(terguride)、喹高利特(quinagolide)。 Anti-Parkinson's disease: bromocriptine mesylate, lysuride maleate, selegiline, para-fluoroselegiline, pull Lazabemide, rasagiline, 2-BUMP[N-(2-butyl)-N-methylpropargylamine], M-2-PP[N-methyl-N- (2-pentyl)-propargylamine], MDL-72145 [β-(fluoromethyl)-3,4-dimethoxy-phenethylamine], Mo Nonfegiline, apomorphine, N-propyl noraporphine, cabergoline, metergoline, nagolide Naxagolide), pergolide, piribedil, ropinirole, terguride, quinagolide.

胃腸藥：比沙可啶(bisacodyl)、西咪替丁(cimetidine)、西沙必利(cisapride)、地芬諾酯HCl(diphenoxylate HCl)、多潘立酮(domperidone)、甲氧氯普胺(metoclopramide)、法莫替丁(famotidine)、洛派丁胺(loperamide)、美沙拉嗪(mesalazine)、尼扎替丁(nizatidine)、艾美拉唑(esomeprazole)、美托哌丙嗪(metopimazine)、泮托拉唑(pantoprazole)、恩丹西酮HCl(ondansetron HCl)、格雷西隆(Granisetron)、托烷司瓊(tropisetron)、多拉司瓊(dolasetron)、雷尼替丁HCl(ranitidine HCl)、柳氮磺吡啶(sulphasalazine)。蘭索拉唑(Lanzoprazole)，組織胺受體拮抗劑：阿伐斯汀(acrivastine)、阿司咪唑(astemizole)、桂利嗪(cinnarizine)、賽克利嗪(cyclizine)、賽庚啶HCl(cyproheptadine HCl)、茶苯海明(dimenhydrinate)、氟桂利嗪HCl(flunarizine HCl)、氯雷他定(loratadine)、美克洛嗪HCl(meclozineHCl)、奧沙米特(oxatomide)、特非那定(terfenadine)、曲普利啶(triprolidine)。 Gastrointestinal drugs: bisacodyl, cimetidine, cisapride, diphenoxylate HCl, domperidone, metoclopramide, method Famotidine, loperamide, mesalazine, nizatidine, esomeprazole, metopimazine, 泮tora Pantoprazole, ondansetron HCl, Granisetron, tropisetron, dolasetron, ranitidine HCl, sulphate Sulphapyridine (sulphasalazine). Lanzoprazole, a histamine receptor antagonist: acrivastine, astemizole, cinnarizine, cyclizine, cyproheptadine HCl), dimenhydrinate, flunarizine HCl, loratadine, meclozine HCl, oxatomide, terfenadine (terfenadine), triprolidine.

激素替代療法：去氫孕酮(dydrogesterone)。 Hormone replacement therapy: dedrogesterone.

高血壓藥：依那普利(Enalapril)。 Hypertensive drug: Enalapril.

泌乳劑(Lactation)：催產素(Oxytocin)、催產素協 同劑(oxytocin agonists)。 Lactation: Oxytocin, Oxytocin Oxytocin agonists.

脂質調節劑：苯扎貝特(bezafibrate)、對氯苯氧異丁酸乙酯(clofibrate)、非諾貝特(fenofibrate)、吉非貝齊(gemfibrozil)、普羅布考(probucol)。 Lipid regulators: bezafibrate, clofibrate, fenofibrate, gemfibrozil, probucol.

局部麻醉劑：阿美索卡因(amethocaine)、阿米洛卡因(amylocaine)、苯佐卡因(benzocaine)、丁吖卡因(bucricaine)、布比卡因(bupivacaine)、布他卡因(butacaine)、布坦卡因(butanilicaine)、丁托西卡因(butoxycaine)、胺基安息香酸丁酯(butyl aminobenzoate)、卡鐵卡因(carticaine)、氯普魯卡因(chloroprocaine)、辛***(cinchocaine)、氯丁卡因(clibucaine)、氯美卡因(clormecaine)、古柯(coca)、古柯鹼(***e)、環美卡因(cyclomethycaine)、奎尼卡因(dimethisoquin)、地呱冬(diperodon)、達克羅寧(dyclocaine)、氯乙烷、對哌啶基乙醯胺苯甲酸乙酯(ethyl p-piperidinoacetylaminobenzoate)、依替卡因(etidocaine)、海克卡因(hexylcaine)、氨苯異丁酯(isobutamben)、凱托卡因(ketocaine)、利諾卡因(lignocaine)、馬比佛卡因(mepivacaine)、美普卡因(meprylcaine)、麥替卡因(myrtecaine)、奧他卡因(octacaine)、奧昔卡因(oxethazaine)、奧布卡因(oxybuprocaine)、對乙氧卡因(parethoxycaine)、普莫卡因(pramoxine)、丙胺卡因(prilocaine)、普羅卡因(procaine)、丙美卡因(propranocaine)、丙氧卡因(propoxycaine)、丙氧間卡因(proxymetacaine)、羅呱卡因(ropivacaine)、托利卡因 (tolycaine)、三卡因(tricaine)、三甲卡因(trimecaine)、伐多卡因(vadocaine)。 Local anesthetics: amethocaine, amylocaine, benzocaine, bucricaine, bupivacaine, butacaine (butacaine) ), butanilicaine, butoxycaine, butyl aminobenzoate, carticaine, chloroprocaine, ***e ( Cinchocaine), clobucaine, clormecaine, coca, ***e, cyclomethycaine, dimethisoquin, mantle Winter (diperodon), dyclocaine, ethyl chloride, ethyl p-piperidinoacetylaminobenzoate, etidocaine, hexylcaine , isobutamben, ketocaine, lignocaine, mepivacaine, meprylcaine, myrtecaine , octacaine, oxethazaine, oxybuprocaine, ethoxy card (parethoxycaine), pramoxine, prilocaine, procaine, propranocaine, propoxycaine, proxymetacaine , ropivacaine, toricaine (tolycaine), tricaine, trimecaine, vadocaine.

動暈藥：二苯胺明(diphenhydramine)。 Motion sickness: diphenhydramine.

神經肌肉劑：吡斯的明(pyridostigmine)。 Neuromuscular agent: pyridostigmine.

硝酸鹽及抗心絞痛劑：酸異戊酯(amyl nitrate)、三***酯(glyceryl trinitrate)、硝酸異山梨酯(isosorbide dinitrate)、單硝酸異山梨酯(isosorbide mononitrate)、四硝酸新戊四酯(pentaerythritol tetranitrate)。 Nitrate and anti-angina agents: amyl nitrate, glyceryl trinitrate, isosorbide dinitrate, isosorbide mononitrate, neopentyl tetranitrate (pentaerythritol tetranitrate).

營養劑：β胡蘿蔔素(betacarotene)、維生素(如維生素A、維生素B2、維生素D、維生素E、維生素K)、礦物質。 Nutritional agents: beta carotene (betacarotene), vitamins (such as vitamin A, vitamin B 2 , vitamin D, vitamin E, vitamin K), minerals.

類鴉片止痛劑：可待因(codeine)、右旋丙氧吩(dextropropyoxyphene)、二乙醯嗎啡(diamorphine)、二氫可待因(dihydrocodeine)、美普他酚(meptazinol)、***(methadone)、嗎啡(morphine)、納布紛(nalbuphine)、潘他唑新(pentazocine)。 Opioid analgesics: codeine, dextropropyoxyphene, diamorphine, dihydrocodeine, meptazinol, methadone , morphine, nalbuphine, pentazocine.

口服疫苗：用於預防或減少下列疾病之症狀，例如流行性感冒、肺結核(Tuberculosis)、腦膜炎(Meningitis)、肝炎(Hepatitis)、百日咳(WhoopingCough)、小兒麻痺症(Polio)、破傷風(Tetanus)、白喉(Diphtheria)、瘧疾(Malaria)、霍亂(Cholera)、皰疹(Herpes)、傷寒(Typhoid)、HIV、AIDS、麻疹(Measles)、萊姆病(Lyme disease)、旅行者腹瀉(Traveller’s Diarrhea)、A、B與C型肝炎、中耳炎(Otitis Media)、登革熱(Dengue Fever)、狂犬病(Rabies)、副流行性 感冒(Parainfluenza)、德國麻疹(Rubella)、黃熱病(Yellow Fever)、痢疾(Dysentery)、退伍軍人症(Legionnaires Disease)、弓蟲症(Toxoplasmosis)、Q-熱(Q-Fever)、出血熱(Haemorrhegic Fever)、阿根廷出血熱(Argentina Haemorrhegic Fever)、骨疽(Caries)、查加斯病(Chagas Disease)、由大腸桿菌引起的尿道感染、肺炎鏈球菌疾病(Pneumococcal Disease)、流行性腮腺炎(Mumps)、屈公病(Chikungunya)、枯草熱(Hayfever)、氣喘(Asthma)、類風濕性關節炎、癌(carcinomas)、球蟲病(Coccidiosis)、新城雞瘟(Newcastle Disease)、地方性肺炎(Enzootic pneumonia)、貓白血病(Feline leukemia)、萎縮性鼻炎(Atrophic rhinitis)、丹毒(Erysipelas)、***與豬肺炎，或者用於預防或減少由下列所引起之疾病的症狀：弧菌屬物種(Vibrio species)、沙門氏菌屬物種(Salmonella species)、包台拉菌屬物種(Bordetella species)、嗜血桿菌屬物種(Haemophilus species)、弓漿蟲(Toxoplasmosis gondii)、巨細胞病毒(Cytomegalovirus)、披衣菌屬物種(Chlamydia species)、鏈球菌屬物種(Streptococcal species)、諾瓦克病毒(Norwalk Virus)、大腸桿菌、幽門螺旋桿菌(Helicobacter pylori)、輪狀病毒(Rotavirus)、淋病奈瑟雙球菌(Neisseria gonorrhae)、腦膜炎奈瑟雙球菌(Neisseria meningiditis)、腺病毒、艾伯斯坦-巴爾病毒(Epstein Barr Virus)、日本腦炎病毒(Japanese Encephalitis Virus)、肺泡囊蟲(Pneumocystis carini)、單純皰疹(Herpes simplex)、梭狀芽胞桿菌屬物種(Clostridia species)、呼吸道融合性病毒(Respiratory Syncytial Virus)、克雷伯氏菌屬物種(Klebsiella species)、志賀氏菌屬物種(Shigella species)、氯膿假單胞桿菌(Pseudomonas aeruginosa)、小病毒(Parvovirus)、曲狀桿菌屬物種(Campylobacter species)、立克次體屬物種(Rickettsia species)、水痘帶狀皰疹(Varicella zoster)、耶氏桿菌屬物種(Yersinia species)、羅氏河病毒(Ross River Virus)、J.C.病毒(J.C.Virus)、馬棒狀桿菌(Rhodococcus equi)、卡他莫拉菌(Moraxella catarrhalis)、伯氏疏螺旋菌(Borrelia burgdorferi)及溶血性巴氏桿菌(Pasteurella haemolytica)。 Oral vaccine: used to prevent or reduce the symptoms of the following diseases, such as influenza, tuberculosis, meningitis, hepatitis, WhoopingCough, Polio, tetanus , Diphtheria, Malaria, Cholera, Herpes, Typhoid, HIV, AIDS, Measles, Lyme disease, Traveller's Diarrhea ), A, B and C hepatitis, Otitis Media, Dengue Fever, Rabies, paradise Parainfluenza, Rubella, Yellow Fever, Dysentery, Legionnaires Disease, Toxoplasmosis, Q-Fever, Hemorrhagic Fever Haemorrhegic Fever), Argentina Haemorrhegic Fever, Caries, Chagas Disease, urinary tract infection caused by Escherichia coli, Pneumococcal Disease, Mumps Mumps), Chikungunya, Hayfever, Asthma, Rheumatoid Arthritis, Cancers, Coccidiosis, Newcastle Disease, Endemic Pneumonia Enzootic pneumonia), feline leukemia, Atrophic rhinitis, erysipelas, foot-and-mouth disease and swine pneumonia, or symptoms used to prevent or reduce diseases caused by: Vibrio species (Vibrio) Species), Salmonella species, Bordetella species, Haemophilus species, Toxoplasmosis gond Ii), Cytomegalovirus, Chlamydia species, Streptococcal species, Norwalk Virus, Escherichia coli, Helicobacter pylori, round Rotavirus, Neisseria gonorrhae, Neisseria meningiditis, adenovirus, Epstein Barr Virus, Japanese Encephalitis Virus ), Pneumocystis carini, herpes simplex (Herpes simplex), Clostridium species (Clostridia) Species), Respiratory Syncytial Virus, Klebsiella species, Shigella species, Pseudomonas aeruginosa, Parvovirus ), Campylobacter species, Rickettsia species, Varicella zoster, Yersinia species, Ros River Virus ), JC virus (JCVirus), Rhodococcus equi, Moraxella catarrhalis, Borrelia burgdorferi, and Pasteurella haemolytica.

排尿功能障礙藥：坦索羅辛(Tamsulosine)、曲司氯銨(trospium chloride)、托特羅定(tolterodine)、羥丁寧(oxybutinin)。 Urinary dysfunction drugs: Tamsulosine, trospium chloride, tolterodine, oxybutinin.

蛋白質、胜肽及重組型藥物：重組型激素及異激素、重組型細胞介素、重組纖維蛋白溶酶原(recombinant plasminogens)、TNF受體融合蛋白、單株抗體、核酸、反義股寡核苷酸、寡核苷酸、醣蛋白及黏著分子。 Proteins, peptides and recombinant drugs: recombinant hormones and estrogens, recombinant interleukins, recombinant plasminogens, TNF receptor fusion proteins, monoclonal antibodies, nucleic acids, antisense oligo Glycosylates, oligonucleotides, glycoproteins and adhesion molecules.

家畜關節炎藥：替泊沙林(Tepoxalin)。 Animal arthritis drug: Tepoxalin.

性激素及避孕藥：克羅米酚檸檬酸鹽(clomiphene citrate)、達那唑(danazol)、去氧孕烯(desogestrel)、乙炔***(ethinyloestradiol)、炔諾醇(ethynodiol)、雙醋炔諾醇(ethynodiol diacetate)、左炔諾孕酮(levonorgestrel)、醋酸甲羥助孕酮(medroxyprogesterone acetate)、美雌醇(mestranol)、甲基睪固酮(methyltestosterone)、降雄甾炔酮 (norethisterone)、庚酸炔諾酮(norethisterone enanthate)、炔諾孕酮(norgestrel)、***(estradiol)、共軛型***(conjugated estrogens)、去氫孕酮(dydrogesterone)、黃體酮(progesterone)、司坦唑醇(stanozolol)、二苯乙烯雌酚(stilboestrol)、睪固酮(testosterone)、替勃龍(tibolone)。 Sex hormones and birth control pills: clomiphene citrate, danazol, desogestrel, ethinyloestradiol, ethynodiol, diacetin Ethynodiol diacetate, levonorgestrel, medroxyprogesterone acetate, mestranol, methyltestosterone, norsonixone (norethisterone), norethisterone enanthate, norgestrel, estradiol, conjugated estrogens, dydrogesterone, progesterone ( Progesterone), stanozolol, stilboestrol, testosterone, tibolone.

精神***症藥物：奧氮平(Olanzapine)、麥角溴菸鹼酯(Nicergoline)。 Schizophrenia drugs: olanzapine (Olanzapine), ergot nicotinic acid (Nicergoline).

性功能障礙藥物：卡麥角林(Cabergolin)、催產素(oxytocin)、他達拉非(tadalafil)、昔多芬(sildenafil)、伐地那非(vardenafil)。 Sexual dysfunction drugs: Cabergolin, oxytocin, tadalafil, sildenafil, vardenafil.

殺精劑：壬苯醇醚9(nonoxynol 9)。 Spermicide: nonoxynol 9 (nonoxynol 9).

興奮劑：***(amphetamine)、右旋***(dexamphetamine)、右芬氟拉明(dexfenfluramine)、芬氟拉明(fenfluramine)、馬吲哚(mazindol)、匹莫林(pemoline)。 Stimulants: amphetamine, dexamphetamine, dexfenfluramine, fenfluramine, mazindol, pemoline.

在一實施例中，該第一活性成分為去氨加壓素或其藥學上可接受鹽類，特別是醋酸去氨加壓素。 In one embodiment, the first active ingredient is desmopressin or a pharmaceutically acceptable salt thereof, particularly desmopressin acetate.

在一實施例中，該第二活性成分(包含在控制釋放珠粒之內)為抗毒蕈鹼化合物。在另一實施例中，該第二活性成分係選自於托特羅定((R)-N,N-二異丙基-3-(2-羥基-5-甲基苯基)-3-苯基丙胺)、托特羅定之5-羥基甲基代謝物((R)-N,N-二異丙基-3-(2-羥基-5-羥基甲基苯基)-3-苯基丙胺)、托特羅定之(S)-鏡像異構物((S)-N,N-二異丙基-3-(2-羥基-5-甲基苯基)-3-苯基丙胺)、托特羅定之(S)-鏡像異構物之5-羥基甲基代謝物((S)-N,N-二異丙基-3-(2-羥基-5-羥基甲 基苯基)-3-苯基丙胺)、托特羅定之外消旋物((R,S)-N,N-二異丙基-3-(2-羥基-5-甲基苯基)-3-苯基丙胺)、其前藥形式及其藥理學上可接受鹽類。在一具體之實施例中，該活性成分為托特羅定或其藥理學上可接受鹽類。在一特定之實施例中，該活性成分為托特羅定酒石酸鹽。 In one embodiment, the second active ingredient (contained within the controlled release beads) is an antimuscarinic compound. In another embodiment, the second active ingredient is selected from tolterodine ((R)-N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3 -Phenylpropylamine), 5-hydroxymethyl metabolite of tolterodine ((R)-N,N-diisopropyl-3-(2-hydroxy-5-hydroxymethylphenyl)-3-benzene (S)-Spiegelomer (S)-N,N-Diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropylamine ), 5-hydroxymethyl metabolite of (S)-mirrible isomer ((S)-N,N-diisopropyl-3-(2-hydroxy-5-hydroxyl) (Phenyl)-3-phenylpropylamine), tolterodine racemate ((R,S)-N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl) 3-Phenylpropylamine), a prodrug form thereof, and a pharmacologically acceptable salt thereof. In a specific embodiment, the active ingredient is tolterodine or a pharmacologically acceptable salt thereof. In a particular embodiment, the active ingredient is tolterodine tartrate.

在一具體、非侷限之實施例中，包含在開放式基質網狀物中的該第一活性成分為去氨加壓素或其藥學上可接受鹽類，特別是醋酸去氨加壓素，及包含在該控制釋放珠粒之中的該第二活性成分為托特羅定或其藥學上可接受鹽類，特別是托特羅定酒石酸鹽。特別較佳為，分別結合醋酸去氨加壓素及托特羅定酒石酸鹽，以作為第一及第二活性成分。在此實施例中，該組成物可用於治療泌尿疾病，例如但不限於，膀胱過動症或膀胱過動症伴隨夜尿症(nocturia)，特別是在女性。 In a specific, non-limiting embodiment, the first active ingredient contained in the open matrix mesh is desmopressin or a pharmaceutically acceptable salt thereof, particularly desmopressin acetate, And the second active ingredient contained in the controlled release bead is tolterodine or a pharmaceutically acceptable salt thereof, particularly tolterodine tartrate. It is particularly preferred to combine desmopressin acetate and tolterodine tartrate as the first and second active ingredients, respectively. In this embodiment, the composition can be used to treat urological disorders such as, but not limited to, overactive bladder or overactive bladder with nocturia, particularly in women.

膀胱過動症的病情會引起頻尿、尿急及/或急迫性尿失禁。膀胱過動症疾病亦可包括夜尿症，亦即夜晚醒來小便。雖然膀胱過動症常與逼尿肌(detrusor muscle)不穩定有關，膀胱功能失調亦可肇因於中樞神經系統的神經病變(逼尿肌反射亢進)，包括脊髓及腦損傷，例如多發性硬化症(multiple sclerosis)及中風。膀胱過動症之症狀亦可起因於，舉例而言，男性膀胱出口阻塞(通常是由於攝護腺肥大)、間質性膀胱炎(interstitial cystitis)、由於局部膀胱癌造成的局部水腫及刺激、由於骨盆的放射線療法造成的放射線膀胱炎，及膀胱炎。 The condition of overactive bladder can cause frequent urination, urgency, and/or urge incontinence. Overactive bladder disease can also include nocturia, which means waking up at night. Although overactive bladder is often associated with instability of the detrusor muscle, bladder dysfunction can also be caused by central nervous system neuropathy (detrusor hyperreflexia), including spinal cord and brain damage, such as multiple sclerosis. Multiple sclerosis and stroke. Symptoms of overactive bladder can also be caused, for example, by male bladder outlet obstruction (usually due to hypertrophy of the prostate), interstitial cystitis, local edema and irritation due to localized bladder cancer, Radiation cystitis caused by radiation therapy of the pelvis, and cystitis.

在一實施例中，醋酸去氨加壓素在該組成物中的含量為0.01-1%w/w，及托特羅定酒石酸鹽在該組成物中的含量為3至10%w/w。在另一實施例中，醋酸去氨加壓素在該組成物中的含量為0.02-0.2%w/w，及托特羅定酒石酸鹽在該組成物中的含量為3至6%w/w。 In one embodiment, the desmopressin acetate is present in the composition at a level of from 0.01 to 1% w/w, and the tolterodine tartrate is present in the composition at a level of from 3 to 10% w/w. . In another embodiment, the content of desmopressin acetate is 0.02-0.2% w/w in the composition, and the content of tolterodine tartrate in the composition is 3 to 6% w/ w.

當以托特羅定為該控制釋放珠粒中的活性成分時，以體外釋放的活性成分之分率係較佳為在1小時後不超過約40%、在3小時後約35至約85%，及在7小時後不低於約65%。 When tolterodine is used as the active ingredient in the controlled release of the beads, the fraction of the active ingredient released in vitro is preferably not more than about 40% after 1 hour and about 35 to about 85 after 3 hours. %, and no less than about 65% after 7 hours.

當以托特羅定為該控制釋放珠粒中的活性成分時，托特羅定自該珠粒(儘管其存在於基質內)的釋放曲線，將類似或甚至相同於托特羅定硬膠囊劑(商業上可購，其商品名為得舒妥(DETRUSITOL XLTM))的釋放曲線。 When tolterodine is used as the active ingredient in the release of the beads, the release profile of tolterodine from the beads (although it is present in the matrix) will be similar or even identical to tolterodine hard capsules. agent (commercially available under the tradename SHU properly (DETRUSITOL XL TM)) release profile.

在一實施例中，該第二活性成分(包含在該控制釋放珠粒之中)為選擇性α-阻斷劑。在另一實施例中，該第二活性成為坦索羅辛((R)-5-(2-{[2-(2-乙氧基苯氧基)乙基]胺基}丙基)-2-甲氧基苯-1-磺醯胺)、其前藥形式及其藥理學上可接受鹽類。在一特定之實施例中，該第二活性成分為鹽酸坦索羅辛。 In one embodiment, the second active ingredient (contained in the controlled release beads) is a selective alpha-blocker. In another embodiment, the second activity is tamsulosin (( R )-5-(2-{[2-(2-ethoxyphenoxy)ethyl)amino}propyl)- 2-methoxybenzene-1-sulfonamide), a prodrug form thereof, and a pharmacologically acceptable salt thereof. In a specific embodiment, the second active ingredient is tamsulosin hydrochloride.

在一具體、非侷限之實施例中，包含在該開放式基質網狀物之中的該第一活性成分為去氨加壓素或其藥學上可接受鹽類，特別是醋酸去氨加壓素，及包含在該控制釋放珠粒之該第二活性成分為坦索羅辛，或其藥學上可接受鹽類，特別是鹽酸坦索羅辛。特別較佳為，分別結合醋 酸去氨加壓素及鹽酸坦索羅辛以作為第一及第二活性成分。在該些實施例中，該組成物可用於治療男性的良性攝護腺肥大症(BPH)。 In a specific, non-limiting embodiment, the first active ingredient contained in the open matrix network is desmopressin or a pharmaceutically acceptable salt thereof, particularly acetic acid desalinated And the second active ingredient contained in the controlled release bead is tamsulosin, or a pharmaceutically acceptable salt thereof, particularly tamsulosin hydrochloride. Particularly preferred, respectively, combined with vinegar Acid desmopressin and tamsulosin hydrochloride are used as the first and second active ingredients. In these embodiments, the composition can be used to treat benign prostate hypertrophy (BPH) in men.

本發明之藥學劑量形式在接觸流體(水性介質或唾液)時會崩解，從而釋放該活性成分及該控制釋放珠粒。 The pharmaceutical dosage form of the present invention disintegrates upon contact with a fluid (aqueous medium or saliva), thereby releasing the active ingredient and the controlled release beads.

典型而言，本發明之藥學劑量形式為口內崩散型藥學劑量形式，其在口中於30秒內崩解，典型上20秒以內，較佳為15秒以內，更佳為10秒以內，及甚而更佳為9、8、7、6、5、4、3、2或1秒內。 Typically, the pharmaceutical dosage form of the present invention is an intra-oral disintegration pharmaceutical dosage form which disintegrates in the mouth within 30 seconds, typically within 20 seconds, preferably within 15 seconds, more preferably within 10 seconds. And even more preferably 9, 8, 7, 6, 5, 4, 3, 2 or 1 second.

術語“口內崩散型”使用於此應被理解為包含，當依據Ph.Eur.1997的2.9.1一節在37℃±0.5℃的水中，於(至多)30秒內崩解或溶解的固體劑量形式。 The term "intraoral collapse" is used herein to be understood to include disintegration or dissolution in (up to) 30 seconds in water at 37 ° C ± 0.5 ° C according to Section 2.9.1 of Ph. Eur. 1997. Solid dosage form.

本發明劑量形式適用的給藥途徑為口服投藥，包括頰的(buccal)及舌下投藥。在一特定之實施例中，該劑量形式係舌下投藥。本發明之劑量形式亦可被置於舌上、舌下或靠著臉頰或牙齦。 Suitable dosage forms for administration of the dosage form of the invention are oral administration, including buccal and sublingual administration. In a particular embodiment, the dosage form is administered sublingually. The dosage form of the invention can also be placed on the tongue, under the tongue, or against the cheeks or gums.

本發明之藥學劑量形式適合於供應該第一活性成分及該控制釋放珠粒至例如口腔。該第一活性成分可在投藥處(例如舌下黏膜)穿過黏膜，及/或其他方式，就口服投藥而言，從口腔(例如穿過頰及/或牙齦黏膜)及/或從腸胃道用於全身性分佈而被吸收。 The pharmaceutical dosage form of the invention is suitable for supplying the first active ingredient and the controlled release beads to, for example, the oral cavity. The first active ingredient can be passed through the mucosa at the site of administration (eg, sublingual mucosa) and/or otherwise, for oral administration, from the oral cavity (eg, through the buccal and/or gingival mucosa) and/or from the gastrointestinal tract It is used for systemic distribution and is absorbed.

該劑量形式之投藥之精確劑量及攝生法(regimen)將必須取決於欲達成之治療效果，及可依特定之活性成分、投藥途徑，及欲進行藥物投藥之個體的年齡及 病況而變。有時在單一投藥時病患可被指示服用二或多種其他數量的單位劑量形式或有時在單一投藥時僅一部份，例如單位劑量形式之一半或四分之一。 The precise dosage and regimen of the dosage form will depend on the therapeutic effect to be achieved and on the particular active ingredient, the route of administration, and the age of the individual to be administered the drug and The condition changes. Sometimes a patient may be instructed to take two or more other amounts of unit dosage form or sometimes only a portion of a single administration, such as one-half or one-quarter of a unit dosage form, in a single administration.

本發明之劑量形式達到性能平衡：抗張強度、穩定性、一致性及快速崩解。其可藉由習知之凍乾技術製造。其可被儲存(及包裝)於泡殼但是由於其抗張強度，亦可被儲存及/或包裝於瓶子或散裝(bulk)。本發明在單一加工步驟中達到這些結果，而無須訴諸多重步驟，包括粒化。 The dosage form of the present invention achieves a balance of properties: tensile strength, stability, consistency, and rapid disintegration. It can be made by conventional freeze-drying techniques. It can be stored (and packaged) in the bulb but can also be stored and/or packaged in bottles or bulk due to its tensile strength. The present invention achieves these results in a single processing step without the need to resort to numerous heavy steps, including granulation.

除了先前所討論的成分外，該基質亦可包括其他賦形劑(輔助劑、助劑)，例如但不限於，填充劑、增稠劑、黏合劑、稀釋劑、潤滑劑、pH調節劑、保護劑、黏度增強劑、蕊吸劑(wicking agents)、非發泡崩解劑(non-effervescent disintegrants)、發泡崩解劑、界面活性劑、抗氧化劑、濕潤劑、著色劑、調味劑、遮味劑(taste-masking agents)、甜味劑、防腐劑等。 In addition to the ingredients previously discussed, the matrix may also include other excipients (auxiliaries, adjuvants) such as, but not limited to, fillers, thickeners, binders, diluents, lubricants, pH adjusters, Protecting agents, viscosity enhancers, wicking agents, non-effervescent disintegrants, foaming disintegrants, surfactants, antioxidants, wetting agents, colorants, flavoring agents, Taste-masking agents, sweeteners, preservatives, and the like.

在一實施例中，本發明之組成物係藉由從溶於溶劑之包含第一活性成分、基質形成劑、控制釋放丸粒，及任擇地第二基質形成劑之液體製備物中昇華溶劑而獲得。典型而言，該液體製備物被置於一模型(mould)中，例如藉此在昇華之後，固體組成物(典型上呈一劑量形式)在該模型內形成。該模型可為開放式泡殼包裝，藉此該固體劑量單位在該泡殼包裝的凹陷內形成，其之後由密封薄膜或箔所密封。 In one embodiment, the composition of the present invention is a sublimation solvent from a liquid preparation comprising a first active ingredient, a matrix forming agent, a controlled release pellet, and optionally a second matrix forming agent dissolved in a solvent. And get. Typically, the liquid preparation is placed in a mold, for example whereby a solid composition (typically in a dosage form) is formed within the mold after sublimation. The mold may be an open blister pack whereby the solid dosage unit is formed within the recess of the blister pack, which is thereafter sealed by a sealing film or foil.

在一實施例中，該方法包含將單位劑量數量之該 製備物導入開放式泡殼包裝之凹陷內；隨後昇華該製備物，以獲得位於該內凹陷之固體劑量形式。 In an embodiment, the method includes the unit dose amount The preparation is introduced into a recess of an open blister pack; the preparation is subsequently sublimed to obtain a solid dosage form in the inner recess.

該昇華可藉由冷凍乾燥溶於溶劑之包含該第一活性成分、基質形成劑、控制釋放珠粒及任擇地第二基質形成劑之液體製備物而進行。在一實施例中，該溶劑為水。 The sublimation can be carried out by freeze-drying a liquid preparation comprising the first active ingredient, a matrix forming agent, a controlled release bead, and optionally a second matrix forming agent dissolved in a solvent. In an embodiment, the solvent is water.

本發明因此揭示一種製備快速分散劑量形式的方法，藉由冷凍乾燥一包含第一活性成分、基質形成劑、控制釋放珠粒及任擇地第二基質形成劑之組合物之溶液、懸浮液或乳液以。該快速分散劑量形式含有該第一活性成分、該基質形成劑、該控制釋放珠粒及任擇地該第二基質形成劑之網狀物，該網狀物已藉由從含有該些成分之液體製備物中昇華溶劑而獲得。 The invention thus discloses a method of preparing a rapidly dispersing dosage form by lyophilizing a solution, suspension or composition comprising a composition of a first active ingredient, a matrix forming agent, a controlled release bead, and optionally a second matrix forming agent. Emulsion to. The rapidly dispersing dosage form comprises a network of the first active ingredient, the matrix forming agent, the controlled release beads, and optionally the second matrix forming agent, the network having been obtained from the composition Obtained by sublimating a solvent in a liquid preparation.

典型而言，先製備溶於溶劑之包含第一活性成分、基質形成劑、控制釋放珠粒及任擇地第二基質形成劑之初始製備物，接著進行昇華。該昇華可藉由冷凍乾燥該製備物而進行。在該快速分散劑量形式之製備期間，可藉由減少液體成分與該控制釋放珠粒之間的接觸時間，例如至不超過45、35、25、20、15或10分鐘或不超過5分鐘的時間，預防該第二活性成分的提前溶解或釋放。 Typically, an initial preparation comprising a first active ingredient, a matrix former, a controlled release bead, and optionally a second matrix former is dissolved in a solvent, followed by sublimation. This sublimation can be carried out by freeze drying the preparation. During the preparation of the fast dispersing dosage form, by reducing the contact time between the liquid component and the controlled release bead, for example up to 45, 35, 25, 20, 15 or 10 minutes or no more than 5 minutes Time to prevent premature dissolution or release of the second active ingredient.

在冷凍乾燥步驟中，溶於溶劑之包含第一活性成分、基質形成劑、控制釋放珠粒及任何其他任擇之基質形成劑之該製備物(呈液體形式)，係裝填至模型中。模型之每一者典型上含有一定義數量之此類製備物，其具有一定義數量之第一活性成分及一定義數量之珠粒。在一另外之實 施例中，該控制釋放珠粒係以所需之數量，預先裝填至模型及任擇地冷卻與冷凍，及隨後將包含該快速分散劑量形式之其餘成分之液體形式製備物加入該模型。位於該模型中的該製備物隨即經冷凍，例如藉由將氣體冷卻介質通入該模型。在該製備物冷凍之後，由其中昇華該溶劑。該昇華係於冷凍乾燥機進行。其結果為，攜帶該第一活性成分及該珠粒之該基質形成劑，任擇地連同其他基質形成劑包含在該製備物之開放式基質網狀物中而形成。 In a freeze-drying step, the preparation (in liquid form) comprising a first active ingredient, a matrix forming agent, a controlled release bead, and any other optional matrix forming agent dissolved in a solvent is loaded into the mold. Each of the models typically contains a defined number of such preparations having a defined number of first active ingredients and a defined number of beads. In a different reality In the embodiment, the controlled release bead is pre-filled into the mold and optionally cooled and frozen in the desired amount, and then the liquid form preparation comprising the remainder of the fast dispersing dosage form is added to the mold. The preparation located in the model is then frozen, for example by passing a gas cooling medium into the mold. After the preparation is frozen, the solvent is sublimed therefrom. The sublimation is carried out in a freeze dryer. As a result, the matrix forming agent carrying the first active ingredient and the beads, optionally together with other matrix forming agents, is formed in the open matrix network of the preparation.

在冷凍乾燥步驟期間，該製備物被包含在模型中，以產生呈現任何所欲形狀之固體形式。在冷凍乾燥之前，該模型可被冷卻及冷凍(例如，在一快速冷凍通道或凍乾機之架上)，例如使用液態氮或固態二氧化碳。在一實施例中，冷凍速率為0.1至2℃/分鐘。在另一實施例中，冷凍速率為0.5至1.5℃/分鐘。在又另一實施例中，冷凍速率為10至260℃/分鐘。在另一實施例中，冷凍速率為20至260℃/分鐘。在一進一步實施例中，冷凍速率為20至160℃/分鐘。 During the freeze-drying step, the preparation is included in the mold to produce a solid form that exhibits any desired shape. The model can be cooled and frozen (e.g., on a fast freezing channel or lyophilizer rack) prior to freeze drying, for example using liquid nitrogen or solid carbon dioxide. In one embodiment, the freezing rate is from 0.1 to 2 ° C / minute. In another embodiment, the freezing rate is from 0.5 to 1.5 ° C / minute. In yet another embodiment, the freezing rate is from 10 to 260 ° C / minute. In another embodiment, the freezing rate is from 20 to 260 ° C / minute. In a further embodiment, the freezing rate is from 20 to 160 ° C / minute.

在冷凍乾燥之後，該些經冷凍乾燥之組成物可視需要從該模型移除或保存於其中，直到後來使用。典型而言，模型之每一者如此被設計，以產生一單位劑量形式之該組成物。如此所獲得之該組成物在與流體接觸時，於至多30秒內(典型上少於10秒內)快速分散及崩解。 After lyophilization, the freeze-dried compositions can be removed from or stored in the model as needed until later use. Typically, each of the models is designed to produce the composition in a unit dosage form. The composition thus obtained rapidly disperses and disintegrates in up to 30 seconds (typically less than 10 seconds) upon contact with a fluid.

用於製備本發明組成物之溶劑典型上為水，但是亦可含有共-溶劑(例如醇類，如第三丁醇)。 The solvent used to prepare the compositions of the present invention is typically water, but may also contain a co-solvent (e.g., an alcohol such as a third butanol).

用於製備本發明組成物之該液體製備物可含有 pH調節劑，以將其pH調整在介於2至10，典型上3.5至9.5或4.5至8之範圍內。檸檬酸及檸檬酸鈉可被作為pH調節劑，但是包括氫氧化鈉、碳酸鈉、鹽酸及蘋果酸等他者亦可被使用。非揮發性pH調節劑將不會被冷凍乾燥或其他昇華方法移除，因此可能會存在最終組成物中。 The liquid preparation for preparing the composition of the present invention may contain The pH adjuster is adjusted to have a pH in the range of 2 to 10, typically 3.5 to 9.5 or 4.5 to 8. Citric acid and sodium citrate can be used as pH adjusters, but others including sodium hydroxide, sodium carbonate, hydrochloric acid and malic acid can also be used. Non-volatile pH modifiers will not be removed by freeze drying or other sublimation methods and may therefore be present in the final composition.

該模型可包含一系列圓柱形或其他形狀的凹陷於其中，該尺寸之每一者皆符合欲形成之劑量形式之所欲尺寸。 The mold may comprise a series of cylindrical or other shaped depressions therein, each of which conforms to the desired size of the dosage form to be formed.

在一實施例中，該模型為在一張薄膜材料的凹陷。該薄膜材料可含有超過一凹陷。該薄膜材料可類似於用於包裝口服錠劑及類似藥物形式之常規泡殼包裝。舉例而言，該薄膜材料可由熱塑性材料(thermoplastic material)製成，其中該凹陷由熱成型(thermoforming)或冷成型(cold forming)形成。聚氯乙烯薄膜可被作為薄膜材料。亦可使用薄膜材料的層板(laminates)。 In one embodiment, the model is a depression in a sheet of film material. The film material can contain more than one depression. The film material can be similar to conventional blister packs for packaging oral lozenges and similar pharmaceutical forms. For example, the film material can be made of a thermoplastic material, wherein the depression is formed by thermoforming or cold forming. A polyvinyl chloride film can be used as a film material. Laminates of film materials can also be used.

範例 example

本發明係於下列範例中進一步描述，其不意欲以任何方式侷限如本發明所請求之範疇。 The invention is further described in the following examples, which are not intended to limit the scope of the invention as claimed.

方法 method 用於檢測基質崩解時間之方法Method for detecting matrix disintegration time

此試驗測定本發明組成物在水性介質中的崩解時間，其亦為其在唾液中的崩解時間的指標。 This test measures the disintegration time of the composition of the invention in an aqueous medium, which is also an indicator of its disintegration time in saliva.

設備：Electrolab，Model ED2 SAPO。 Equipment: Electrolab, Model ED2 SAPO.

步驟：該方法係遵照USP 31-NF 26(一般章節， <701>崩解)及Ph Eur.1997(2.9.1.錠劑及膠囊之崩解)。將水裝填至燒杯並利用水浴將溫度維持在37℃±0.5℃。將該劑量形式置於由具有直徑約0.5mm(±0.05mm)及長度約15mm之銅線製成的沈錘(sinker)。隨後，將該沈錘被置於籃架配件的籃內，及啟動儀器。該崩解時間以秒記錄。 Step: This method is in accordance with USP 31-NF 26 (General Section, <701> Disintegration) and Ph Eur. 1997 (2.9.1. Disintegration of tablets and capsules). Water was charged to the beaker and the temperature was maintained at 37 °C ± 0.5 °C using a water bath. This dosage form was placed on a sinker made of copper wire having a diameter of about 0.5 mm (± 0.05 mm) and a length of about 15 mm. The hammer is then placed in the basket of the basket accessory and the instrument is activated. This disintegration time is recorded in seconds.

用於檢測該第一活性成分之速釋之溶解方法Dissolution method for detecting immediate release of the first active ingredient

此試驗測定取自本發明組成物之該第一活性成分於水性介質中的溶解(%)，其為該第一活性成分之釋放曲線之指標。 This test measures the dissolution (%) of the first active ingredient from the composition of the present invention in an aqueous medium, which is an indicator of the release profile of the first active ingredient.

設備：Varian，Model VK7025。 Equipment: Varian, Model VK7025.

步驟：該方法係遵照USP 32-NF 27(一般章節，<711>溶解)。溶解介質(0.1N HCl、磷酸鹽緩衝液，pH 6.8、醋酸鹽緩衝液，pH 4.5，或溶於水之0.5% SLS(月桂基硫酸鈉))的選取，係以在組成物中的活性成分為依據。以在組成物中的活性成分為依據之適當的介質體積(500mL或900mL)裝填至溶解缽，並利用水浴將介質之溫度維持在37℃±0.5℃。所使用之裝置為USP II型(槳法)，並設定在50rpm。在5分鐘、10分鐘、15分鐘及30分鐘時取出樣本。若適用，以層析法或UV分析樣本，並計算%釋放。 Procedure: This method is in accordance with USP 32-NF 27 (general section, <711> Dissolution). The dissolution medium (0.1N HCl, phosphate buffer, pH 6.8, acetate buffer, pH 4.5, or 0.5% SLS (sodium lauryl sulfate) dissolved in water) is selected as the active ingredient in the composition. Based on. The appropriate medium volume (500 mL or 900 mL) based on the active ingredient in the composition was loaded into the dissolved mash, and the temperature of the medium was maintained at 37 ° C ± 0.5 ° C using a water bath. The device used was USP Type II (paddle method) and set at 50 rpm. Samples were taken at 5 minutes, 10 minutes, 15 minutes, and 30 minutes. If applicable, analyze the sample by chromatography or UV and calculate % release.

用於檢測該第二活性成分之延釋之溶解方法Dissolution method for detecting delayed release of the second active ingredient

此試驗測定取自本發明組成物之該第二活性成分於水性介質中的溶解(%)，其為該第二活性成分之釋放曲線之指標。 This test measures the dissolution (%) of the second active ingredient from the composition of the present invention in an aqueous medium, which is an indicator of the release profile of the second active ingredient.

設備：Varian，Model VK7025。 Equipment: Varian, Model VK7025.

步驟：該方法係遵照USP 32-NF 27(一般章節，<711>溶解)。溶解介質(0.1N HCl、磷酸鹽緩衝液，pH 6.8、醋酸鹽緩衝液，pH 4.5，或溶於水之0.5% SLS)的選取，係以在組成物中的活性成分為依據。以在組成物中的活性成分為依據之適當的介質體積(900mL)裝填至溶解缽，並利用水浴將介質之溫度維持在37℃±0.5℃。所使用之裝置為USP I型(藍式法)並設定在100rpm。在1小時、2小時、3小時、5小時、7小時、9小時及12小時取出樣本。若適用，以層析法或UV分析樣本，並計算%釋放。 Procedure: This method is in accordance with USP 32-NF 27 (general section, <711> Dissolution). The choice of dissolution medium (0.1 N HCl, phosphate buffer, pH 6.8, acetate buffer, pH 4.5, or 0.5% SLS in water) is based on the active ingredient in the composition. The appropriate medium volume (900 mL) based on the active ingredient in the composition was loaded into the dissolved mash, and the temperature of the medium was maintained at 37 ° C ± 0.5 ° C using a water bath. The device used was USP Type I (blue method) and set at 100 rpm. Samples were taken at 1 hour, 2 hours, 3 hours, 5 hours, 7 hours, 9 hours, and 12 hours. If applicable, analyze the sample by chromatography or UV and calculate % release.

用於測量該核心顆粒大小之方法Method for measuring the core particle size

此試驗利用標準篩測定核心之顆粒大小(BSS,ASTM)。該方法係遵照USP 35-NF 30(一般章節，<786>藉由分析篩法評估顆粒大小分佈)。將感興趣範圍之篩子彼此堆疊於其上，以增加粗糙程度，並將該核心丸粒/珠粒/顆粒置於篩子頂部。以該套篩子進行標準化週期之攪拌，隨後精確測定保留在各篩子上的材料重量。 This test uses a standard sieve to determine the core particle size (BSS, ASTM). The method is in accordance with USP 35-NF 30 (General Section, <786> Evaluation of Particle Size Distribution by Analytical Sieve Method). Sieves of the range of interest are stacked on top of each other to increase the degree of roughness and the core pellets/beads/particles are placed on top of the sieve. The set of sieves was subjected to a standardization cycle of agitation, and then the weight of the material remaining on each sieve was accurately determined.

範例1 Example 1 托特羅定ER顆粒Tolterodine ER granules

簡易製造步驟：Easy manufacturing steps:

於流動床處理機製備托特羅定ER顆粒(伍斯特塗佈法)。該ER顆粒之不同組分/製備步驟為： Tolterodine ER granules (Worst coating method) were prepared in a fluid bed processor. The different components/preparation steps of the ER particles are:

a.惰性核心1：選取150-180μm大小範圍的糖球(Pharm-a-spheres USP/NF,EP)，用於封合塗佈、藥物分層及ER塗佈。 a. Inert Core 1: Pitch-a-spheres USP/NF (EP) in the 150-180 μm size range was selected for seal coating, drug delamination, and ER coating.

b.封合塗層2：將稀釋至20% w/w濃度之尤特奇NE 30D(Colorcon)用於該第一水不溶性層。將尤特奇NE 30D分散液(聚合物：滑石之比例為1：0.5)噴灑在糖球上以取得30%w/w之增重(weight gain)。 b. Sealing Coating 2: Utech NE 30D (Colorcon) diluted to a concentration of 20% w/w was used for the first water insoluble layer. An Eudragit NE 30D dispersion (polymer: talc ratio of 1:0.5) was sprayed onto the sugar spheres to achieve a 30% w/w weight gain.

c.藥物層3：將藥物與黏合劑之水溶液噴灑在該經封合塗層之糖球上，以達到~46% w/w之目標增重。托特羅定酒石酸鹽：HPMC 5cps之比例為5：1。 c. Drug layer 3: An aqueous solution of the drug and the binder is sprayed onto the sealed coated sugar sphere to achieve a target weight gain of ~46% w/w. Tolterodine tartrate: HPMC 5cps ratio of 5:1.

d.延釋塗層5：此層為尤特奇NE 30D+HPMC 5 cps+滑石之結合；將~20% w/w的尤特奇NE 30D+HPMC 5 cps(尤特奇NE 30D：HPMC 5 cps之比例為94.34：5.66；滑石：聚合物含量的~43.1%)水性分散 液，噴灑在該藥物塗佈顆粒上，以取得40% w/w之增重。 d. Extended Release Coating 5: This layer is a combination of Eudragit NE 30D+HPMC 5 cps + talc; ~20% w/w of Utech NE 30D+HPMC 5 cps (Euctech NE 30D: HPMC 5 The ratio of cps was 94.34:5.66; talc: ~43.1% of polymer content) aqueous dispersion was sprayed on the coated particles of the drug to obtain a weight gain of 40% w/w.

e.托特羅定ER顆粒之固化：該托特羅定ER顆粒於40℃下固化12小時。 e. Curing of tolterodine ER granules: The tolterodine ER granules were cured at 40 ° C for 12 hours.

冷凍乾燥物組成：Freeze-dried composition:

冷凍乾燥物之簡易製造步驟：Easy manufacturing steps for freeze-dried products:

1.將所有的賦形劑溶於純水中以產生基質組成物。最終體積以純水調整並利用5% w/v檸檬酸溶液將pH值調整至pH 4.5。 1. Dissolve all excipients in pure water to produce a matrix composition. The final volume was adjusted with pure water and the pH was adjusted to pH 4.5 using a 5% w/v citric acid solution.

2.將精確量的托特羅定ER顆粒裝填至預製之泡殼空腔。 2. Fill a pre-made blister cavity with a precise amount of tolterodine ER granules.

3.將步驟1之基質溶液裝填至含有托特羅定ER顆粒之泡殼空腔。 3. The substrate solution of step 1 is loaded into a blister cavity containing tolterodine ER particles.

4.在液態氮通道中冷凍該經裝填之泡殼。 4. Freeze the filled bulb in a liquid nitrogen channel.

5.將泡殼維持在冷凍溫度之下直到整批被冷凍。 5. Maintain the bulb below the freezing temperature until the entire batch is frozen.

6.將經冷凍之泡殼填入冷凍乾燥機以進行冷凍乾燥。 6. The frozen blister is filled into a freeze dryer for lyophilization.

7.藉由壓力上升試驗偵測冷凍乾燥終點(end point)。 7. The freeze-drying end point is detected by a pressure rise test.

8.從該冷凍乾燥機卸載經乾燥之泡殼。 8. Unload the dried bulb from the freeze dryer.

9.將泡殼密封，隨後印刷。 9. Seal the bulb and print subsequently.

圖2係顯示托特羅定ER顆粒及範例1之冷凍乾燥物，及用於比較的得舒妥XL(Detrusitol XL)，在pH 6.8磷酸鹽緩衝液之托特羅定藥物釋放(溶解曲線)。 Figure 2 shows tolterodine ER particles and the lyophilized product of Example 1, and Detroit XL for comparison, tolterodine drug release (dissolution curve) in phosphate buffer at pH 6.8 .

範例2 Example 2 托特羅定ER顆粒Tolterodine ER granules

簡易製造步驟：Easy manufacturing steps:

於流動床處理機製備托特羅定ER顆粒(伍斯特塗佈法)。 Tolterodine ER granules (Worst coating method) were prepared in a fluid bed processor.

該ER顆粒之不同組分/製備步驟為： The different components/preparation steps of the ER particles are:

a.惰性核心1：選取150-180μm大小範圍的糖球(Pharm-a-spheres USP/NF,EP)用於封合塗佈、藥物分 層及ER塗佈。 a. Inert core 1: Sugar spheres (Pharm-a-spheres USP/NF, EP) in the 150-180 μm size range were selected for seal coating, drug layering and ER coating.

b.封合塗層2：將稀釋至15% w/w濃度之蘇利釋(Colorcon)用於該第一水不溶性層。將蘇利釋分散液噴灑在糖球上，以取得30%w/w之增重。 b. Sealing Coating 2: Colorcon diluted to a concentration of 15% w/w was used for the first water insoluble layer. The sulixide dispersion was sprayed onto the sugar spheres to achieve a 30% w/w weight gain.

c.藥物層3：將藥物與黏合劑之水溶液噴灑在該經封合塗層之糖球上，以達到~46% w/w之目標增重。托特羅定酒石酸鹽：HPMC 5cps之比例為5：1。 c. Drug layer 3: An aqueous solution of the drug and the binder is sprayed onto the sealed coated sugar sphere to achieve a target weight gain of ~46% w/w. Tolterodine tartrate: HPMC 5cps ratio of 5:1.

d.延釋塗層5：此層為蘇利釋+HPMC 5 cps之結合。 將~15% w/w的蘇利釋+HPMC 5 cps(蘇利釋：HPMC 5 cps之比例：84：16)水性分散液，噴灑在該經藥物塗佈之顆粒上，以取得100% w/w之增重。 d. Extended Release Coating 5: This layer is a combination of Sullixide + HPMC 5 cps. An aqueous dispersion of ~15% w/w of sulide + HPMC 5 cps (Sullipide: HPMC 5 cps ratio: 84:16) was sprayed onto the drug-coated granules to obtain 100% w /w gain.

e.托特羅定ER顆粒之固化：該托特羅定ER顆粒於70℃下固化3小時。 e. Curing of tolterodine ER granules: The tolterodine ER granules were cured at 70 ° C for 3 hours.

冷凍乾燥物組成：Freeze-dried composition:

冷凍乾燥物之簡易製造步驟：Easy manufacturing steps for freeze-dried products:

1.將所有的賦形劑溶於純水中。以純水調整最終體積並利用5% w/v檸檬酸溶液將pH值調整至pH 4.5。 1. Dissolve all excipients in pure water. The final volume was adjusted with pure water and the pH was adjusted to pH 4.5 using a 5% w/v citric acid solution.

2.將精確量的托特羅定ER顆粒裝填至預製之泡殼空腔。 2. Fill a pre-made blister cavity with a precise amount of tolterodine ER granules.

3.將步驟1的去氨加壓素分散液裝填至含有托特羅定ER顆粒之泡殼空腔。 3. The desmopressin dispersion of step 1 is loaded into a blister cavity containing tolterodine ER particles.

4.在液態氮通道中冷凍該經裝填之泡殼。 4. Freeze the filled bulb in a liquid nitrogen channel.

5.將泡殼維持在冷凍溫度之下直到整批被冷凍。 5. Maintain the bulb below the freezing temperature until the entire batch is frozen.

6.將經冷凍之泡殼填入冷凍乾燥機以進行冷凍乾燥。 6. The frozen blister is filled into a freeze dryer for lyophilization.

7.藉由壓力上升試驗偵測乾燥終點。 7. The dry end point is detected by a pressure rise test.

8.從該冷凍乾燥機卸載經乾燥之泡殼。 8. Unload the dried bulb from the freeze dryer.

9.將泡殼密封，隨後印刷。 9. Seal the bulb and print subsequently.

圖3係顯示範例2之劑量形式在pH 6.8磷酸鹽緩衝液之活性成分之釋放。 Figure 3 is a graph showing the release of the active ingredient of the dosage form of Example 2 in a pH 6.8 phosphate buffer.

範例3 Example 3 托特羅定ER顆粒Tolterodine ER granules

簡易製造步驟：Easy manufacturing steps:

於流動床處理機製備托特羅定ER顆粒(伍斯特塗佈法)。 Tolterodine ER granules (Worst coating method) were prepared in a fluid bed processor.

該ER顆粒之不同組分/製備步驟為： The different components/preparation steps of the ER particles are:

a.惰性核心1：選取150-180μm大小範圍的糖球(Pharm-a-spheres USP/NF,EP)用於封合塗佈、藥物分層及ER塗佈。 a. Inert core 1: Sugar spheres (Pharm-a-spheres USP/NF, EP) in the 150-180 μm size range were selected for seal coating, drug layering and ER coating.

b.封合塗層2：將稀釋至15% w/w濃度之蘇利釋(Colorcon)用於該第一水不溶性層。將蘇利釋分散液噴灑在糖球上以取得30%w/w之增重。 b. Sealing Coating 2: Colorcon diluted to a concentration of 15% w/w was used for the first water insoluble layer. The sulixide dispersion was sprayed onto the sugar spheres to achieve a 30% w/w weight gain.

c.藥物層3：將藥物與黏合劑之水溶液噴灑在該經封合塗層之糖球上以達到~46% w/w之目標增重。托特羅定酒石酸鹽：HPMC 5cps之比例為5：1。 c. Drug layer 3: An aqueous solution of the drug and the binder is sprayed onto the sealed coated sugar sphere to achieve a target weight gain of ~46% w/w. Tolterodine tartrate: HPMC 5cps ratio of 5:1.

d.延釋塗層5：此層為蘇利釋+HPMC 5 cps之結合。 將~15% w/w的蘇利釋+HPMC 5 cps(蘇利釋：HPMC 5 cps之比例：84：16)水性分散液噴灑在該經藥物分層之顆粒上以取得100% w/w之增重。 d. Extended Release Coating 5: This layer is a combination of Sullixide + HPMC 5 cps. Spraying ~15% w/w of sulide + HPMC 5 cps (Sullip: HPMC 5 cps ratio: 84:16) aqueous dispersion onto the drug-stratified particles to obtain 100% w/w Weight gain.

e.托特羅定ER顆粒之固化：該托特羅定ER顆粒於70℃下固化3小時。 e. Curing of tolterodine ER granules: The tolterodine ER granules were cured at 70 ° C for 3 hours.

冷凍乾燥物組成：Freeze-dried composition:

冷凍乾燥物之簡易製造步驟：Easy manufacturing steps for freeze-dried products:

1.將所有的賦形劑溶於純水中。以純水調整最終體積，並利用5% w/v檸檬酸溶液將pH值調整至pH 4.5。 1. Dissolve all excipients in pure water. The final volume was adjusted with pure water and the pH was adjusted to pH 4.5 using a 5% w/v citric acid solution.

2.將精確量的托特羅定ER顆粒裝填至預製之泡殼空腔。 2. Fill a pre-made blister cavity with a precise amount of tolterodine ER granules.

3.將去氨加壓素分散液裝填至含有托特羅定ER顆粒之泡殼空腔。 3. The desmopressin dispersion is filled into a blister cavity containing tolterodine ER particles.

4.在液態氮通道中冷凍該經裝填之泡殼。 4. Freeze the filled bulb in a liquid nitrogen channel.

5.將泡殼維持在冷凍溫度之下直到整批被冷凍。 5. Maintain the bulb below the freezing temperature until the entire batch is frozen.

6.將經冷凍之泡殼填入冷凍乾燥機以進行冷凍乾燥。 6. The frozen blister is filled into a freeze dryer for lyophilization.

7.藉由壓力上升試驗偵測乾燥終點。 7. The dry end point is detected by a pressure rise test.

8.從該冷凍乾燥機卸載經乾燥之泡殼。 8. Unload the dried bulb from the freeze dryer.

9.將泡殼密封及隨後印刷。 9. Seal the bulb and print it subsequently.

圖4係顯示範例3之劑量形式在pH 6.8磷酸鹽緩衝液之活性成分之釋放。 Figure 4 is a graph showing the release of the active ingredient of the dosage form of Example 3 in a pH 6.8 phosphate buffer.

範例4 Example 4 托特羅定ER顆粒Tolterodine ER granules

簡易製造步驟：Easy manufacturing steps:

於流動床處理機製備托特羅定ER顆粒(伍斯特塗佈法)。 Tolterodine ER granules (Worst coating method) were prepared in a fluid bed processor.

ER顆粒之不同組分/製備步驟為： The different components/preparation steps of the ER particles are:

a.惰性核心1：選取150-180μm大小範圍的糖球(Pharm-a-spheres USP/NF,EP)用於封合塗佈、藥物分層及ER塗佈。 a. Inert core 1: Sugar spheres (Pharm-a-spheres USP/NF, EP) in the 150-180 μm size range were selected for seal coating, drug layering and ER coating.

b.封合塗層2：將稀釋至15% w/w濃度之蘇利釋(Colorcon)用於該第一水不溶性層。將蘇利釋分散液噴灑在糖球上以取得30%w/w之增重。 b. Sealing Coating 2: Colorcon diluted to a concentration of 15% w/w was used for the first water insoluble layer. The sulixide dispersion was sprayed onto the sugar spheres to achieve a 30% w/w weight gain.

c.藥物層3：將藥物與黏合劑之水溶液噴灑在該經封合塗佈之糖球上以達到~46% w/w之目標增重。托特羅定酒石酸鹽：HPMC 5cps之比例為5：1。 c. Drug Layer 3: An aqueous solution of the drug and binder is sprayed onto the sealed coated sugar sphere to achieve a target weight gain of ~46% w/w. Tolterodine tartrate: HPMC 5cps ratio of 5:1.

d.延釋塗層5：此層為蘇利釋+HPMC 5 cps之結合。將~15% w/w的蘇利釋+HPMC 5 cps(蘇利釋：HPMC 5 cps之比例：84：16)水性分散液噴灑在該 經藥物分層之顆粒上以取得100% w/w之增重。 d. Extended Release Coating 5: This layer is a combination of Sullixide + HPMC 5 cps. Spraying ~15% w/w of sulide + HPMC 5 cps (Sullip: HPMC 5 cps ratio: 84:16) aqueous dispersion onto the drug-stratified particles to obtain 100% w/w Weight gain.

e.托特羅定ER顆粒之固化：托特羅定ER顆粒於70℃下固化3小時。 e. Curing of tolterodine ER pellets : Tolterodine ER pellets were cured at 70 ° C for 3 hours.

冷凍乾燥物組成：Freeze-dried composition:

冷凍乾燥物之簡易製造步驟：Easy manufacturing steps for freeze-dried products:

1.將所有的賦形劑溶於純水中。以純水調整最終體積，並利用5% w/v檸檬酸溶液將pH值調整至pH 4.5。 1. Dissolve all excipients in pure water. The final volume was adjusted with pure water and the pH was adjusted to pH 4.5 using a 5% w/v citric acid solution.

2.將精確量的托特羅定ER顆粒裝填至預製之泡殼空腔。 2. Fill a pre-made blister cavity with a precise amount of tolterodine ER granules.

3.將去氨加壓素分散液裝填至含有托特羅定ER顆粒之泡殼空腔。 3. The desmopressin dispersion is filled into a blister cavity containing tolterodine ER particles.

4.在液態氮通道中冷凍該經裝填之泡殼。 4. Freeze the filled bulb in a liquid nitrogen channel.

5.將泡殼維持在冷凍溫度之下直到整批被冷凍。 5. Maintain the bulb below the freezing temperature until the entire batch is frozen.

6.將經冷凍之泡殼填入冷凍乾燥機以進行冷凍乾燥。 6. The frozen blister is filled into a freeze dryer for lyophilization.

7.藉由壓力上升試驗偵測乾燥終點。 7. The dry end point is detected by a pressure rise test.

8.從該冷凍乾燥機卸載經乾燥之泡殼。 8. Unload the dried bulb from the freeze dryer.

9.將泡殼密封，隨後印刷。 9. Seal the bulb and print subsequently.

圖5係顯示範例4之劑量形式在pH 6.8磷酸鹽緩衝液之活性成分之釋放。 Figure 5 is a graph showing the release of the active ingredient of the dosage form of Example 4 in a pH 6.8 phosphate buffer.

範例5 Example 5 托特羅定ER顆粒Tolterodine ER granules

簡易製造步驟：Easy manufacturing steps:

於流動床處理機製備托特羅定ER顆粒(伍斯特塗佈法)。 Tolterodine ER granules (Worst coating method) were prepared in a fluid bed processor.

該ER顆粒之不同組分/製備步驟為： The different components/preparation steps of the ER particles are:

a.惰性核心1：選取150-180μm大小範圍的糖球(Pharm-a-spheres USP/NF,EP)用於封合塗佈、藥物分層及ER塗佈。 a. Inert core 1: Sugar spheres (Pharm-a-spheres USP/NF, EP) in the 150-180 μm size range were selected for seal coating, drug layering and ER coating.

b.封合塗層2：將稀釋至15% w/w濃度之蘇利釋 (Colorcon)用於該第一水不溶性層。將蘇利釋分散液噴灑在糖球上以取得30%w/w之增重。 b. Sealing Coating 2: Colorcon diluted to a concentration of 15% w/w was used for the first water insoluble layer. The sulixide dispersion was sprayed onto the sugar spheres to achieve a 30% w/w weight gain.

c.藥物層3：將藥物-黏合劑之水溶液噴灑在該經封合塗佈之糖球上以達到~46% w/w之目標增重。托特羅定酒石酸鹽：HPMC 5cps之比例為5：1。 c. Drug Layer 3: An aqueous solution of the drug-binder is sprayed onto the sealed coated sugar sphere to achieve a target weight gain of ~46% w/w. Tolterodine tartrate: HPMC 5cps ratio of 5:1.

d.延釋塗層5：此層為蘇利釋+HPMC 5 cps之結合。 將~15% w/w的蘇利釋+HPMC 5 cps(蘇利釋：HPMC 5 cps之比例：84：16)水性分散液噴灑在該經藥物分層之顆粒上以取得100% w/w之增重。 d. Extended Release Coating 5: This layer is a combination of Sullixide + HPMC 5 cps. Spraying ~15% w/w of sulide + HPMC 5 cps (Sullip: HPMC 5 cps ratio: 84:16) aqueous dispersion onto the drug-stratified particles to obtain 100% w/w Weight gain.

e.托特羅定ER顆粒之固化：托特羅定ER顆粒於70℃下固化3小時。 e. Curing of tolterodine ER pellets : Tolterodine ER pellets were cured at 70 ° C for 3 hours.

冷凍乾燥物組成：Freeze-dried composition:

冷凍乾燥物之簡易製造步驟：Easy manufacturing steps for freeze-dried products:

1.將所有的賦形劑溶於純水中。以純水調整最終體積並利用5% w/v檸檬酸溶液將pH值調整至pH 4.5。 1. Dissolve all excipients in pure water. The final volume was adjusted with pure water and the pH was adjusted to pH 4.5 using a 5% w/v citric acid solution.

2.將精確量的托特羅定ER顆粒裝填至預製之泡殼空 腔。 2. Loading a precise amount of tolterodine ER granules into a prefabricated blister Cavity.

3.將去氨加壓素分散液裝填至含有托特羅定ER顆粒之泡殼空腔。 3. The desmopressin dispersion is filled into a blister cavity containing tolterodine ER particles.

4.在液態氮通道中冷凍該經裝填之泡殼。 4. Freeze the filled bulb in a liquid nitrogen channel.

5.將泡殼維持在冷凍溫度之下直到整批被冷凍。 5. Maintain the bulb below the freezing temperature until the entire batch is frozen.

6.將經冷凍之泡殼填入冷凍乾燥機以進行冷凍乾燥。 6. The frozen blister is filled into a freeze dryer for lyophilization.

7.藉由壓力上升試驗偵測乾燥終點。 7. The dry end point is detected by a pressure rise test.

8.從該冷凍乾燥機卸載經乾燥之泡殼。 8. Unload the dried bulb from the freeze dryer.

9.將泡殼密封及隨後印刷。 9. Seal the bulb and print it subsequently.

圖6係顯示範例5之劑量形式在pH 6.8磷酸鹽緩衝液之活性成分之釋放。 Figure 6 is a graph showing the release of the active ingredient of the dosage form of Example 5 in a pH 6.8 phosphate buffer.

範例6 Example 6 托特羅定ER顆粒Tolterodine ER granules

簡易製造步驟：Easy manufacturing steps:

於流動床處理機製備托特羅定ER顆粒(伍斯特塗佈法)。 Tolterodine ER granules (Worst coating method) were prepared in a fluid bed processor.

ER顆粒之不同組分/製備步驟為： The different components/preparation steps of the ER particles are:

a.惰性核心1：選取106-125μm大小範圍的糖球(Pharm-a-spheres USP/NF,EP)用於封合塗佈、藥物分層及ER塗佈。 a. Inert core 1: Sugar spheres (Pharm-a-spheres USP/NF, EP) in the size range of 106-125 μm were selected for seal coating, drug layering and ER coating.

b.封合塗層2：將稀釋至15% w/w濃度之蘇利釋(Colorcon)用於該第一水不溶性層。將蘇利釋分散液噴灑在糖球上以取得30%w/w之增重。 b. Sealing Coating 2: Colorcon diluted to a concentration of 15% w/w was used for the first water insoluble layer. The sulixide dispersion was sprayed onto the sugar spheres to achieve a 30% w/w weight gain.

c.藥物層3：將藥物與黏合劑之水溶液噴灑在該經封合塗佈之糖球上以達到~46% w/w之目標增重。托特羅定酒石酸鹽：HPMC 5cps之比例為5：1。 c. Drug Layer 3: An aqueous solution of the drug and binder is sprayed onto the sealed coated sugar sphere to achieve a target weight gain of ~46% w/w. Tolterodine tartrate: HPMC 5cps ratio of 5:1.

d.延釋塗層5：此層為蘇利釋+HPMC 5 cps之結合。將~15% w/w的蘇利釋+HPMC 5 cps(蘇利釋：HPMC 5 cps之比例：84：16)水性分散液噴灑在該經藥物分層之顆粒上以取得120% w/w之增重。 d. Extended Release Coating 5: This layer is a combination of Sullixide + HPMC 5 cps. Spraying ~15% w/w of Sulilix + HPMC 5 cps (Sullipide: HPMC 5 cps ratio: 84:16) aqueous dispersion on the drug-stratified particles to obtain 120% w/w Weight gain.

e.托特羅定ER顆粒之固化：托特羅定ER顆粒於70℃下固化3小時。 e. Curing of tolterodine ER pellets : Tolterodine ER pellets were cured at 70 ° C for 3 hours.

f.塗層6：此層為蘇利釋+HPMC 5 cps+尤特奇L100之結合。將~15% w/w的蘇利釋：尤特奇L100：HPMC 5cps 82：10：8水性分散液噴灑在該托特羅定ER顆粒上以取得60% w/w之增重。 f. Coating 6: This layer is a combination of Sullixide + HPMC 5 cps + Eudragit L100. A ~15% w/w Sulliber: Eudragit L100:HPMC 5cps 82:10:8 aqueous dispersion was sprayed onto the tolterodine ER granules to achieve a 60% w/w weight gain.

g.托特羅定顆粒之固化：經塗佈之顆粒於70℃下固化3小時。 g. Curing of tolterodine particles: The coated granules were cured at 70 ° C for 3 hours.

冷凍乾燥物組成：Freeze-dried composition:

冷凍乾燥物之簡易製造步驟：Easy manufacturing steps for freeze-dried products:

1.將所有的賦形劑溶於純水中以產生基質組成物。以純水調整最終體積並利用5% w/v檸檬酸溶液將pH值調整至pH 4.5。 1. Dissolve all excipients in pure water to produce a matrix composition. The final volume was adjusted with pure water and the pH was adjusted to pH 4.5 using a 5% w/v citric acid solution.

2.將精確量的托特羅定顆粒裝填至預製之泡殼空腔。 2. Fill a pre-made blister cavity with a precise amount of tolterodine particles.

3.將步驟1之基質溶液裝填至含有托特羅定顆粒之泡殼空腔。 3. The substrate solution of step 1 is loaded into a blister cavity containing tolterodine particles.

4.在液態氮通道中冷凍該經裝填之泡殼。 4. Freeze the filled bulb in a liquid nitrogen channel.

5.將泡殼維持在冷凍溫度之下直到整批被冷凍。 5. Maintain the bulb below the freezing temperature until the entire batch is frozen.

6.將經冷凍之泡殼填入冷凍乾燥機以進行冷凍乾燥。 6. The frozen blister is filled into a freeze dryer for lyophilization.

7.藉由壓力上升試驗偵測乾燥終點。 7. The dry end point is detected by a pressure rise test.

8.從該冷凍乾燥機卸載經乾燥之泡殼。 8. Unload the dried bulb from the freeze dryer.

9.將泡殼密封及隨後印刷。 9. Seal the bulb and print it subsequently.

圖7係顯示托特羅定ER顆粒及範例6之冷凍乾燥物，及用於比較之得舒妥，在pH 6.8磷酸鹽緩衝液之托特羅定藥物釋放(溶解曲線)。 Figure 7 shows tolterodine ER particles and the lyophilized product of Example 6, and the drug release (dissolution curve) of tolterodine in phosphate buffer at pH 6.8 for comparison.

範例7 Example 7 托特羅定ER顆粒Tolterodine ER granules

簡易製造步驟：Easy manufacturing steps:

於流動床處理機製備托特羅定ER顆粒(伍斯特塗佈法)。 Tolterodine ER granules (Worst coating method) were prepared in a fluid bed processor.

ER顆粒之不同組分/製備步驟為： The different components/preparation steps of the ER particles are:

a.惰性核心1：選取150-200μm大小範圍的微結晶纖維素球(Cellets 175)用於藥物分層及ER塗佈。 a. Inert core 1: Microcrystalline cellulose spheres (Cellets 175) ranging in size from 150 to 200 μm were selected for drug delamination and ER coating.

b.藥物層3：將藥物與溶於黏合劑溶液之滑石的水性分散液噴灑在核心上以達到~27% w/w之目標增重。托特羅定酒石酸鹽：HPMC 5cps之比例為5：1。 b. Drug Layer 3: An aqueous dispersion of the drug and talc dissolved in the binder solution was sprayed onto the core to achieve a target weight gain of ~27% w/w. Tolterodine tartrate: HPMC 5cps ratio of 5:1.

c.延釋塗層5：此層為尤特奇NE 30D、HPMC 5 cps及滑石之結合。將尤特奇NE 30D、HPMC 5 cps及滑石的水性分散液噴灑在經藥物分層之顆粒上以取得~20% w/w之增重。 c. Extended release coating 5: This layer is a combination of Eudragit NE 30D, HPMC 5 cps and talc. An aqueous dispersion of Eudragit NE 30D, HPMC 5 cps and talc was sprayed onto the drug-stratified granules to achieve a weight gain of ~20% w/w.

d.托特羅定ER顆粒之固化：托特羅定ER顆粒於40℃下固化24小時。 d. Curing of tolterodine ER granules : Tolterodine ER granules were cured at 40 ° C for 24 hours.

冷凍乾燥物組成：Freeze-dried composition:

冷凍乾燥物之簡易製造步驟：Easy manufacturing steps for freeze-dried products:

1.將所有的賦形劑溶於純水中。以純水調整最終體積並利用5% w/v檸檬酸溶液將pH值調整至pH 4.5。 1. Dissolve all excipients in pure water. The final volume was adjusted with pure water and the pH was adjusted to pH 4.5 using a 5% w/v citric acid solution.

2.將精確量的托特羅定ER顆粒裝填至預製之泡殼空 腔。 2. Loading a precise amount of tolterodine ER granules into a prefabricated blister Cavity.

3.將步驟1之基質溶液裝填至含有托特羅定ER顆粒之泡殼空腔。 3. The substrate solution of step 1 is loaded into a blister cavity containing tolterodine ER particles.

4.在液態氮通道中冷凍該經裝填之泡殼。 4. Freeze the filled bulb in a liquid nitrogen channel.

5.將泡殼維持在冷凍溫度之下直到整批被冷凍。 5. Maintain the bulb below the freezing temperature until the entire batch is frozen.

6.將經冷凍之泡殼填入冷凍乾燥機以進行冷凍乾燥。 6. The frozen blister is filled into a freeze dryer for lyophilization.

7.藉由壓力上升試驗偵測冷凍乾燥終點。 7. The freeze-drying endpoint was detected by a pressure rise test.

8.從該冷凍乾燥機卸載經乾燥之泡殼。 8. Unload the dried bulb from the freeze dryer.

9.將泡殼密封及隨後印刷。 9. Seal the bulb and print it subsequently.

圖8係顯示托特羅定ER顆粒及範例7之冷凍乾燥物，及用於比較之得舒妥，在pH 6.8磷酸鹽緩衝液之托特羅定藥物釋放(溶解曲線)。 Figure 8 shows tolterodine ER particles and the lyophilized product of Example 7, and the drug release (dissolution curve) of tolterodine in phosphate buffer at pH 6.8 for comparison.

範例8 Example 8 托特羅定ER顆粒Tolterodine ER granules

簡易製造步驟：Easy manufacturing steps:

於流動床處理機製備托特羅定顆粒(伍斯特塗佈法)。 Tolterodine granules (Worst Coating) were prepared in a fluid bed processor.

該顆粒之不同組分/製備步驟為： The different components/preparation steps of the granules are:

a.惰性核心1：選取150-200μm大小範圍的微結晶纖維素球(Cellets 175)用於藥物分層及ER塗佈。 a. Inert core 1: Microcrystalline cellulose spheres (Cellets 175) ranging in size from 150 to 200 μm were selected for drug delamination and ER coating.

b.藥物層3：將藥物與溶於黏合劑溶液之滑石的水性分散液噴灑在核心上以達到~27% w/w之目標增重。托特羅定酒石酸鹽：HPMC 5cps之比例為5：1。 b. Drug Layer 3: An aqueous dispersion of the drug and talc dissolved in the binder solution was sprayed onto the core to achieve a target weight gain of ~27% w/w. Tolterodine tartrate: HPMC 5cps ratio of 5:1.

c.延釋塗層5：此層為尤特奇NE 30D、HPMC 5 cps及滑石之結合。將尤特奇NE 30D、HPMC 5 cps及滑石的水性分散液噴灑在經藥物分層之顆粒上以取得~20% w/w之增重。 c. Extended release coating 5: This layer is a combination of Eudragit NE 30D, HPMC 5 cps and talc. An aqueous dispersion of Eudragit NE 30D, HPMC 5 cps and talc was sprayed onto the drug-stratified granules to achieve a weight gain of ~20% w/w.

d.托特羅定ER顆粒之固化：托特羅定ER顆粒於40℃下固化24小時。 d. Curing of tolterodine ER granules : Tolterodine ER granules were cured at 40 ° C for 24 hours.

e.塗層6：此層為尤特奇L 30D-55、滑石及檸檬酸三乙酯之結合。The aqueous dispersion of將尤特奇L 30D-55、滑石及檸檬酸三乙酯水性分散液噴灑在該經延釋塗佈之顆粒上以取得~20% w/w之增重。 e. Coating 6: This layer is a combination of Eudragit L 30D-55, talc and triethyl citrate. The aqueous dispersion of Eudragit L 30D-55, talc and triethyl citrate was sprayed onto the extended release coated granules to achieve a weight gain of ~20% w/w.

f.顆粒之固化：托特羅定塗佈顆粒於40℃下固化2小時。 f. Curing of the granules: Tolterodine coated granules were cured at 40 ° C for 2 hours.

冷凍乾燥物組成：Freeze-dried composition:

冷凍乾燥物之簡易製造步驟：Easy manufacturing steps for freeze-dried products:

1.將所有的賦形劑溶於純水中。以純水調整最終體積並利用5% w/v檸檬酸溶液將pH值調整至pH 4.5。 1. Dissolve all excipients in pure water. The final volume was adjusted with pure water and the pH was adjusted to pH 4.5 using a 5% w/v citric acid solution.

2.將精確量的托特羅定ER顆粒裝填至預製之泡殼空腔。 2. Fill a pre-made blister cavity with a precise amount of tolterodine ER granules.

3.將步驟1之基質溶液裝填至含有托特羅定ER顆粒之泡殼空腔。 3. The substrate solution of step 1 is loaded into a blister cavity containing tolterodine ER particles.

4.在液態氮通道中冷凍該經裝填之泡殼。 4. Freeze the filled bulb in a liquid nitrogen channel.

5.將泡殼維持在冷凍溫度之下直到整批被冷凍。 5. Maintain the bulb below the freezing temperature until the entire batch is frozen.

6.將經冷凍之泡殼填入冷凍乾燥機以進行冷凍乾燥。 6. The frozen blister is filled into a freeze dryer for lyophilization.

7.藉由壓力上升試驗偵測冷凍乾燥終點。 7. The freeze-drying endpoint was detected by a pressure rise test.

8.從該冷凍乾燥機卸載經乾燥之泡殼。 8. Unload the dried bulb from the freeze dryer.

9.將泡殼密封及隨後印刷。 9. Seal the bulb and print it subsequently.

圖9係顯示托特羅定ER顆粒及範例8之冷凍乾燥物，及用於比較之得舒妥，在pH 6.8磷酸鹽緩衝液之托特羅定藥物釋放(溶解曲線)。 Figure 9 shows tolterodine ER particles and the lyophilized product of Example 8, and the drug release (dissolution curve) of tolterodine in phosphate buffer at pH 6.8 for comparison.

範例9 Example 9 托特羅定ER顆粒Tolterodine ER granules

簡易製造步驟：Easy manufacturing steps:

於流動床處理機製備托特羅定ER顆粒(伍斯特塗佈法)。 Tolterodine ER granules (Worst coating method) were prepared in a fluid bed processor.

該ER顆粒之不同組分/製備步驟為： The different components/preparation steps of the ER particles are:

a.惰性核心1：選取150-180μm大小範圍的糖球 (Pharm-a-spheres USP/NF,EP)用於封合塗佈、藥物分層、屏障塗佈、ER塗佈及外部塗佈。 a. Inert core 1: Sugar spheres (Pharm-a-spheres USP/NF, EP) ranging in size from 150-180 μm were selected for seal coating, drug delamination, barrier coating, ER coating and external coating.

b.封合塗層2：將稀釋至15% w/w濃度之蘇利釋(Colorcon)用於該第一水不溶性層。將蘇利釋分散液噴灑在糖球上以取得30%w/w之增重。 b. Sealing Coating 2: Colorcon diluted to a concentration of 15% w/w was used for the first water insoluble layer. The sulixide dispersion was sprayed onto the sugar spheres to achieve a 30% w/w weight gain.

c.藥物層3：將藥物-黏合劑之水溶液噴灑在該經封合塗佈之糖球上以達到~46% w/w之目標增重。托特羅定酒石酸鹽：HPMC 5cps之比例為5：1。 c. Drug Layer 3: An aqueous solution of the drug-binder is sprayed onto the sealed coated sugar sphere to achieve a target weight gain of ~46% w/w. Tolterodine tartrate: HPMC 5cps ratio of 5:1.

d.外部(屏障)封合塗層4：將HPMC 5 cps(5% w/v)之水溶液噴灑在該經藥物分層及封合塗佈之糖球上以達到~10% w/w之目標增重。 d. External (barrier) sealing coating 4: An HPMC 5 cps (5% w/v) aqueous solution was sprayed onto the drug layered and sealed coated sugar spheres to achieve ~10% w/w Target weight gain.

e.延釋塗層5：此層為尤特奇NE 30D+HPMC 5 cps+滑石之結合。將~20% w/w的尤特奇NE30D+HPMC 5 cps+滑石(尤特奇NE30D：HPMC 5 cps之比例為94.34：5.66，及滑石之含量為聚合物的43.1%)水性分散液噴灑在該屏障分層顆粒上以取得40% w/w之增重。 e. Extended Release Coating 5: This layer is a combination of Eudragit NE 30D+HPMC 5 cps + talc. Spraying ~20% w/w of Eudragit NE30D+HPMC 5 cps+ talc (Euters NE30D: HPMC 5 cps ratio 94.34: 5.66, and talc content 43.1% of polymer) aqueous dispersion The barrier layered the particles to achieve a 40% w/w weight gain.

f.外部塗層6：此層為尤特奇NE30D+滑石之結合。將~20% w/w的尤特奇NE30D+滑石(尤特奇NE30D：滑石之比例為50：50)水性分散液噴灑在該ER分層顆粒上以取得50% w/w之增重。 f. External coating 6: This layer is a combination of Eudragit NE30D + talc. An aqueous dispersion of ~20% w/w of Eudragit NE30D+ talc (Euters NE30D: talc ratio 50:50) was sprayed onto the ER layered granules to achieve a 50% w/w weight gain.

g.托特羅定ER顆粒之固化：托特羅定ER顆粒於40℃下固化12小時。 g. Curing of tolterodine ER granules : Tolterodine ER granules were cured at 40 ° C for 12 hours.

冷凍乾燥物組成：Freeze-dried composition:

冷凍乾燥物之簡易製造步驟：Easy manufacturing steps for freeze-dried products:

1.將所有的賦形劑溶於或分散於純水中。以純水調整最終體積並利用5% w/v檸檬酸溶液將pH值調整至pH 4.5。 1. Dissolve or disperse all excipients in pure water. The final volume was adjusted with pure water and the pH was adjusted to pH 4.5 using a 5% w/v citric acid solution.

2.將精確量的托特羅定ER顆粒裝填至預製之泡殼空腔。 2. Fill a pre-made blister cavity with a precise amount of tolterodine ER granules.

3.將去氨加壓素分散液裝填至含有托特羅定ER顆粒之泡殼空腔。 3. The desmopressin dispersion is filled into a blister cavity containing tolterodine ER particles.

4.在液態氮通道中冷凍該經裝填之泡殼。 4. Freeze the filled bulb in a liquid nitrogen channel.

5.將泡殼維持在冷凍溫度之下直到整批被冷凍。 5. Maintain the bulb below the freezing temperature until the entire batch is frozen.

6.將經冷凍之泡殼填入冷凍乾燥機以進行冷凍乾燥。 6. The frozen blister is filled into a freeze dryer for lyophilization.

7.藉由壓力上升試驗偵測乾燥終點。 7. The dry end point is detected by a pressure rise test.

8.從該冷凍乾燥機卸載經乾燥之泡殼。 8. Unload the dried bulb from the freeze dryer.

9.將泡殼密封及隨後印刷。 9. Seal the bulb and print it subsequently.

圖10係顯示範例9之冷凍乾燥物劑量形式在pH 6.8磷酸鹽緩衝液之活性成分之釋放。 Figure 10 is a graph showing the release of the active ingredient of the lyophilized dosage form of Example 9 in a pH 6.8 phosphate buffer.

範例10 Example 10 冷凍乾燥物組成：Freeze-dried composition:

冷凍乾燥物之簡易製造步驟：Easy manufacturing steps for freeze-dried products:

1.將所有的賦形劑溶於純水中。以純水調整最終體積並利用5% w/v檸檬酸溶液將pH值調整至pH 4.5。 1. Dissolve all excipients in pure water. The final volume was adjusted with pure water and the pH was adjusted to pH 4.5 using a 5% w/v citric acid solution.

2.將精確量的托特羅定ER顆粒裝填至預製之泡殼空腔。 2. Fill a pre-made blister cavity with a precise amount of tolterodine ER granules.

3.將去氨加壓素分散液裝填至含有托特羅定ER顆粒之泡殼空腔。 3. The desmopressin dispersion is filled into a blister cavity containing tolterodine ER particles.

4.在液態氮通道中冷凍該經裝填之泡殼。 4. Freeze the filled bulb in a liquid nitrogen channel.

5.將泡殼維持在冷凍溫度之下直到整批被冷凍。 5. Maintain the bulb below the freezing temperature until the entire batch is frozen.

6.將經冷凍之泡殼填入冷凍乾燥機以進行冷凍乾燥。 6. The frozen blister is filled into a freeze dryer for lyophilization.

7.藉由壓力上升試驗偵測乾燥終點。 7. The dry end point is detected by a pressure rise test.

8.從該冷凍乾燥機卸載經乾燥之泡殼。 8. Unload the dried bulb from the freeze dryer.

9.將泡殼密封及隨後印刷。 9. Seal the bulb and print it subsequently.

圖11係顯示範例10之冷凍乾燥物劑量形式，在pH 6.8磷酸鹽緩衝液之活性成分之釋放。 Figure 11 is a graph showing the release of the active ingredient of the lyophilized product dosage form of Example 10 in phosphate buffer at pH 6.8.

範例11 Example 11 冷凍乾燥物組成：Freeze-dried composition:

冷凍乾燥物之簡易製造步驟：Easy manufacturing steps for freeze-dried products:

1.將所有的賦形劑溶於純水中。以純水調整最終體積並利用5% w/v檸檬酸溶液將pH值調整至pH 4.5。 1. Dissolve all excipients in pure water. The final volume was adjusted with pure water and the pH was adjusted to pH 4.5 using a 5% w/v citric acid solution.

2.將精確量的托特羅定ER顆粒裝填至預製之泡殼空腔。 2. Fill a pre-made blister cavity with a precise amount of tolterodine ER granules.

3.將去氨加壓素分散液裝填至含有托特羅定ER顆粒之泡殼空腔。 3. The desmopressin dispersion is filled into a blister cavity containing tolterodine ER particles.

4.在液態氮通道中冷凍該經裝填之泡殼。 4. Freeze the filled bulb in a liquid nitrogen channel.

5.將泡殼維持在冷凍溫度之下直到整批被冷凍。 5. Maintain the bulb below the freezing temperature until the entire batch is frozen.

6.將經冷凍之泡殼填入冷凍乾燥機以進行冷凍乾燥。 6. The frozen blister is filled into a freeze dryer for lyophilization.

7.藉由壓力上升試驗偵測乾燥終點。 7. The dry end point is detected by a pressure rise test.

8.從該冷凍乾燥機卸載經乾燥之泡殼。 8. Unload the dried bulb from the freeze dryer.

9.將泡殼密封及隨後印刷。 9. Seal the bulb and print it subsequently.

圖12係顯示範例11之冷凍乾燥物劑量形式在pH 6.8磷酸鹽緩衝液之活性成分之釋放。 Figure 12 is a graph showing the release of the active ingredient of the lyophilized dosage form of Example 11 in a pH 6.8 phosphate buffer.

範例12 Example 12 冷凍乾燥物組成：Freeze-dried composition:

冷凍乾燥物之簡易製造步驟：Easy manufacturing steps for freeze-dried products:

1.將所有的賦形劑溶於純水中。以純水調整最終體積並利用5% w/v檸檬酸溶液將pH值調整至pH 4.5。 1. Dissolve all excipients in pure water. The final volume was adjusted with pure water and the pH was adjusted to pH 4.5 using a 5% w/v citric acid solution.

2.將精確量的托特羅定ER顆粒裝填至預製之泡殼空腔。 2. Fill a pre-made blister cavity with a precise amount of tolterodine ER granules.

3.將去氨加壓素分散液裝填至含有托特羅定ER顆粒之泡殼空腔。 3. The desmopressin dispersion is filled into a blister cavity containing tolterodine ER particles.

4.在液態氮通道中冷凍該經裝填之泡殼。 4. Freeze the filled bulb in a liquid nitrogen channel.

5.將泡殼維持在冷凍溫度之下直到整批被冷凍。 5. Maintain the bulb below the freezing temperature until the entire batch is frozen.

6.將經冷凍之泡殼填入冷凍乾燥機以進行冷凍乾燥。 6. The frozen blister is filled into a freeze dryer for lyophilization.

7.藉由壓力上升試驗偵測乾燥終點。 7. The dry end point is detected by a pressure rise test.

8.從該冷凍乾燥機卸載經乾燥之泡殼。 8. Unload the dried bulb from the freeze dryer.

9.將泡殼密封及隨後印刷。 9. Seal the bulb and print it subsequently.

圖13係顯示範例12之冷凍乾燥物劑量形式在pH 6.8磷酸鹽緩衝液之活性成分之釋放。 Figure 13 is a graph showing the release of the active ingredient of the lyophilized dosage form of Example 12 in a pH 6.8 phosphate buffer.

範例13 Example 13 托特羅定ER顆粒Tolterodine ER granules

簡易製造步驟：Easy manufacturing steps:

於流動床處理機製備托特羅定ER顆粒(伍斯特塗佈法)。 Tolterodine ER granules (Worst coating method) were prepared in a fluid bed processor.

ER顆粒之不同組分/製備步驟為： The different components/preparation steps of the ER particles are:

1.惰性核心1：選取150-200μm大小範圍的MCC丸粒(Cellets 175)作為藥物分層之起始材料及隨後進行ER塗佈。 1. Inert core 1: MCC pellets (Cellets 175) in the range of 150-200 μm were selected as starting materials for drug delamination and subsequently subjected to ER coating.

2.藥物層3：將藥物-黏合劑之水性分散液噴灑在該MCC丸粒上以達到~26.58% w/w之目標增重。托特羅定酒石酸鹽：HPMC 5cps之比例為5：1。 2. Drug Layer 3: An aqueous dispersion of the drug-binder was sprayed onto the MCC pellet to achieve a target weight gain of ~26.58% w/w. Tolterodine tartrate: HPMC 5cps ratio of 5:1.

3.延釋塗層5：此層為尤特奇NE30D+HPMC 5 cps+滑石之結合。將~20% w/w的尤特奇NE30D+HPMC 5 cps+滑石(尤特奇NE30D：HPMC 5 cps之比例為94.34：5.66及滑石之含量為聚合物的43.1%)水性分散液噴灑在該經藥物分層之顆粒上以取得20% w/w之增重。 3. Extended Release Coating 5: This layer is a combination of Eudragit NE30D+HPMC 5 cps + talc. Spraying ~20% w/w of Eudragit NE30D+HPMC 5 cps+ talc (Utchi NE30D: HPMC 5 cps ratio 94.34: 5.66 and talc content 43.1% of polymer) aqueous dispersion The stratified particles were dosed to achieve a 20% w/w weight gain.

4.外部塗層6：此層為尤特奇L30 D55+TEC+滑石之結合。將~20% w/w的尤特奇L30 D55+TEC+滑石(尤特奇L30 D55：滑石之比例為1：0.5，而TEC為實際尤特奇聚合物含量的10%)水性分散液噴灑在該ER顆粒上以取得20% w/w之增重。 4. External coating 6: This layer is a combination of Eudragit L30 D55 + TEC + talc. Spraying ~20% w/w of Eudragit L30 D55+TEC+ talc (Educic L30 D55: talc ratio 1:0.5, while TEC is 10% of actual Eudragit polymer content) The ER particles were subjected to a weight gain of 20% w/w.

5.托特羅定ER顆粒之固化：在以2%滑石作為外相(external phase)進行摻合之後，托特羅定ER顆粒於40℃下固化24小時。 5. Curing of tolterodine ER granules: Tolterodine ER granules were cured at 40 ° C for 24 hours after blending with 2% talc as the external phase.

冷凍乾燥物組成：Freeze-dried composition:

冷凍乾燥物之簡易製造步驟：Easy manufacturing steps for freeze-dried products:

1.將所有的賦形劑溶於純水中。以純水調整最終體積並利用5% w/v檸檬酸溶液將pH值調整至pH 4.5。 1. Dissolve all excipients in pure water. The final volume was adjusted with pure water and the pH was adjusted to pH 4.5 using a 5% w/v citric acid solution.

2.將精確量的托特羅定ER顆粒裝填至預製之泡殼空腔。 2. Fill a pre-made blister cavity with a precise amount of tolterodine ER granules.

3.將去氨加壓素分散液裝填至含有托特羅定ER顆粒之泡殼空腔。 3. The desmopressin dispersion is filled into a blister cavity containing tolterodine ER particles.

4.在液態氮通道中冷凍該經裝填之泡殼。 4. Freeze the filled bulb in a liquid nitrogen channel.

5.將泡殼維持在冷凍溫度之下直到整批被冷凍。 5. Maintain the bulb below the freezing temperature until the entire batch is frozen.

6.將經冷凍之泡殼填入冷凍乾燥機以進行冷凍乾燥。 6. The frozen blister is filled into a freeze dryer for lyophilization.

7.藉由壓力上升試驗偵測乾燥終點。 7. The dry end point is detected by a pressure rise test.

8.從該冷凍乾燥機卸載經乾燥之泡殼。 8. Unload the dried bulb from the freeze dryer.

9.將泡殼密封及隨後印刷。 9. Seal the bulb and print it subsequently.

圖14係顯示範例13之冷凍乾燥物劑量形式在pH 6.8磷酸鹽緩衝液之活性成分之釋放。 Figure 14 is a graph showing the release of the lyophilizate dosage form of Example 13 in the pH 6.8 phosphate buffer.

範例14 Example 14 托特羅定ER顆粒Tolterodine ER granules

簡易製造步驟：Easy manufacturing steps:

於流動床處理機製備托特羅定ER顆粒(伍斯特塗佈法)。 Tolterodine ER granules (Worst coating method) were prepared in a fluid bed processor.

ER顆粒之不同組分/製備步驟為： The different components/preparation steps of the ER particles are:

1.惰性核心1：選取150-200μm大小範圍的MCC丸粒(Cellets 175)作為藥物分層之起始材料及隨後進行ER塗佈。 1. Inert core 1: MCC pellets (Cellets 175) in the range of 150-200 μm were selected as starting materials for drug delamination and subsequently subjected to ER coating.

2.藥物層3：將藥物-黏合劑之水性分散液噴灑在該MCC丸粒上以達到~26.58% w/w之目標增重。托特羅定酒石酸鹽：HPMC 5cps之比例為5：1。 2. Drug Layer 3: An aqueous dispersion of the drug-binder was sprayed onto the MCC pellet to achieve a target weight gain of ~26.58% w/w. Tolterodine tartrate: HPMC 5cps ratio of 5:1.

3.延釋塗層5：此層為尤特奇NE30D+HPMC 5 cps+滑石之結合。將~20% w/w的尤特奇NE30D+HPMC 5 cps+滑石(尤特奇NE30D：HPMC 5 cps之比例為94.34：5.66及滑石之含量為聚合物的43.1%)水性分散液噴灑在該經藥物分層之顆粒上以取得20% w/w之增重。 3. Extended Release Coating 5: This layer is a combination of Eudragit NE30D+HPMC 5 cps + talc. Spraying ~20% w/w of Eudragit NE30D+HPMC 5 cps+ talc (Utchi NE30D: HPMC 5 cps ratio 94.34: 5.66 and talc content 43.1% of polymer) aqueous dispersion The stratified particles were dosed to achieve a 20% w/w weight gain.

4.托特羅定ER顆粒之固化：在以2%滑石作為外相(external phase)進行摻合之後，托特羅定ER顆粒於40℃下固化24小時。 4. Curing of tolterodine ER granules: Tolterodine ER granules were cured at 40 ° C for 24 hours after blending with 2% talc as the external phase.

冷凍乾燥物組成：Freeze-dried composition:

冷凍乾燥物之簡易製造步驟：Easy manufacturing steps for freeze-dried products:

1.將所有的賦形劑溶於純水中。以純水調整最終體積並利用5% w/v檸檬酸溶液將pH值調整至pH 4.5。 1. Dissolve all excipients in pure water. The final volume was adjusted with pure water and the pH was adjusted to pH 4.5 using a 5% w/v citric acid solution.

2.將精確量的托特羅定ER顆粒裝填至預製之泡殼空腔。 2. Fill a pre-made blister cavity with a precise amount of tolterodine ER granules.

3.將去氨加壓素分散液裝填至含有托特羅定ER顆粒之泡殼空腔。 3. The desmopressin dispersion is filled into a blister cavity containing tolterodine ER particles.

4.在液態氮通道中冷凍該經裝填之泡殼。 4. Freeze the filled bulb in a liquid nitrogen channel.

5.將泡殼維持在冷凍溫度之下直到整批被冷凍。 5. Maintain the bulb below the freezing temperature until the entire batch is frozen.

6.將經冷凍之泡殼填入冷凍乾燥機以進行冷凍乾燥。 6. The frozen blister is filled into a freeze dryer for lyophilization.

7.藉由壓力上升試驗偵測乾燥終點。 7. The dry end point is detected by a pressure rise test.

8.從該冷凍乾燥機卸載經乾燥之泡殼。 8. Unload the dried bulb from the freeze dryer.

9.將泡殼密封及隨後印刷。 9. Seal the bulb and print it subsequently.

圖15係顯示範例14之冷凍乾燥物劑量形式在pH 6.8磷酸鹽緩衝液之活性成分之釋放。 Figure 15 is a graph showing the release of the lyophilizate dosage form of Example 14 in the pH 6.8 phosphate buffer.

Claims (40)

一種包含一開放式基質網狀物(open matrix network)之藥學組成物，該藥學組成物其包含一第一藥學活性成分；一或多種基質形成劑；以及包含一第二藥學活性成分之控制釋放珠粒。 A pharmaceutical composition comprising an open matrix network comprising a first pharmaceutically active ingredient; one or more matrix forming agents; and controlled release comprising a second pharmaceutically active ingredient Beads. 如請求項1之藥學組成物，其中該一或多種基質形成劑係選自於由左聚糖(levan)、菊糖(inulin)、聚三葡萄糖(pullulan)、HPMC、麥芽糊精(maltodextrin)、***膠(acacia)、海藻酸鈉(sodium alginate)及其組合物所組成之群組。 The pharmaceutical composition of claim 1, wherein the one or more matrix forming agents are selected from the group consisting of levan, inulin, pullulan, HPMC, maltodextrin ), a group of acacia, sodium alginate, and combinations thereof. 如請求項1或2之藥學組成物，其中該開放式基質網狀物更包含甘露糖醇、菌藻糖及/或棉子糖。 The pharmaceutical composition of claim 1 or 2, wherein the open matrix network further comprises mannitol, saccharin and/or raffinose. 如請求項1至3任一項之藥學組成物，其在30秒內溶解在標準水性介質中。 A pharmaceutical composition according to any one of claims 1 to 3 which is dissolved in a standard aqueous medium within 30 seconds. 如請求項4之藥學組成物，其在10秒內溶解在標準水性介質中。 The pharmaceutical composition of claim 4, which is dissolved in a standard aqueous medium within 10 seconds. 如請求項1至5任一項之藥學組成物，其中該第一藥學活性成分為醋酸去氨加壓素(desmopressin acetate)。 The pharmaceutical composition according to any one of claims 1 to 5, wherein the first pharmaceutically active ingredient is desmopressin acetate. 如請求項1至6任一項之藥學組成物，其中該控制釋放珠粒包含一水溶性、水不溶性或水可膨脹性惰性材料的核心(1)，其具有：(i)一位於該核心(1)上之任擇之具實質上水不溶性或實質上水溶性之聚合物之內部封合塗層(2)； (ii)一內部含藥層(3)，其覆蓋於該核心(1)或該內部封合塗層(2)，並含有該第二活性成分；以及(iii)一位於該內部含藥層(3)上之聚合物外部膜層(5)，其係有效用於自該內部含藥層(3)中控制釋放該第二活性成分。 The pharmaceutical composition according to any one of claims 1 to 6, wherein the controlled release bead comprises a core (1) of a water-soluble, water-insoluble or water-swellable inert material having: (i) one located in the core (1) an internal sealing coating (2) of a polymer which is substantially water-insoluble or substantially water-soluble; (ii) an inner drug-containing layer (3) covering the core (1) or the inner seal coating (2) and containing the second active ingredient; and (iii) one of the inner drug-containing layers (3) A polymeric outer film layer (5) effective for controlling the release of the second active ingredient from the inner drug-containing layer (3). 如請求項7之藥學組成物，其中該核心(1)為水溶性糖球。 The pharmaceutical composition of claim 7, wherein the core (1) is a water-soluble sugar sphere. 如請求項7之藥學組成物，其中該核心(1)為水可膨脹性微結晶纖維素核心。 The pharmaceutical composition of claim 7, wherein the core (1) is a water-swellable microcrystalline cellulose core. 如請求項7至9任一項之藥學組成物，其中該內部封合塗層(2)之量係構成該控制釋放珠粒之從約4至約15%(w/w)。 The pharmaceutical composition according to any one of claims 7 to 9, wherein the amount of the inner seal coating (2) is from about 4 to about 15% (w/w) of the controlled release beads. 如請求項7至10任一項之藥學組成物，其中該內部含藥層(3)之量係構成該控制釋放珠粒之從約5至約25%(w/w)。 The pharmaceutical composition of any one of claims 7 to 10, wherein the amount of the inner drug-containing layer (3) is from about 5 to about 25% (w/w) of the controlled release beads. 如請求項7至11任一項之藥學組成物，其中該外部膜層(5)之量係構成該控制釋放珠粒之從約25至約55%(w/w)。 The pharmaceutical composition of any one of claims 7 to 11, wherein the amount of the outer film layer (5) is from about 25 to about 55% (w/w) of the controlled release beads. 如請求項7至12任一項之藥學組成物，其中該外部膜層(5)係以一一具有pH-依賴型通透度之塗層的另一的聚合物層(6)所塗佈。 The pharmaceutical composition according to any one of claims 7 to 12, wherein the outer film layer (5) is coated with another polymer layer (6) having a coating having a pH-dependent permeability. . 如請求項7至13任一項之藥學組成物，其中該內部封合塗層(2)之實質上水不溶性聚合物包含乙基纖維素。 The pharmaceutical composition according to any one of claims 7 to 13, wherein the substantially water-insoluble polymer of the inner seal coating (2) comprises ethyl cellulose. 如請求項7至14任一項之藥學組成物，其中該內部含藥層(3)包含作為黏合劑之羥基丙基甲基纖維素。 The pharmaceutical composition according to any one of claims 7 to 14, wherein the inner drug-containing layer (3) comprises hydroxypropylmethylcellulose as a binder. 如請求項7至15任一項之藥學組成物，其中有效於控制釋放該第二活性成分的該外部膜層(5)，包含羥基丙基甲基纖維素與乙基纖維素的組合物。 The pharmaceutical composition according to any one of claims 7 to 15, wherein the outer film layer (5) effective for controlling the release of the second active ingredient comprises a composition of hydroxypropylmethylcellulose and ethylcellulose. 如請求項1至16任一項之藥學組成物，其中該第二活性成分為一抗毒蕈鹼化合物(antimuscarinic compound)。 The pharmaceutical composition according to any one of claims 1 to 16, wherein the second active ingredient is an antimuscarinic compound. 如請求項17之藥學組成物，其中該抗毒蕈鹼化合物係選自於托特羅定(tolterodine)、托特羅定之5-羥基甲基代謝物、托特羅定之(S)-鏡像異構物、托特羅定之該(S)-鏡像異構物之5-羥基甲基代謝物、托特羅定之外消旋物、其前藥形式，以及其藥理學上可接受鹽類。 The pharmaceutical composition according to claim 17, wherein the antimuscarinic compound is selected from the group consisting of tolterodine, tolterodine 5-hydroxymethyl metabolite, tolterodine (S)-mirror The construct, the 5-hydroxymethyl metabolite of the (S)-mirrible isomer of tolterodine, the racemate of tolterodine, its prodrug form, and its pharmacologically acceptable salts. 如請求項18之藥學組成物，其中該抗毒蕈鹼化合物為托特羅定或其藥理學上可接受鹽類。 The pharmaceutical composition of claim 18, wherein the antimuscarinic compound is tolterodine or a pharmacologically acceptable salt thereof. 如請求項19之藥學組成物，其中該抗毒蕈鹼化合物為托特羅定酒石酸鹽(tolterodine tartrate)。 The pharmaceutical composition of claim 19, wherein the antimuscarinic compound is tolterodine tartrate. 如請求項20之藥學組成物，其中該托特羅定酒石酸鹽在體外釋放的分率(fraction)在1小時後不超過約40%、在3小時後為從約35至約85%，及在7小時後不低於約65%。 The pharmaceutical composition of claim 20, wherein the fraction of the tolterodine tartrate released in vitro is no more than about 40% after 1 hour, and from about 35 to about 85% after 3 hours, and Not less than about 65% after 7 hours. 如請求項17至21任一項之藥學組成物，其用於膀胱過動症之治療。 A pharmaceutical composition according to any one of claims 17 to 21 for use in the treatment of overactive bladder. 如請求項17至21任一項之藥學組成物，其用於膀胱過動症伴隨夜尿症(nocturia)之治療。 A pharmaceutical composition according to any one of claims 17 to 21 for use in the treatment of overactive bladder with nocturia. 如請求項17至21任一項之藥學組成物，其用於女性膀胱過動症伴隨夜尿症之治療。 A pharmaceutical composition according to any one of claims 17 to 21 for use in the treatment of female overactive bladder with nocturia. 如請求項1至16任一項之藥學組成物，其中該第二活性 成分為選擇性α-阻斷劑。 The pharmaceutical composition according to any one of claims 1 to 16, wherein the second active The ingredient is a selective alpha-blocker. 如請求項25之藥學組成物，其中該選擇性α-阻斷劑為坦索羅辛(tamsulosin)、其前藥形式或其藥學上可接受鹽類。 The pharmaceutical composition of claim 25, wherein the selective alpha-blocker is tamsulosin, a prodrug thereof, or a pharmaceutically acceptable salt thereof. 如請求項1至26任一項之藥學組成物，其呈一口服藥劑形式。 The pharmaceutical composition according to any one of claims 1 to 26, which is in the form of an oral medicament. 如請求項27之藥學組成物，其適合於舌下投藥。 A pharmaceutical composition according to claim 27 which is suitable for sublingual administration. 如請求項1至28任一項之藥學組成物，其以下列步驟獲得：(i)於一溶劑中混合該控制釋放珠粒與含有該第一活性成分及該一或多種基質形成劑之液體製備物，以形成一混合物；(ii)從該混合物中昇華該溶劑。 The pharmaceutical composition according to any one of claims 1 to 28, which is obtained by the following steps: (i) mixing the controlled release beads with a liquid containing the first active ingredient and the one or more matrix forming agents in a solvent Preparing the product to form a mixture; (ii) sublimating the solvent from the mixture. 如請求項29之藥學組成物，其中該昇華係藉由冷凍乾燥該製備物來進行。 The pharmaceutical composition of claim 29, wherein the sublimation is carried out by freeze-drying the preparation. 一種用於製備藥學組成物之方法，其包括從一包含第一藥學活性成分、一或多種基質形成劑、含有第二藥學活性成分之控制釋放丸粒及一溶劑的液體製備物中，昇華該溶劑。 A method for preparing a pharmaceutical composition comprising sublimating from a liquid preparation comprising a first pharmaceutically active ingredient, one or more matrix forming agents, a controlled release pellet comprising a second pharmaceutically active ingredient, and a solvent Solvent. 如請求項31之方法，其中該昇華係藉由冷凍乾燥該液體製備物來進行。 The method of claim 31, wherein the sublimation is performed by freeze drying the liquid preparation. 如請求項31或32之方法，其中該溶劑為水。 The method of claim 31 or 32, wherein the solvent is water. 一種用於製備藥學組成物之方法，其包含下列步驟：(a)製備一包含第一活性成分、含有第二活性成分之控 制釋放珠粒、一或多種基質形成劑及一溶劑的混合物；(b)冷凍該溶液；(c)從該經冷凍之溶液中昇華該溶劑，其中因此獲得之藥學組成物在與標準水性介質接觸後，於30秒內崩解。 A method for preparing a pharmaceutical composition comprising the steps of: (a) preparing a control comprising a first active ingredient and containing a second active ingredient Preparing a mixture of beads, one or more matrix forming agents and a solvent; (b) freezing the solution; (c) sublimating the solvent from the frozen solution, wherein the pharmaceutical composition thus obtained is in a standard aqueous medium After contact, it disintegrates within 30 seconds. 如請求項33之方法，其中該組成物在與標準水性介質接觸後，於10秒內崩解。 The method of claim 33, wherein the composition disintegrates within 10 seconds after contact with a standard aqueous medium. 如請求項31至35任一項之方法，其中該組成物為如請求項1至28任一項之組成物。 The method of any one of claims 1 to 3, wherein the composition is a composition according to any one of claims 1 to 28. 一種用於治療有其需求個體之膀胱過動症、夜尿症或其結合病症之方法，其包含投予該個體一治療有效量之如請求項17至21任一項之組成物。 A method for treating overactive bladder, nocturia, or a combination thereof, in a subject in need thereof, comprising administering to the individual a therapeutically effective amount of a composition according to any one of claims 17 to 21. 如請求項37之方法，其中該個體為女性個體。 The method of claim 37, wherein the individual is a female individual. 一種用於治療有其需求個體之良性攝護腺肥大症(benign prostatic hyperplasia)之方法，其包含投予該個體一治療有效量之如請求項25至26之組成物。 A method for treating benign prostatic hyperplasia in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a composition as claimed in claims 25 to 26. 如請求項39之方法，其中該個體為男性個體。 The method of claim 39, wherein the individual is a male individual.
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PH12015501096A1 (en) 2015-07-27
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AU2013349682A1 (en) 2015-06-04
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