TW201542212A - Unit dosage form comprising emtricitabine, tenofovir, darunavir and ritonavir and a monolithic tablet comprising darunavir and ritonavir - Google Patents

Unit dosage form comprising emtricitabine, tenofovir, darunavir and ritonavir and a monolithic tablet comprising darunavir and ritonavir Download PDF

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TW201542212A
TW201542212A TW103129876A TW103129876A TW201542212A TW 201542212 A TW201542212 A TW 201542212A TW 103129876 A TW103129876 A TW 103129876A TW 103129876 A TW103129876 A TW 103129876A TW 201542212 A TW201542212 A TW 201542212A
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ritonavir
darunavir
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Nitzan Shahar
Elina Haronsky
Julia Hrakovsky
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Teva Pharma
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
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    • A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
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    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
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    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
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    • A61K9/00—Medicinal preparations characterised by special physical form
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    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • 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
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    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Abstract

The present invention relates to an oral unit dosage form comprising Emtricitabine, Tenofovir, Darunavir and Ritonavir and a monolithic tablet comprising Darunavir and Ritonavir and their use to treat HIV infection.

Description

包括恩曲他濱、泰諾福韋、地瑞那韋與利托那韋的單位劑量形式以及包括地瑞那韋與利托那韋的單體錠劑 Includes unit dosage forms of emtricitabine, tenofovir, darunavir and ritonavir, and monomeric lozenges including darunavir and ritonavir

本發明是關於一種包括恩曲他濱(emtricitabine)、泰諾福韋(tenofovir)、地瑞那韋(darunavir)與利托那韋(ritonavir)的口服單位劑量形式及包括地瑞那韋與利托那韋的單體錠劑以及其治療HIV感染之用途。本發明更關於製備含有上述醫藥活性成分之口服劑量形式之方法。 The present invention relates to an oral unit dosage form comprising emtricitabine, tenofovir, darunavir and ritonavir and comprising darunavir and elixi Tonavi's monomeric lozenges and their use in the treatment of HIV infection. The invention further relates to a method of preparing an oral dosage form containing the above-described pharmaceutically active ingredient.

泰諾福韋，化學名稱為({[(2R)-1-(6-胺基-9H-嘌呤-9-基)丙-2-基]氧基}甲基)膦酸，是核苷逆轉錄酶抑制劑(nucleoside reverse transcriptase inhibitor；NRTI)，其用於治療HIV-I之感染。泰諾福韋之合成、類似物、調配物及用途描述於不同公開案中，特別是包含美國專利第5,922,695號、第5,935,946號、第5,977,089 號以及第6,043,230號。 Tenofovir, chemical name ({[(2R)-1-(6-amino-9H-fluoren-9-yl)propan-2-yl]oxy}methyl)phosphonic acid, is a nucleoside inverse A nucleoside reverse transcriptase inhibitor (NRTI) for the treatment of HIV-I infection. The synthesis, analogs, formulations and uses of tenofovir are described in various publications, in particular, including U.S. Patent Nos. 5,922,695, 5,935,946, 5,977,089. No. 6,043,230.

包括泰諾福韋及另一非核苷逆轉錄酶抑制劑(non-nucleoside reverse transcriptase inhibitor；NNRTI)或蛋白酶抑制劑(protease inhibitor；PI)之組合的醫藥調配物描述於不同公開案中，特別是包含US 8,592,397、US 8,716,264以及US20140037732中。 Pharmaceutical formulations comprising tenofovir and another combination of non-nucleoside reverse transcriptase inhibitor (NNRTI) or protease inhibitor (PI) are described in various publications, in particular Contains US 8,592,397, US 8,716,264, and US20140037732.

反丁烯二酸泰諾福韋酯(tenofovir disoproxil fumarate；TDF)為泰諾福韋之前藥形式。TDF由吉利德科技公司(Gilead Sciences)以商標名韋瑞德®(VIREAD®)銷售。韋瑞德錠劑可以150mg、200mg、250mg以及300mg反丁烯二酸泰諾福韋酯之劑型購得，其分別等效於123mg、163mg、204mg以及245mg泰諾福韋酯。所述錠劑亦包含以下非活性成分：交聯羧甲纖維素鈉、單水合乳糖、硬脂酸鎂、微晶纖維素以及預膠凝化澱粉。 Tenofovir disoproxil fumarate (TDF) is a prodrug form of tenofovir. Gilead Sciences TDF by the company (Gilead Sciences) trademark Mingweiruide ® (VIREAD ®) sales. Verrex tablets are commercially available as 150 mg, 200 mg, 250 mg, and 300 mg of tenofovir disoproxil, which are equivalent to 123 mg, 163 mg, 204 mg, and 245 mg of tenofovir. The tablet also contains the following inactive ingredients: croscarmellose sodium, monohydrated lactose, magnesium stearate, microcrystalline cellulose, and pregelatinized starch.

泰諾福韋亦可以與恩曲他濱以固定劑量組合為商品名特魯瓦達®(TRUVADA®)之產品，已批准所述產品用於一天一次的給藥。每一錠特魯瓦達錠劑含有200mg恩曲他濱及300mg反丁烯二酸泰諾福韋酯(其等效於245mg泰諾福韋酯)作為活性成分。所述錠劑亦包含以下非活性成分：交聯羧甲纖維素鈉、單水合乳糖、硬脂酸鎂、微晶纖維素以及預膠凝化澱粉。特魯瓦達錠劑之總重量為1045mg，尺寸為19mm×8.5mm。 Tenofovir also be with emtricitabine fixed dose combination product名特鲁瓦达 ® (TRUVADA ®) of the product, the product has been approved for once-daily dosing. Each of the inflections of the brovada tablet contains 200 mg of emtricitabine and 300 mg of tenofovir disoproxil (which is equivalent to 245 mg of tenofovir) as an active ingredient. The tablet also contains the following inactive ingredients: croscarmellose sodium, monohydrated lactose, magnesium stearate, microcrystalline cellulose, and pregelatinized starch. The total weight of the Trovada lozenge is 1045 mg and the size is 19 mm x 8.5 mm.

恩曲他濱，系統化學名稱為4-胺基-5-氟-1-[2-(羥基甲基)-1,3-氧雜硫代戊環-5-基]-嘧啶-2-酮，是用於治療HIV-I之感染的另一核苷逆轉錄酶抑制劑(NRTI)。其合成及用途描述於不同公開案中，特別是包含美國專利第5,210,085號、第5,814,639號、 第5,914,331號、第6,642,245號以及第7,402,588號。 Emtricitabine, the system chemical name is 4-amino-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]-pyrimidin-2-one Is another nucleoside reverse transcriptase inhibitor (NRTI) for the treatment of HIV-I infection. Its synthesis and use are described in various publications, in particular, including U.S. Patent Nos. 5,210,085 and 5,814,639. Nos. 5,914,331, 6,642,245 and 7,402,588.

恩曲他濱(FTC)由吉利德科技公司以商標名恩替瓦®(EMTRIVA®)銷售。恩替瓦可以膠囊形式或口服溶液形式購得。各膠囊含有200mg恩曲他濱以及以下非活性成分：交聯聚維酮、硬脂酸鎂、微晶纖維素、聚維酮、二氧化鈦、明膠以及FD&C藍色2號(FD&C blue No.2)。 Emtricitabine (FTC) by the Gilead Sciences under the trade name entecavir W ® (EMTRIVA ®) sales. Enteva is commercially available in capsule form or as an oral solution. Each capsule contains 200 mg of emtricitabine and the following inactive ingredients: crospovidone, magnesium stearate, microcrystalline cellulose, povidone, titanium dioxide, gelatin, and FD&C blue No. 2 .

地瑞那韋，系統名稱為N-[(2S,3R)-4-[(4-胺基苯基)磺醯基-(2-甲基丙基)胺基]-3-羥基-1-苯基-丁-2-基]胺基甲酸[(1R,5S,6R)-2,8-二氧雙環[3.3.0]辛-6-酯]，是用於治療HIV-I之蛋白酶抑制劑類別之另一抗逆轉錄病毒藥物。其合成、用途、鹽類、調配物以及其組合描述於不同公開案中，包含美國專利第6,335,460號、第6,248,775號、第5,843,946號、第USRE43596號以及第WO2013004816號。 Derivinavir, the system name is N-[(2S,3R)-4-[(4-aminophenyl)sulfonyl-(2-methylpropyl)amino]-3-hydroxy-1- Phenyl-butan-2-yl]carbamic acid [(1R,5S,6R)-2,8-dioxobicyclo[3.3.0]oct-6-ester] is used for the treatment of HIV-I protease inhibition Another antiretroviral drug in the class of agents. The synthesis, use, salts, formulations, and combinations thereof are described in various publications, including U.S. Patent Nos. 6,335,460, 6,248,775, 5,843,946, USRE 4,359, and WO 2013004816.

地瑞那韋由蒂博特克制藥(Tibotec)(強生公司(Janssen))以商標名普利司他®(PREZISTA®)銷售。普利司他錠劑可以75mg、150mg、400mg、600mg以及800mg之劑型購得。各錠劑亦含有非活性成分膠態二氧化矽、交聯聚維酮、硬脂酸鎂以及微晶纖維素。800mg錠劑亦含有羥丙甲纖維素。普利司他800mg錠劑之總重量為1048mg，尺寸為20mm×8mm。 Darunavir by the Diboteke Pharmaceuticals (Tibotec) (Johnson & Johnson (Janssen)) trademark Ming Puli orlistat ® (PREZISTA ®) sales. Plystatin tablets are commercially available in dosage forms of 75 mg, 150 mg, 400 mg, 600 mg, and 800 mg. Each tablet also contains inactive ingredients colloidal cerium oxide, crospovidone, magnesium stearate, and microcrystalline cellulose. The 800 mg tablet also contains hypromellose. The total weight of the prilistan 800 mg lozenge is 1048 mg and the size is 20 mm x 8 mm.

利托那韋，系統化學名稱為N-[(2S,3S,5S)-3-羥基-5-[(2S)-3-甲基-2-{[甲基({[2-(丙-2-基)-1,3-噻唑-4-基]甲基})胺甲醯基]胺基}丁醯胺基-]1,6二苯基丁-2-基]胺基甲酸-1,3-噻唑-5-基甲酯，為是於治療HIV-I之感染之蛋白酶抑制劑類別的另一抗逆轉錄病毒藥物。其合成、用途、調配物以及其組合描述於不同公 開案中，特別是包含美國專利第5,541,206號、第5,648,497號、第6,037,157號、第7,364,752號以及第US8,268,349號。 Ritonavir, the system chemical name is N-[(2S,3S,5S)-3-hydroxy-5-[(2S)-3-methyl-2-{[methyl({[2-(propyl-)- 2-yl)-1,3-thiazol-4-yl]methyl})amine-methylmethyl]amino}butanosyl-]1,6-diphenylbutan-2-yl]carbamic acid-1 , 3-thiazol-5-ylmethyl ester, another antiretroviral drug that is a class of protease inhibitors for the treatment of HIV-I infection. Its synthesis, use, formulation, and combinations thereof are described in different public In particular, U.S. Patent Nos. 5,541,206, 5,648,497, 6,037,157, 7,364,752, and US 8,268,349 are incorporated herein by reference.

利托那韋由亞培(Abbott Laboratories)以商標名諾韋®(NORVIR®)銷售。諾韋可以100mg錠劑或膠囊形式及80mg/ml口服溶液形式購得。利托那韋為生物醫藥分類系統(biopharmaceutical classification system；BCS)第IV類材料。因此，利托那韋具有極低溶解度及滲透率。亞培以熱熔擠壓製造方法使用非晶形利托那韋與高量聚合物製備得到諾韋錠劑(NDA 22-417-化學評論(chemistry review),http：//www.accessdata.fda.gov/drugsatfda_docs/nda/2010/022417s000_ChemR.pdf)。諾韋錠劑含有：100mg利托那韋、共聚維酮、脫水山梨糖醇月桂酸酯、無水磷酸氫鈣、無水膠態二氧化矽、硬脂醯反丁烯二酸鈉且塗佈有由羥丙甲纖維素、二氧化鈦(E171)、聚乙二醇、羥丙基纖維素、滑石、無水膠態二氧化矽以及聚山梨醇酯80形成之膜塗層。諾韋錠劑之總重量為800mg，且所述錠劑之尺寸為17.2mm×5.8mm。 Ritonavir by the Abbott (Abbott Laboratories) trademark Ming Nuowei ® (NORVIR ®) sales. Novi can be purchased as a 100 mg lozenge or capsule form and as an 80 mg/ml oral solution. Ritonavir is a Class IV material of the biopharmaceutical classification system (BCS). Therefore, ritonavir has very low solubility and permeability. Abbott is prepared by a hot melt extrusion process using amorphous ritonavir with a high amount of polymer to obtain a novo lozenge (NDA 22-417 - chemistry review, http://www.accessdata.fda. Gov/drugsatfda_docs/nda/2010/022417s000_ChemR.pdf). Novi tablet contains: 100mg ritonavir, copovidone, sorbitan laurate, anhydrous calcium hydrogen phosphate, anhydrous colloidal cerium oxide, stearyl succinate and coated with A film coating formed of hypromellose, titanium dioxide (E171), polyethylene glycol, hydroxypropyl cellulose, talc, anhydrous colloidal cerium oxide, and polysorbate 80. The total weight of the Novi tablet was 800 mg, and the size of the tablet was 17.2 mm x 5.8 mm.

已證明當單獨投與時，多數抗逆轉錄病毒藥劑僅部分有效，通常不能夠有效地阻斷HIV複製而獲得病毒負荷(viral load)之最佳減少或阻止其上升。 It has been shown that when administered alone, most antiretroviral agents are only partially effective and generally do not effectively block HIV replication to achieve an optimal reduction in viral load or prevent it from rising.

為克服此不足，多年來已開發高度活性抗逆轉錄病毒療法(highly active antiretroviral therapy；HAART)。HAART是透過共投與三種抗逆轉錄病毒藥劑所達成。其投與方式可以採分別投與所述三種藥物或以含有三種活性成分之單位劑量形式投與所述三種藥物。 To overcome this deficiency, highly active antiretroviral therapy (HAART) has been developed for many years. HAART is achieved by co-administering three antiretroviral agents. The administration may be carried out by administering the three drugs separately or in a unit dosage form containing the three active ingredients.

在專利申請案WO 2011/061302及WO 2011/061303中提出投與三種或四種活性成分以治療人體中之人類免疫缺乏病毒(HIV)之方式。WO 1996/030025及WO 2006/135933揭露製造三重固定劑量組合。 The administration of three or four active ingredients to treat human immunodeficiency virus (HIV) in humans is proposed in the patent applications WO 2011/061302 and WO 2011/061303. The manufacture of triple fixed dose combinations is disclosed in WO 1996/030025 and WO 2006/135933.

專利申請案WO2009/081174描述一種利托那韋及地瑞那韋之雙重組合調配物；其中利托那韋在第一層中且地瑞那韋在第二層中。根據其內容，當利托那韋及地瑞那韋混合時因其不相容性會致使活性成分之穩定性受損。因此，WO2009/081174揭露兩種活性成分必須彼此分離，亦即藉由提供各藥劑存在於獨立層中之組成物。儘管如此，從易於製造之觀點來說，相比於多層組成物，單體組成物一般較佳。然而，單體劑量形式調配成功是取決於確保劑量形式中之活性成分的穩定性不受損，以及確保劑量形式具有使其能夠易於投與之尺寸。 Patent application WO 2009/081174 describes a dual combination formulation of ritonavir and darunavir; wherein ritonavir is in the first layer and darinavir is in the second layer. According to its content, when ritonavir and darunavir are mixed, the stability of the active ingredient is impaired due to incompatibility. Thus, WO 2009/081174 discloses that the two active ingredients must be separated from one another, i.e. by providing a composition in which the individual agents are present in separate layers. Nevertheless, from the standpoint of ease of manufacture, monomer compositions are generally preferred over multilayer compositions. However, the successful formulation of the monomer dosage form is dependent on ensuring that the stability of the active ingredient in the dosage form is not compromised, as well as ensuring that the dosage form has a size that allows it to be readily administered.

WO2013057469描述一種套組形式之組合組成物。套組可包括不同的抗逆轉錄病毒藥物之獨立單位劑量形式以及其投與使用方式之說明書。儘管如此，根據說明書投與獨立劑量形式並無法確保改良患者之順應性，特別是需要在不同時間服用劑量形式時更是困難。此外，說明書可能誤置或可能被患者不正確地遵循。 WO2013057469 describes a combined composition in the form of a kit. The kit may include separate unit dosage forms of different antiretroviral drugs and instructions for their mode of administration. Nonetheless, the administration of separate dosage forms according to the instructions does not ensure improved patient compliance, especially when it is necessary to take the dosage form at different times. In addition, the instructions may be misplaced or may be incorrectly followed by the patient.

因此需要提供易於製造且含有利托那韋及地瑞那韋之化學穩定劑量形式。另外需要提供組合組成物之劑量形式，將諸如恩曲他濱、泰諾福韋、地瑞那韋以及利托那韋之抗逆轉錄病毒藥物組合成單一組成物的劑量形式，使其易於投，以進一步改良患者順應性。特別是，需要較不麻煩的給藥方案，諸如每日一次 的口服給藥，更佳是以具有所需穩定性及生物可用性之一粒丸劑給藥。 There is therefore a need to provide chemically stable dosage forms that are easy to manufacture and contain ritonavir and darunavir. In addition, it is desirable to provide a dosage form of the combined composition that combines antiretroviral drugs such as emtricitabine, tenofovir, darunavir, and ritonavir into a single dosage form, making it easy to administer. To further improve patient compliance. In particular, less cumbersome dosing regimens are needed, such as once a day. For oral administration, it is more preferred to administer the pellet in one of the desired stability and bioavailability.

本發明首次闡述製備含有恩曲他濱、泰諾福韋、地瑞那韋以及利托那韋之單位劑量形式及含有地瑞那韋與利托那韋之單體錠劑。 The present invention is the first to describe the preparation of unit dosage forms containing emtricitabine, tenofovir, darunavir, and ritonavir, and a monomeric lozenge containing darunavir and ritonavir.

在一個態樣中，本發明提供一種包括下述者的單位劑量形式之醫藥調配物：泰諾福韋或其生理學上之功能衍生物；恩曲他濱或其生理學上之功能衍生物；地瑞那韋或其生理學上之功能衍生物；以及利托那韋或其生理學上之功能衍生物。 In one aspect, the invention provides a pharmaceutical formulation comprising a unit dosage form of: tenofovir or a physiologically functional derivative thereof; emtricitabine or a physiologically functional derivative thereof ; darunavir or a physiologically functional derivative thereof; and ritonavir or a physiologically functional derivative thereof.

在另一態樣中，本發明提供一種包括下述者之單體錠劑：地瑞那韋或其生理學上之功能衍生物；以及利托那韋或其生理學上之功能衍生物。 In another aspect, the invention provides a monomeric tablet comprising: darunavir or a physiologically functional derivative thereof; and ritonavir or a physiologically functional derivative thereof.

本發明更提供用作藥物之上述單位劑量調配物或上述單體錠劑。 The present invention further provides the above unit dose formulation or the above-described monomer tablet for use as a medicament.

本發明更提供用於治療HIV-1感染之上述單位劑量調配物或上述單體錠劑。 The present invention further provides the above unit dose formulation or the above monomer tablet for the treatment of HIV-1 infection.

本發明更提供一種治療HIV-1感染之方法，包括投與醫藥學上有效量之上述單位劑量調配物或上述單體錠劑。 The invention further provides a method of treating HIV-1 infection comprising administering a pharmaceutically effective amount of the above unit dose formulation or the above-described monomer tablet.

除非另外說明，否則如本文所用之以下術語及片語意欲具有以下含義： Unless otherwise stated, the following terms and phrases as used herein are intended to have the following meanings:

本發明之化合物或其組合可稱為「活性成分」或「醫藥活性成分」。 The compound of the present invention or a combination thereof may be referred to as "active ingredient" or "pharmaceutically active ingredient".

術語「生理學上之功能衍生物」包含任何：醫藥學上可接受之鹽、其醫藥學上可接受之對映異構體、醫藥學上可接受之固態形式(結晶、半結晶或非晶)、醫藥學上可接受之多晶型物、醫藥學上可接受之溶劑合物、醫藥學上可接受之代謝物或醫藥學上可接受之前藥(其中前藥例如為酯)或所述對映異構體、固態形式、多晶型物、溶劑合物、代謝物或前藥(例如酯前藥)之醫藥學上可接受之鹽。 The term "physiologically functional derivative" encompasses any: a pharmaceutically acceptable salt, a pharmaceutically acceptable enantiomer thereof, a pharmaceutically acceptable solid form (crystalline, semi-crystalline or amorphous). a pharmaceutically acceptable polymorph, a pharmaceutically acceptable solvate, a pharmaceutically acceptable metabolite or a pharmaceutically acceptable prodrug (wherein the prodrug is, for example, an ester) or A pharmaceutically acceptable salt of an enantiomer, a solid form, a polymorph, a solvate, a metabolite or a prodrug such as an ester prodrug.

從廣義來說，通篇提及之術語「恩曲他濱」、「泰諾福韋」、「地瑞那韋」以及「利托那韋」不僅包含恩曲他濱、泰諾福韋、地瑞那韋以及利托那韋本身，且亦包含其生理學上之功能衍生物。較佳地，在本發明之任何實施例或任何態樣中，泰諾福韋是以其產物泰諾福韋酯之形式呈現。更佳地，泰諾福韋酯是以其反丁烯二酸鹽形式呈現，亦即反丁烯二酸泰諾福韋酯。較佳地，在本發明之任何實施例或任何態樣中，地瑞那韋是以地瑞那韋或其生理學上之功能衍生物形式呈現，例如地瑞那韋可為地瑞那韋乙醇化物、水合物或任何其他結晶形態以及非晶形地瑞那韋。 Broadly speaking, the terms "encitabine", "tenofovir", "darinavir" and "ritonavir" mentioned throughout include not only emtricitabine, tenofovir, Derivinavir and ritonavir itself, and also contain physiologically functional derivatives. Preferably, in any embodiment or in any aspect of the invention, tenofovir is presented in the form of its product, tenofovir. More preferably, tenofovir is present in the form of its fumarate, i.e., tenofovir, fumarate. Preferably, in any embodiment or in any aspect of the invention, darunavir is presented as darunavir or a physiologically functional derivative thereof, for example, darinavir may be darunavir Ethanolate, hydrate or any other crystalline form and amorphous darunavir.

較佳地，在本發明之任何實施例或任何態樣中，利托那韋是以利托那韋或其生理學上之功能衍生物形式呈現。更佳地，利托那韋是以其結晶形態以及非晶形利托那韋形式呈現，結晶形 態可例如為形態I(form I)或形態II(form II)，實質上如EP1097148中所述。利托那韋形態I之粉末X射線繞射圖案之特徵峰可發現於3.33°±0.1°、6.76°±0.1°、8.33°±0.1°、14.61°±0.1°、16.33°±0.1°、16.76°±0.1°、17.03°±0.1°、18.02°±0.1°、18.62°±0.1°、19.47°±0.1°、19.86°±0.1°、20.25°±0.1°、21.46°±0.1°、23.46°±0.1°以及24.36°±0.1°(2θ)中。利托那韋形態II之粉末X射線繞射圖案之特徵峰可發現於8.67°±0.1°、9.88°±0.1°、16.11°±0.1°、16.70°±0.1°、17.36°±0.1°、17.78°±0.1°、18.40°±0.1°、18.93°±0.1°、20.07°±0.1°、20.65°±0.1°、21.71°±0.1°以及25.38°±0.1°(2θ)中。 Preferably, in any embodiment or in any aspect of the invention, ritonavir is presented as ritonavir or a physiologically functional derivative thereof. More preferably, ritonavir is present in its crystalline form as well as in the form of amorphous ritonavir. The state can be, for example, Form I or Form II, substantially as described in EP 1097148. The characteristic peaks of the powder X-ray diffraction pattern of ritonavir form I can be found at 3.33 ° ± 0.1 °, 6.76 ° ± 0.1 °, 8.33 ° ± 0.1 °, 14.61 ° ± 0.1 °, 16.33 ° ± 0.1 °, 16.76 °±0.1°, 17.03°±0.1°, 18.02°±0.1°, 18.62°±0.1°, 19.47°±0.1°, 19.86°±0.1°, 20.25°±0.1°, 21.46°±0.1°, 23.46°± 0.1 ° and 24.36 ° ± 0.1 ° (2θ). The characteristic peaks of the powder X-ray diffraction pattern of ritonavir form II can be found at 8.67°±0.1°, 9.88°±0.1°, 16.11°±0.1°, 16.70°±0.1°, 17.36°±0.1°, 17.78. °±0.1°, 18.40°±0.1°, 18.93°±0.1°, 20.07°±0.1°, 20.65°±0.1°, 21.71°±0.1°, and 25.38°±0.1° (2θ).

除非另外指明，否則提及之劑量形式之重量%在錠劑之情況下意謂相對於除任何塗飾/裝飾塗層以外的劑量形式之重量之重量%，且在膠囊之情況下，劑量形式之重量是指膠囊內含物(亦即排除膠囊殼層)之總重量。 Unless otherwise indicated, the weight % of the dosage form recited in the context of a lozenge means a weight % relative to the weight of the dosage form other than any finishing/decorative coating, and in the case of a capsule, the dosage form Weight refers to the total weight of the contents of the capsule (ie, excluding the shell of the capsule).

術語「化學穩定性」意謂組合中之活性成分對於化學降解實質上穩定。較佳地，其於物理組合中充分穩定以准許組合產品的商業上有用之存放期。典型地，「化學穩定」意謂當兩種組分引入至物理組合中以形成醫藥劑量形式時，混合物之第一組分不起降解第二組分之作用。較佳地，本發明之任何態樣之任何實施例中之「化學穩定」，術語「化學穩定」是指一種調配物當儲存於40℃及75%相對濕度下1個月至6個月時，地瑞那韋及利托那韋中之每一者之量；及/或泰諾福韋及恩曲他濱中之每一者之量不比儲存之前的調配物中之地瑞那韋及利托那韋中之每一者之量；及/或泰諾福韋及恩曲他濱中之每一者之量顯著減少。 The term "chemical stability" means that the active ingredients in the combination are substantially stable to chemical degradation. Preferably, it is sufficiently stable in the physical combination to permit a commercially useful shelf life of the combined product. Typically, "chemically stable" means that when the two components are introduced into a physical combination to form a pharmaceutical dosage form, the first component of the mixture does not degrade the second component. Preferably, "chemically stable" in any embodiment of any aspect of the invention, the term "chemically stable" means a formulation that is stored at 40 ° C and 75% relative humidity for from 1 month to 6 months. , the amount of each of darunavir and ritonavir; and/or each of tenofovir and emtricitabine is no more than darunavir and in the formulation before storage. The amount of each of Tonavir; and/or the amount of each of tenofovir and emtricitabine is significantly reduced.

特定言之，若在40℃及75%相對濕度下儲存1個月至6 個月之後保留緊鄰儲存之前的調配物中之地瑞那韋及利托那韋含量中之每一者，及/或泰諾福韋及恩曲他濱含量中之每一者之至少約97%、較佳至少約98%、更佳至少約99%、最佳至少約99.5%且尤其為至少約99.9%，則可將根據本發明之任何態樣或實施例之調配物視為化學穩定的。較佳地，根據本發明之任何態樣或實施例，術語「化學穩定」是指一種調配物，其中在40℃及75%相對濕度下儲存調配物1個月至6個月之後保留緊鄰儲存之前的調配物中之地瑞那韋及利托那韋含量中之每一者及/或泰諾福韋及恩曲他濱含量中之每一者之約90%至約100%、約95%至約100%、約98%至約100%、約99%至約100%、99.5%至約100%或99.9%至約100%。更佳地，保留約99.95%至約100%。在本發明之尤佳實施例中，術語「化學穩定」是指一種調配物，其中在40℃及75%相對濕度下儲存1個月至6個月之後保留緊鄰儲存之前的調配物中之地瑞那韋及利托那韋含量中之每一者及/或泰諾福韋及恩曲他濱含量中之每一者之至少約99.95%。在本發明之尤佳實施例中，術語「化學穩定」是指一種調配物，其中在緊鄰儲存之前及在40℃及75%相對濕度下儲存1個月至6個月之後的調配物中，地瑞那韋及利托那韋含量及/或泰諾福韋及恩曲他濱含量中之每一者沒有偵測到改變。 Specifically, if stored at 40 ° C and 75% relative humidity for 1 month to 6 Retaining at least about 97 of each of darunavir and ritonavir content in the formulation immediately prior to storage, and/or each of tenofovir and emtricitabine content after one month Formulations according to any aspect or embodiment of the invention may be considered chemically stable, preferably at least about 98%, more preferably at least about 99%, optimally at least about 99.5%, and especially at least about 99.9%. of. Preferably, according to any aspect or embodiment of the invention, the term "chemically stable" means a formulation wherein the formulation is stored immediately after storage for 1 month to 6 months at 40 ° C and 75% relative humidity. About 90% to about 100%, about 95% of each of darunavir and ritonavir content in the previous formulation and/or each of tenofovir and emtricitabine levels % to about 100%, from about 98% to about 100%, from about 99% to about 100%, from 99.5% to about 100% or from 99.9% to about 100%. More preferably, it is retained from about 99.95% to about 100%. In a particularly preferred embodiment of the invention, the term "chemically stable" means a formulation in which the formulation is retained immediately prior to storage after storage for 1 month to 6 months at 40 ° C and 75% relative humidity. At least about 99.95% of each of nerave and ritonavir levels and/or each of tenofovir and emtricitabine levels. In a preferred embodiment of the invention, the term "chemically stable" means a formulation wherein the formulation is stored immediately after storage and after storage for 1 month to 6 months at 40 ° C and 75% relative humidity, No changes were detected in each of darunavir and ritonavir content and/or tenofovir and emtricitabine levels.

可藉由技術人員熟知之標準分析技術量測調配物之地瑞那韋及利托那韋含量，及/或泰諾福韋及恩曲他濱含量之任何改變。HPLC為用於此目的之較佳方法。舉例而言，可採用使用標準溶液之HPLC分析，其實例陳述於下文中。 Any change in the darunavir and ritonavir content of the formulation, and/or the content of tenofovir and emtricitabine can be measured by standard analytical techniques well known to the skilled artisan. HPLC is the preferred method for this purpose. For example, HPLC analysis using standard solutions can be employed, examples of which are set forth below.

提及的恩曲他濱、泰諾福韋、地瑞那韋以及利托那韋之 醫藥學上可接受之鹽之重量%是指相對於游離鹼形式之量。當恩曲他濱、泰諾福韋、地瑞那韋及/或利托那韋以前藥形式呈現時，重量%是指相對於前藥形式之量。因此，舉例而言，提及的反丁烯二酸泰諾福韋酯之重量%為相對於泰諾福韋酯之量。 Mention of emtricitabine, tenofovir, darunavir and ritonavir The weight percent of a pharmaceutically acceptable salt refers to the amount relative to the free base form. When embritabine, tenofovir, darunavir and/or ritonavir are presented as prodrug forms, % by weight refers to the amount relative to the prodrug form. Thus, for example, the weight % of tenofovir fumarate mentioned is relative to the amount of tenofovir.

術語「生物可用性」意謂活性成分或活性部分自藥品吸收且在作用位點變為可用之速率及程度。提高醫藥活性成分之生物可用性可為患者提供更高效及有效之治療，因為對於給定劑量，更多醫藥活性成分將在目標組織位點處為可用的。 The term "bioavailability" means the rate and extent to which an active ingredient or active moiety is absorbed from a drug and becomes available at the site of action. Increasing the bioavailability of a pharmaceutically active ingredient can provide a more efficient and effective treatment for the patient since more pharmaceutically active ingredients will be available at the target tissue site for a given dose.

可例如藉由本領域的普通技術人員已知的任何藥物動力學參數測定醫藥組成物之生物可用性。所述參數之實例包含：t1/2(half-life；半衰期)、Cmin(minimal plasma concentration；最小血漿濃度)、谷底濃度(C trough concentration)、Cmax(maximal plasma concentration；最大血漿濃度)、AUC(area under the curve；曲線下面積)Tmax(time to maximal concentration；到達最大濃度時間)以及Css(steady state concentration；穩態濃度)。 The bioavailability of the pharmaceutical composition can be determined, for example, by any pharmacokinetic parameters known to those of ordinary skill in the art. Examples of the parameters include: t 1/2 (half-life; half-life), C min (minimal plasma concentration), C trough concentration, C max (maximal plasma concentration) , AUC (area under the curve) T max (time to maximal concentration; and C ss (steady state concentration).

相同/可比藥物動力學生物可用性之評估可基於研究中的參數之總體幾何平均值之比(測試/參考)的90%信賴區間。此方法可等同於在生物非等效性為5%顯著性水平之虛無假設之情況下的兩個單邊測試。 The assessment of the same/comparable pharmacokinetic bioavailability can be based on a 90% confidence interval for the ratio of the overall geometric mean of the parameters in the study (test/reference). This method can be equated to two unilateral tests with a null hypothesis that the biononequivalence is 5% significance level.

可使用ANOVA分析研究中之藥物動力學參數。資料可在分析之前使用對數轉換進行轉換。可自ANOVA模型獲得對數轉換尺度上的調配物之間的差異之信賴區間。此信賴區間可隨後經反轉換以獲得初始尺度上的比率之所需信賴區間。 ANOVA can be used to analyze pharmacokinetic parameters in the study. Data can be converted using logarithmic transformations prior to analysis. A confidence interval for the difference between the formulations on the logarithmic scale can be obtained from the ANOVA model. This confidence interval can then be inversely transformed to obtain the desired confidence interval for the ratio on the initial scale.

利托那韋可用作『藥物動力學強化子』(輔助劑)以增 加地瑞那韋之血液含量。因此，當以商業利托那韋(諾韋)作為藥物動力學強化子投與時，地瑞那韋之生物可用性可與商業地瑞那韋之生物可用性相比。 Ritonavir can be used as a "pharmacokinetic enhancer" (adjuvant) to increase The blood content of darinavir. Thus, when commercial ritonavir (Nove) is administered as a pharmacokinetic enhancer, the bioavailability of darinavir can be compared to the bioavailability of commercial darunavir.

除非另外陳述，否則在下文中提及之醫藥調配物是指含有組合或亦含有其生理學上之功能衍生物之醫藥調配物。 Unless otherwise stated, a pharmaceutical formulation as referred to hereinafter refers to a pharmaceutical formulation containing a combination or also a physiologically functional derivative thereof.

具4種醫藥活性成分(API)之單位劑量形式使得患者更能夠免於使用多劑量藥物方案且簡化必須記住且遵守之複雜的每日給藥時間及時程所需做出的努力。藉由將泰諾福韋酯、恩曲他濱、地瑞那韋以及利托那韋合併為單一劑量形式，所需每日方案可以每日單一劑量形式呈現。共調配泰諾福韋、恩曲他濱、地瑞那韋以及利托那韋之醫藥調配物可以單一劑量形式每日投與一次。 The unit dosage form with four pharmaceutical active ingredients (APIs) allows patients to be more immune to multi-dose drug regimens and to simplify the effort required to remember and follow the complex daily dosing schedules and schedules. By combining tenofovir, emtricitabine, darunavir, and ritonavir in a single dosage form, the desired daily regimen can be presented in a single daily dose. Pharmaceutical formulations that are formulated with tenofovir, emtricitabine, darunavir, and ritonavir can be administered once daily in a single dose.

理想地，應投與醫藥調配物以達到分別投與含有活性醫藥成分中之每一者之分開的單位劑量時，化合物/活性醫藥成分中之每一者之峰值血漿濃度，同時避免損害醫藥調配物之穩定性及尺寸。 Desirably, the pharmaceutical formulation should be administered to achieve a peak plasma concentration of each of the compound/active pharmaceutical ingredients when administered separately in separate unit doses containing each of the active pharmaceutical ingredients, while avoiding damaging the pharmaceutical formulation. Stability and size of the object.

可以包括適合於確保所需治療效果之日劑量之量的各化合物/活性醫藥成分之單位劑量調配物形式調配醫藥調配物。 A unit dosage formulation in the form of an amount of each compound/active pharmaceutical ingredient suitable for ensuring the desired therapeutic effect will be formulated as a pharmaceutical formulation.

本發明提供一種包括下述者的單位劑量形式之醫藥調配物：泰諾福韋或其生理學上之功能衍生物；恩曲他濱或其生理學上之功能衍生物；地瑞那韋或其生理學上之功能衍生物；以及利托那韋或其生理學上之功能衍生物。 The present invention provides a pharmaceutical formulation comprising a unit dosage form of: tenofovir or a physiologically functional derivative thereof; emtricitabine or a physiologically functional derivative thereof; darunavir or a physiologically functional derivative thereof; and ritonavir or a physiologically functional derivative thereof.

包括泰諾福韋酯或其生理學上之功能衍生物、恩曲他濱或其生理學上之功能衍生物、地瑞那韋或其生理學上之功能衍生 物以及利托那韋或其生理學上之功能衍生物的上述醫藥調配物可為化學穩定的。 Including tenofovir disoproxil or a physiologically functional derivative thereof, emtricitabine or a physiologically functional derivative thereof, darinavir or a physiologically functional derivative thereof The above pharmaceutical formulations of the substance and ritonavir or a physiologically functional derivative thereof may be chemically stable.

包括上述4種API之本發明之醫藥調配物之總重量可小於或等於約2.800g、小於或等於約2.600g、小於或等於約2.500g、小於或等於約2.400g、小於或等於約2.300g、小於或等於約2.200g、小於或等於約1.900g或小於或等於約1.800g、或小於或等於約1.700g、或小於或等於約1.600g、或小於或等於約1.500g。在本發明之一個特定實施例中，總劑量形式重量在1.500g至約1.600g、至約1.700g、至約1.800g、至約1.900g、至約2.000g、至約2.200g、至約2.300g、至約2.400g、至約2.500g、至約2.600g、至約2.800g之間，或在1.600g至約1.700g、至約1.800g、至約1.900g、至約2.000g、至約2.200g、至約2.300g、至約2.400g、至約2.500g、至約2.600g、至約2.800g之間，或在1.700g至約1.800g、至約1.900g、至約2.000g、至約2.200g、至約2.300g、至約2.400g、至約2.500g、至約2.600g、至約2.800g之間，或在1.800g至約1.900g、至約2.000g、至約2.200g、至約2.300g、至約2.400g、至約2.500g、至約2.600g、至約2.800g之間，或在1.900g至約2.000g、至約2.200g、至約2.300g、至約2.400g、至約2.500g、至約2.600g、至約2.800g之間，或在2.000g至約2.200g、至約2.300g、至約2.400g、至約2.500g、至約2.600g、至約2.800g之間，或在約2.200g至約2.300g、至約2.400g、至約2.500g、至約2.600g、至約2.800g之間，或在約2.300g至約2.400g、至約2.500g、至約2.600g、至約2.800g之間，或在約2.400g至約2.500g、至約2.600g、至約2.800g 之間，或在約2.500g至約2.600g、至約2.800g之間，或在約2.600g至約2.800g之間。 The pharmaceutical formulation of the present invention comprising the above 4 APIs may have a total weight of less than or equal to about 2.800 g, less than or equal to about 2.600 g, less than or equal to about 2.500 g, less than or equal to about 2.400 g, less than or equal to about 2.300 g. , less than or equal to about 2.200 g, less than or equal to about 1.900 g or less than or equal to about 1.800 g, or less than or equal to about 1.700 g, or less than or equal to about 1.600 g, or less than or equal to about 1.500 g. In a particular embodiment of the invention, the total dosage form weight ranges from 1.500 g to about 1.600 g, to about 1.700 g, to about 1.800 g, to about 1.900 g, to about 2.000 g, to about 2.200 g, to about 2.300. g, to about 2.400 g, to about 2.500 g, to about 2.600 g, to about 2.800 g, or between 1.600 g to about 1.700 g, to about 1.800 g, to about 1.900 g, to about 2.000 g, to about 2.200g, to about 2.300g, to about 2.400g, to about 2.500g, to about 2.600g, to about 2.800g, or between 1.700g to about 1.800g, to about 1.900g, to about 2.000g, to From about 2.200 g, to about 2.300 g, to about 2.400 g, to about 2.500 g, to about 2.600 g, to about 2.800 g, or between 1.800 g to about 1.900 g, to about 2.000 g, to about 2.200 g, To about 2.300 g, to about 2.400 g, to about 2.500 g, to about 2.600 g, to about 2.800 g, or between 1.900 g to about 2.000 g, to about 2.200 g, to about 2.300 g, to about 2.400 g From about 2.500 g, to about 2.600 g, to about 2.800 g, or between 2.000 g to about 2.200 g, to about 2.300 g, to about 2.400 g, to about 2.500 g, to about 2.600 g, to about 2.800 Between g, or at about 2.200 g to about 2.300 g, to about 2.400 g, to about 2.500 g, to about 2 Between 600g, to about 2.800g, or between about 2.300g to about 2.400g, to about 2.500g, to about 2.600g, to about 2.800g, or between about 2.400g to about 2.500g, to about 2.600 g, to about 2.800g Between, or between about 2.500 g to about 2.600 g, to about 2.800 g, or between about 2.600 g to about 2.800 g.

舉例而言，本發明之醫藥調配物包括約150mg至350mg反丁烯二酸泰諾福韋酯、約100mg至300mg恩曲他濱、約75mg至800mg地瑞那韋以及約100mg利托那韋。地瑞那韋之量可為75mg、150mg、300mg、400mg、600mg或800mg(對應於市售普利司他之劑量)。所述地瑞那韋可為地瑞那韋乙醇化物、水合物或任何其他結晶形態以及非晶形地瑞那韋。利托那韋之量可為100mg利托那韋(對應於市售諾韋錠劑之劑量)。 For example, a pharmaceutical formulation of the invention comprises from about 150 mg to 350 mg of tenofovir disoproxil, from about 100 mg to 300 mg of emtricitabine, from about 75 mg to 800 mg of darunavir, and from about 100 mg of ritonavir. . The amount of darunavir may be 75 mg, 150 mg, 300 mg, 400 mg, 600 mg or 800 mg (corresponding to the dosage of commercially available prilistat). The darunavir may be darunavir ethanolate, hydrate or any other crystalline form and amorphous darunavir. The amount of ritonavir may be 100 mg ritonavir (corresponding to the dosage of a commercially available Novo lozenge).

較佳地，本發明之醫藥調配物包括約300mg反丁烯二酸泰諾福韋酯、約200mg恩曲他濱、約800mg地瑞那韋以及約100mg利托那韋。 Preferably, the pharmaceutical formulation of the invention comprises about 300 mg of tenofovir disoproxil, about 200 mg of emtricitabine, about 800 mg of darunavir, and about 100 mg of ritonavir.

在某些實施例中，本發明之醫藥調配物包括約20重量%至約85重量%之以其總重量計的所有4種醫藥學活性成分。本發明之醫藥調配物包括約20重量%至約25重量%、至約30重量%、至約35重量%、至約40重量%、至約45重量%、至約50重量%、至約55重量%、至約60重量%、至約65重量%、至約70重量%、至約75重量%、至約80重量%或至約85重量%之以其總重量計的所有4種醫藥學活性成分，或包括約25重量%至約30重量%、至約35重量%、至約40重量%、至約45重量%、至約50重量%、至約55重量%、至約60重量%、至約65重量%、至約70重量%、至約75重量%、至約80重量%或至約85重量%，或約30重量%至約35重量%、至約40重量%、至約45重量%、至約50重量%、至約55重量%、至約60重量%、至約65重量%、至約70重量%、 至約75重量%、至約80重量%或至約85重量%，或約40重量%至約45重量%、至約50重量%、至約55重量%、至約60重量%、至約65重量%、至約70重量%、至約75重量%、至約80重量%或至約85重量%，或約45重量%至約50重量%、至約55重量%、至約60重量%、至約65重量%、至約70重量%、至約75重量%、至約80重量%或至約85重量%，或約50重量%至約55重量%、至約60重量%、至約65重量%、至約70重量%、至約75重量%、至約80重量%或至約85重量%，或約55重量%至約60重量%、至約65重量%、至約70重量%、至約75重量%、至約80重量%或至約85重量%，或約60重量%至約65重量%、至約70重量%、至約75重量%、至約80重量%或約85重量%，或約65重量%至約70重量%、至約75重量%、至約80重量%或至約85重量%，或約70重量%至約75重量%、至約80重量%或至約85重量%，或約75重量%至約80重量%或至約85重量%，或約80重量%至約85重量%之所有4種醫藥學活性成分。 In certain embodiments, the pharmaceutical formulations of the present invention comprise from about 20% to about 85% by weight of all four pharmaceutically active ingredients, based on their total weight. Pharmaceutical formulations of the present invention comprise from about 20% to about 25%, from about 30%, to about 35%, to about 40%, to about 45%, to about 50%, to about 55 % by weight, to about 60% by weight, to about 65% by weight, to about 70% by weight, to about 75% by weight, to about 80% by weight or to about 85% by weight, based on the total weight of all four medicines The active ingredient, or comprises from about 25% to about 30% by weight, to about 35% by weight, to about 40% by weight, to about 45% by weight, to about 50% by weight, to about 55% by weight, to about 60% by weight To about 65 wt%, to about 70 wt%, to about 75 wt%, to about 80 wt% or to about 85 wt%, or from about 30 wt% to about 35 wt%, to about 40 wt%, to about 45% by weight, to about 50% by weight, to about 55% by weight, to about 60% by weight, to about 65% by weight, to about 70% by weight, To about 75% by weight, to about 80% by weight or to about 85% by weight, or about 40% to about 45% by weight, to about 50% by weight, to about 55% by weight, to about 60% by weight, to about 65. % by weight, to about 70% by weight, to about 75% by weight, to about 80% by weight or to about 85% by weight, or from about 45% to about 50% by weight, to about 55% by weight, to about 60% by weight, To about 65% by weight, to about 70% by weight, to about 75% by weight, to about 80% by weight or to about 85% by weight, or from about 50% to about 55% by weight, to about 60% by weight, to about 65. % by weight, to about 70% by weight, to about 75% by weight, to about 80% by weight or to about 85% by weight, or from about 55% to about 60% by weight, to about 65% by weight, to about 70% by weight, To about 75% by weight, to about 80% by weight or to about 85% by weight, or about 60% to about 65% by weight, to about 70% by weight, to about 75% by weight, to about 80% by weight or about 85% by weight %, or from about 65% to about 70% by weight, to about 75% by weight, to about 80% by weight or to about 85% by weight, or from about 70% to about 75% by weight, to about 80% by weight or to about 85 wt%, or about 75 wt% to about 80 wt% or to about 85 wt%, or about 80 wt% to about 85 wt% 4 kinds of pharmaceutically active ingredients.

本發明之醫藥調配物可適合於經口投與。出於本發明之目的，口服劑量形式包含膠囊、錠劑、丸劑、顆粒、散劑及其醫藥調配物。舉例而言，可以經包覆或未經包覆、起泡、可溶、口內崩散、腸溶或緩釋錠劑；糖衣錠劑；硬膠囊；軟膠囊；顆粒；丸劑；片劑形式調配醫藥組成物。較佳地，口服劑量形式為錠劑。錠劑可為化學穩定的。 The pharmaceutical formulations of the invention may be suitable for oral administration. For the purposes of the present invention, oral dosage forms comprise capsules, troches, pills, granules, powders, and pharmaceutical formulations thereof. For example, coated or uncoated, foamed, soluble, intraoral disintegration, enteric or sustained release tablets; sugar-coated tablets; hard capsules; soft capsules; granules; pills; Pharmaceutical composition. Preferably, the oral dosage form is a lozenge. Tablets can be chemically stable.

關於本發明之醫藥調配物之總重量，包括上述4種API之錠劑可具有如上所述的重量。 Regarding the total weight of the pharmaceutical formulation of the present invention, the tablet comprising the above four APIs may have a weight as described above.

包括4種API之本發明之錠劑之最大直徑可為約27mm 或小於約27mm且深度可為小於約12.5mm；較佳地，最大直徑可在約26mm至約27mm之間且深度可在約12.5mm至約10mm之間；更佳地，最大直徑可在約25mm至約26mm之間且深度可在約12mm至約11mm之間，最佳地，最大直徑可為約25mm且深度可為約11mm。 The maximum diameter of the tablet of the present invention comprising 4 APIs can be about 27 mm Or less than about 27 mm and the depth may be less than about 12.5 mm; preferably, the largest diameter may be between about 26 mm and about 27 mm and the depth may be between about 12.5 mm and about 10 mm; more preferably, the maximum diameter may be about Between 25 mm and about 26 mm and depth may be between about 12 mm and about 11 mm, and optimally, the maximum diameter may be about 25 mm and the depth may be about 11 mm.

如藉由Electronic D-64291達木士塔(Darmstadt)100-240V量測，包括4種API之本發明之錠劑之硬度可為約75科布強度單位(Strong-Cobb Unit；SCU)至約20C，較佳約55SCU至約25SCU。 The hardness of the tablet of the present invention comprising 4 APIs can be about 75 Strong-Cobb Unit (SCU) to about 100 gauges as measured by Electronic D-64291 Darmstadt 100-240V. 20C, preferably about 55 SCU to about 25 SCU.

舉例而言，本發明之錠劑包括約150mg至350mg反丁烯二酸泰諾福韋酯、約100mg至300mg恩曲他濱、約75mg至800mg地瑞那韋以及約100mg利托那韋。地瑞那韋之量可為75mg、150mg、300mg、400mg、600mg或800mg(對應於市售普利司他之劑量)。所述地瑞那韋可為地瑞那韋乙醇化物、水合物或任何其他結晶形態以及非晶形地瑞那韋。利托那韋之量可為100mg利托那韋(對應於市售諾韋錠劑之劑量)。 For example, the tablet of the present invention comprises from about 150 mg to 350 mg of tenofovir disoproxil, from about 100 mg to 300 mg of emtricitabine, from about 75 mg to 800 mg of darunavir, and about 100 mg of ritonavir. The amount of darunavir may be 75 mg, 150 mg, 300 mg, 400 mg, 600 mg or 800 mg (corresponding to the dosage of commercially available prilistat). The darunavir may be darunavir ethanolate, hydrate or any other crystalline form and amorphous darunavir. The amount of ritonavir may be 100 mg ritonavir (corresponding to the dosage of a commercially available Novo lozenge).

較佳地，本發明之錠劑包括約300mg反丁烯二酸泰諾福韋酯、約200mg恩曲他濱、約800mg地瑞那韋以及100mg利托那韋。 Preferably, the tablet of the present invention comprises about 300 mg of tenofovir, fumarate, about 200 mg of emtricitabine, about 800 mg of darunavir, and 100 mg of ritonavir.

在某些實施例中，本發明之錠劑包括約20重量%至約70重量%之以其總重量計的醫藥學活性成分。本發明之錠劑包括約20重量%至約85重量%之以其總重量計的所有4種醫藥學活性成分。本發明之醫藥調配物包括約20重量%至約25重量%、至約30重量%、至約35重量%、至約40重量%、至約45重量%、至 約50重量%、至約55重量%、至約60重量%、至約65重量%、至約70重量%、至約75重量%、至約80重量%或至約85重量%之以其總重量計的所有4種醫藥學活性成分，或包括約25重量%至約30重量%、至約35重量%、至約40重量%、至約45重量%、至約50重量%、至約55重量%、至約60重量%、至約65重量%、至約70重量%、至約75重量%、至約80重量%或至約85重量%，或約30重量%至約35重量%、至約40重量%、至約45重量%、至約50重量%、至約55重量%、至約60重量%、至約65重量%、至約70重量%、至約75重量%、至約80重量%或至約85重量%，或約40重量%至約45重量%、至約50重量%、至約55重量%、至約60重量%、至約65重量%、至約70重量%、至約75重量%、至約80重量%或至約85重量%，或約45重量%至約50重量%、至約55重量%、至約60重量%、至約65重量%、至約70重量%、至約75重量%、至約80重量%或至約85重量%，或約50重量%至約55重量%、至約60重量%、至約65重量%、至約70重量%、至約75重量%、至約80重量%或至約85重量%，或約55重量%至約60重量%、至約65重量%、至約70重量%、至約75重量%、至約80重量%或至約85重量%，或約60重量%至約65重量%、至約70重量%、至約75重量%、至約80重量%或約85重量%，或約65重量%至約70重量%、至約75重量%、至約80重量%或至約85重量%，或約70重量%至約75重量%、至約80重量%或至約85重量%，或約75重量%至約80重量%或至約85重量%，或約80重量%至約85重量%之所有4種醫藥學活性成分。 In certain embodiments, the tablet of the present invention comprises from about 20% to about 70% by weight, based on the total weight of the pharmaceutically active ingredient. Tablets of the invention comprise from about 20% to about 85% by weight of all four pharmaceutically active ingredients, based on their total weight. The pharmaceutical formulation of the present invention comprises from about 20% to about 25% by weight, to about 30% by weight, to about 35% by weight, to about 40% by weight, to about 45% by weight, to From about 50% by weight, to about 55% by weight, to about 60% by weight, to about 65% by weight, to about 70% by weight, to about 75% by weight, to about 80% by weight or to about 85% by weight of total All 4 pharmaceutically active ingredients by weight, or include from about 25% to about 30% by weight, to about 35% by weight, to about 40% by weight, to about 45% by weight, to about 50% by weight, to about 55. % by weight, to about 60% by weight, to about 65% by weight, to about 70% by weight, to about 75% by weight, to about 80% by weight or to about 85% by weight, or from about 30% to about 35% by weight, To about 40% by weight, to about 45% by weight, to about 50% by weight, to about 55% by weight, to about 60% by weight, to about 65% by weight, to about 70% by weight, to about 75% by weight, to about 80% by weight or to about 85% by weight, or about 40% to about 45% by weight, to about 50% by weight, to about 55% by weight, to about 60% by weight, to about 65% by weight, to about 70% by weight To about 75% by weight, to about 80% by weight or to about 85% by weight, or about 45% to about 50% by weight, to about 55% by weight, to about 60% by weight, to about 65% by weight, to about 70% by weight, to about 75% by weight, to about 80% by weight or to about 85% by weight, or about 50% by weight to From about 55% by weight, to about 60% by weight, to about 65% by weight, to about 70% by weight, to about 75% by weight, to about 80% by weight or to about 85% by weight, or from about 55% to about 60% by weight %, to about 65 wt%, to about 70 wt%, to about 75 wt%, to about 80 wt% or to about 85 wt%, or from about 60 wt% to about 65 wt%, to about 70 wt%, to From about 75% by weight, to about 80% by weight or about 85% by weight, or from about 65% by weight to about 70% by weight, to about 75% by weight, to about 80% by weight or to about 85% by weight, or about 70% by weight Up to about 75% by weight, to about 80% by weight or to about 85% by weight, or about 75% to about 80% by weight or to about 85% by weight, or about 80% to about 85% by weight of all 4 medicines Learn about active ingredients.

根據一些實施例，本發明提供視情況可藉由分割溝分成 兩個或多於兩個離散區段之錠劑。所述分割溝有助於將劑量分成對應片段且因此使得易於分成含有大致相同比例之活性物質之部分劑量。本發明之錠劑可例如具有一個至三個、較佳兩個位於頂表面及底表面上之側向擴展凹溝及一個位於側面上之小側向開口凹溝以便於容易地分開錠劑。 According to some embodiments, the present invention provides that the division can be divided by the division groove as the case may be Two or more discrete segments of tablets. The dividing groove helps to divide the dose into corresponding segments and thus makes it easy to divide into partial doses containing substantially the same proportion of active substance. The tablet of the present invention may, for example, have from one to three, preferably two, laterally extending grooves on the top and bottom surfaces and a small lateral opening on the sides to facilitate easy separation of the tablet.

可例如以單體錠劑(單層)、雙層(兩層)或多層錠劑(三個或多於三個相異層)之形式提供根據本發明之呈錠劑形式之醫藥調配物，調配物可較佳為單體錠劑。 The pharmaceutical formulation in the form of a lozenge according to the present invention may be provided, for example, in the form of a monomeric tablet (single layer), a double layer (two layers) or a multilayer tablet (three or more than three distinct layers), The formulation may preferably be a monomer tablet.

根據本發明之單體錠劑可包含四種化合物/活性醫藥成分混合及壓縮為單層錠劑。單層可包含地瑞那韋與粒外型利托那韋或地瑞那韋與粒內型利托那韋(亦即地瑞那韋-利托那韋之粒化物)、恩曲他濱顆粒，及泰諾福韋顆粒，或包括恩曲他濱及泰諾福韋二者之顆粒。可向這些顆粒中添加至少一種崩解劑，諸如交聯羧甲纖維素鈉(Ac-Di-Sol)以形成摻合物，隨後將所述摻合物壓縮為錠劑核心。可隨後用膜衣材料包覆錠劑核心以產生膜衣錠劑。 The monomer tablet according to the present invention may comprise a mixture of four compounds/active pharmaceutical ingredients and compressed into a single layer tablet. The monolayer may comprise darunavir and extragranular ritonavir or darunavir with intragranular ritonavir (ie granulation of darunavir-ritonavir), emtricitabine Granules, and tenofovir particles, or particles comprising both emtricitabine and tenofovir. At least one disintegrant such as croscarmellose sodium (Ac-Di-Sol) may be added to these granules to form a blend, which is then compressed into a tablet core. The tablet core can then be coated with a film coating material to produce a film-coated lozenge.

可藉由地瑞那韋之濕式粒化製備地瑞那韋-利托那韋之粒化物。濕式粒化可包含頂噴製程將溶解於適合液體(例如水)中之至少一種黏合劑(諸如羥丙甲纖維素)噴於地瑞那韋上、獲得濕顆粒、接著乾燥濕顆粒以及研磨乾燥顆粒。 Granulation of darunavir-ritonavir can be prepared by wet granulation of darunavir. Wet granulation may comprise a top spray process spraying at least one binder (such as hypromellose) dissolved in a suitable liquid (such as water) onto darunavir, obtaining wet granules, followed by drying wet granules, and grinding Dry the granules.

隨後，可將諸如硬脂醯反丁烯二酸鈉之至少一種潤滑劑添加至所獲得之混合物中以獲得地瑞那韋-利托那韋(亦即地瑞那韋與粒外型利托那韋)之最終摻合物。 Subsequently, at least one lubricant such as stearin sodium fumarate can be added to the obtained mixture to obtain darunavir-ritonavir (ie, darunavir and extragranular Lito The final blend of Nave.

或者，可藉由濕式粒化製備地瑞那韋-利托那韋之粒化物，可以頂噴製程將溶解於適合之液體(例如水)中之至少一種 黏合劑(諸如羥丙甲纖維素)噴於地瑞那韋及利托那韋預混物之混合物上，或接著乾燥濕顆粒及研磨乾燥顆粒。所獲得之地瑞那韋及利托那韋之粒化物可隨後與諸如微晶纖維素之至少一種填充劑、諸如交聯聚維酮之至少一種崩解劑以及諸如二氧化矽之至少一種滑動劑混合。可視情況添加蓖麻油至所獲得之混合物中。隨後，可將諸如硬脂醯反丁烯二酸鈉之至少一種潤滑劑添加至所獲得之混合物中以獲得地瑞那韋-利托那韋(亦即地瑞那韋與粒內型利托那韋)之最終摻合物。 Alternatively, the granulation of darunavir-ritonavir can be prepared by wet granulation, and at least one of the suitable liquids (for example, water) can be dissolved by a top spray process. A binder, such as hypromellose, is sprayed onto the mixture of darunavir and ritonavir premix, or dried wet granules and ground dry granules. The obtained granulation of darunavir and ritonavir may be subsequently slid with at least one filler such as microcrystalline cellulose, at least one disintegrant such as crospovidone, and at least one such as cerium oxide. Mix the agents. Castor oil can be added to the mixture obtained as appropriate. Subsequently, at least one lubricant such as stearin fumarate can be added to the obtained mixture to obtain darunavir-ritonavir (ie, darunavir and intragranular Lito The final blend of Nave.

可藉由將利托那韋與諸如共聚維酮之至少一種載劑混合，視情況亦與諸如脫水山梨糖醇月桂酸酯之至少一種增溶劑以及諸如二氧化矽之至少一種滑動劑混合，獲得混合物，所述混合物與諸如乙醇之溶劑組合以產生第二混合物來製備利托那韋預混物。隨後藉由諸如噴霧乾燥之蒸發技術自第二混合物移除溶劑。所得混合物可呈粉末形式，可對其進行粒度縮減步驟(例如藉由研磨至D(0.1)約9μm、D(0.5)約55μm、D(0.9)約176μm)。 It may be obtained by mixing ritonavir with at least one carrier such as copolyvidone, optionally with at least one solubilizing agent such as sorbitan laurate and at least one slip agent such as cerium oxide. A mixture, the mixture is combined with a solvent such as ethanol to produce a second mixture to prepare a ritonavir premix. The solvent is then removed from the second mixture by an evaporation technique such as spray drying. The resulting mixture may be in the form of a powder which may be subjected to a particle size reduction step (e.g., by grinding to D (0.1) about 9 μm, D (0.5) about 55 μm, D (0.9) about 176 μm).

可藉由組合API及至少一種選自微晶纖維素、乳糖及/或預膠凝化澱粉之填充劑以及視情況存在之至少一種崩解劑(諸如交聯羧甲纖維素鈉)獲得粉末狀混合物，其可隨後在濕式粒化製程中與水組合來製備包括恩曲他濱及泰諾福韋二者之顆粒。濕式粒化製程提供濕顆粒，其可隨後乾燥之。或者，恩曲他濱及泰諾福韋可分別藉由相同方法粒化以產生獨立的恩曲他濱及泰諾福韋粒化物。 The powder may be obtained by combining an API and at least one filler selected from the group consisting of microcrystalline cellulose, lactose and/or pregelatinized starch, and optionally at least one disintegrant such as croscarmellose sodium. A mixture, which can then be combined with water in a wet granulation process to prepare granules comprising both emtricitabine and tenofovir. The wet granulation process provides wet granules which can be subsequently dried. Alternatively, emtricitabine and tenofovir can be granulated by the same method to produce independent emtricitabine and tenofovir granules, respectively.

或者，可藉由組合恩曲他濱與至少一種選自微晶纖維素、預膠凝化澱粉之填充劑以及至少一種崩解劑(諸如交聯羧甲 纖維素鈉)以獲得粉末狀混合物，其可隨後在濕式粒化製程中用水粒化來製備恩曲他濱顆粒。濕式粒化製程提供濕顆粒，其可隨後乾燥。可藉由組合泰諾福韋與至少一種選自微晶纖維素及預膠凝化澱粉之填充劑以獲得粉末狀混合物，其可隨後在濕式粒化製程中用水粒化來製備泰諾福韋粒化物。濕式粒化製程提供濕顆粒，其可隨後乾燥之。 Alternatively, by combining emtricitabine with at least one filler selected from microcrystalline cellulose, pregelatinized starch, and at least one disintegrant (such as crosslinked carboxymethyl Sodium cellulose) to obtain a powdery mixture which can then be granulated with water in a wet granulation process to prepare emtricitabine particles. The wet granulation process provides wet granules which can be subsequently dried. The tenofovir can be prepared by combining tenofovir with at least one filler selected from the group consisting of microcrystalline cellulose and pregelatinized starch, which can then be granulated by water granulation in a wet granulation process. Wei granules. The wet granulation process provides wet granules which can be subsequently dried.

根據本發明的包括恩曲他濱、泰諾福韋、地瑞那韋以及利托那韋之雙層錠劑由化合物/活性醫藥成分之兩個相異層組成。舉例而言，第一層可具有恩曲他濱及泰諾福韋且第二層可具有地瑞那韋及利托那韋。第一層可更包含至少一種潤滑劑(諸如硬脂酸鎂)以形成第一層之摻合物。第二層之摻合物可包含上述地瑞那韋-利托那韋之粒化物(亦即地瑞那韋及粒外型形式之利托那韋或地瑞那韋及粒內型形式之利托那韋)。兩種摻合物均可隨後經壓縮為具有兩個相異層之一個錠劑核心。可隨後用膜衣材料包覆錠劑核心。 A bilayer tablet comprising emtricitabine, tenofovir, darunavir and ritonavir according to the invention consists of two distinct layers of the compound/active pharmaceutical ingredient. For example, the first layer can have emtricitabine and tenofovir and the second layer can have darunavir and ritonavir. The first layer may further comprise at least one lubricant, such as magnesium stearate, to form a blend of the first layer. The second layer blend may comprise the above-described granules of darunavir-ritonavir (i.e., ritonavir and granular form of ritonavir or darunavir and intragranular form) Ritonavir). Both blends can then be compressed into a tablet core having two distinct layers. The tablet core can then be coated with a film coating material.

根據本發明之多層錠劑由化合物/活性醫藥成分之三個或大於三個相異層組成。 The multi-layered tablet according to the invention consists of three or more than three distinct layers of the compound/active pharmaceutical ingredient.

根據本發明的錠劑形式之醫藥調配物可未經包覆或可藉由包含微囊封裝之已知技術塗佈以延緩於胃腸道中之崩解及吸收且從而提供經較長時段之持續作用。舉例而言，可單獨或伴以蠟採用諸如單硬脂酸甘油酯或二硬脂酸甘油酯之時間延遲材料。 Pharmaceutical formulations in the form of lozenges according to the present invention may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and absorption in the gastrointestinal tract and thereby provide sustained action over a longer period of time. . For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed alone or with wax.

根據本發明的錠劑形式之醫藥調配物可更包覆有塗層。塗層可包括(例如)安置於藥物層上方之保護性頂塗層。根據一些實施例，保護性頂塗層可包括塗佈聚合物及視情況存在之 一或多種賦形劑，諸如塑化劑、抗黏劑或滑動劑、一或多種顏料/失透劑以及其組合。 The pharmaceutical formulation in the form of a tablet according to the invention may be further coated with a coating. The coating can include, for example, a protective topcoat disposed over the drug layer. According to some embodiments, the protective top coat may comprise a coated polymer and optionally One or more excipients, such as plasticizers, anti-adherents or slip agents, one or more pigments/devitalizers, and combinations thereof.

塗層可為對活性物質之釋放無影響的水可溶塗膜。可溶塗膜之厚度可為約20μm至約100μm。 The coating may be a water-soluble coating film which has no effect on the release of the active material. The soluble coating film may have a thickness of from about 20 μm to about 100 μm.

適合之膜衣材料包含例如纖維素衍生物，諸如纖維素醚，例如甲基纖維素、羥丙基纖維素或羥丙基甲基纖維素；聚乙烯吡咯啶酮或聚乙烯吡咯啶酮及聚乙酸乙烯酯與羥丙基甲基纖維素之共聚物之混合物；蟲膠與羥丙基甲基纖維素、聚乙酸乙烯酯之混合物或其與聚乙烯吡咯啶酮之共聚物；或水可溶纖維素衍生物，諸如羥丙基甲基纖維素及水不溶性乙基纖維素之混合物。必要時，這些塗佈劑可用於與其他佐劑，諸如滑石、濕潤劑，例如聚山梨醇酯(例如用於促進塗覆)或顏料(例如用於標記目的)之混雜物中。取決於成分之溶解度，可將這些塗層施用於水溶液或有機溶液(例如蟲膠或乙基纖維素於有機溶劑中之溶液)中。亦可使用本身為水不溶性的丙烯酸酯之混合物。舉例而言，可與一或多種水可溶佐劑，諸如乳糖、聚乙烯基吡咯啶、聚乙二醇或羥丙基甲基纖維素一起在水性分散液中使用丙烯酸乙酯及甲基丙烯酸甲酯之共聚物。 Suitable film coating materials include, for example, cellulose derivatives such as cellulose ethers such as methylcellulose, hydroxypropylcellulose or hydroxypropylmethylcellulose; polyvinylpyrrolidone or polyvinylpyrrolidone and poly a mixture of a copolymer of vinyl acetate and hydroxypropyl methylcellulose; a mixture of shellac with hydroxypropylmethylcellulose, polyvinyl acetate or a copolymer thereof with polyvinylpyrrolidone; or water soluble A cellulose derivative such as a mixture of hydroxypropylmethylcellulose and water-insoluble ethylcellulose. If desired, these coating agents can be used in admixture with other adjuvants, such as talc, wetting agents, such as polysorbates (for example to facilitate coating) or pigments (for example for marking purposes). These coatings can be applied to an aqueous solution or an organic solution (for example, a solution of shellac or ethylcellulose in an organic solvent) depending on the solubility of the ingredients. It is also possible to use a mixture of acrylates which are themselves water-insoluble. For example, ethyl acrylate and methacrylic acid can be used in aqueous dispersions together with one or more water soluble adjuvants such as lactose, polyvinylpyrrolidine, polyethylene glycol or hydroxypropyl methylcellulose. a copolymer of methyl ester.

用於保護性頂塗層之適合之塑化劑包含例如三乙酸甘油酯、鄰苯二甲酸二乙酯、癸二酸二丁酯、癸二酸三丁酯、聚乙二醇以及其混合物。聚乙二醇為較佳塑化劑。 Suitable plasticizers for the protective top coat include, for example, triacetin, diethyl phthalate, dibutyl sebacate, tributyl sebacate, polyethylene glycol, and mixtures thereof. Polyethylene glycol is a preferred plasticizer.

用於保護性頂塗層之適合之抗黏劑或滑動劑包含例如滑石、煙霧狀二氧化矽、硬脂酸鎂以及其混合物。 Suitable anti-adhesives or slip agents for the protective top coat include, for example, talc, aerosolized cerium oxide, magnesium stearate, and mixtures thereof.

本發明之錠劑可藉由包括下述各步驟之方法製備： (a)摻合包括泰諾福韋酯、恩曲他濱、地瑞那韋、利托那韋以及視情況存在之一或多種醫藥學上可接受之賦形劑之混合物；(b)將摻合物壓縮為錠劑核心；以及(c)視情況在錠劑核心上塗覆一或多個塗層。 The lozenge of the present invention can be prepared by a process comprising the following steps: (a) blending a mixture comprising tenofovir, emtricitabine, darunavir, ritonavir, and optionally one or more pharmaceutically acceptable excipients; (b) The blend is compressed into a tablet core; and (c) one or more coatings are applied to the tablet core as appropriate.

較佳地，藉由此方法獲得之錠劑為單體錠劑。 Preferably, the tablet obtained by this method is a monomer tablet.

或者，本發明之錠劑可藉由包括下述各步驟之方法製備：(a)提供兩個摻合物層，其中：(i)第一層包括恩曲他濱粒化物及泰諾福韋粒化物之混合物，或包括恩曲他濱及泰諾福韋之混合物之粒化物；且(ii)第二層包括地瑞那韋與粒外型利托那韋或地瑞那韋與粒內型利托那韋(亦即地瑞那韋-利托那韋之粒化物)；(b)將所述兩個摻合物層壓縮為錠劑；以及(c)視情況在錠劑核心上塗覆一或多個塗層。較佳地，藉由此方法獲得之錠劑為雙層錠劑。可使用諸如翻轉摻合器之設備實現摻合。 Alternatively, the tablet of the present invention can be prepared by a process comprising the following steps: (a) providing two blend layers, wherein: (i) the first layer comprises emtricitabine granulate and tenofovir a mixture of granules, or a granulate comprising a mixture of emtricitabine and tenofovir; and (ii) a second layer comprising darunavir and extragranular ritonavir or darunavir with intragranular Type ritonavir (i.e., granulation of darunavir-ritonavir); (b) compressing the two blend layers into tablets; and (c) optionally coating the core of the tablet Cover one or more coatings. Preferably, the tablet obtained by this method is a bilayer tablet. Blending can be achieved using equipment such as a flip blender.

可使用例如活性成分及賦形劑之摻合物穿過輥裝置以壓實來實現壓縮。然而，亦可使用其他用於壓實API混合物，例如壓實為錠塊(或「壓錠(slugging)」)之構件。 Compression can be achieved using, for example, a blend of the active ingredient and excipients through a roller device for compaction. However, other means for compacting the API mixture, such as compacting into ingots (or "slugging"), may also be used.

或者，步驟(a)之活性醫藥成分摻合物可加工成其他單一劑量形式，諸如膠囊或類似物。 Alternatively, the active pharmaceutical ingredient blend of step (a) can be processed into other single dosage forms, such as capsules or the like.

如上文所述，可在摻合之前將步驟(a)之混合物中之活性醫藥成分中之每一者個別加工。 As described above, each of the active pharmaceutical ingredients in the mixture of step (a) can be processed individually prior to blending.

可使用習知設備實現濕式粒化。舉例而言，粉末摻合於 粒化機中且接著使用水進行粒化。在粒化及濕式集結操作期間，葉輪及切碎機速度於摻合器中保持恆定於低設定。在添加水之後，葉輪及切碎機停止且打開粒化機槽以觀測粒化一致性及質地。 Wet granulation can be achieved using conventional equipment. For example, powder blending Granulation is carried out in a granulator and then using water. During granulation and wet agglomeration operations, the impeller and shredder speeds remain constant at low settings in the blender. After the addition of water, the impeller and chopper were stopped and the granulator tank was opened to observe granulation consistency and texture.

可使用習知設備實現濕式研磨。舉例而言，為促進均一乾燥方法，可藉由裝配有篩網及葉輪之磨機對各濕式粒化進行解黏聚。 Wet grinding can be achieved using conventional equipment. For example, to promote a uniform drying process, each wet granulation can be deagglomerated by a mill equipped with a screen and an impeller.

可使用習知設備實現乾燥。舉例而言，可使用流化床乾燥器乾燥研磨之濕顆粒。 Drying can be achieved using conventional equipment. For example, the wetted granules can be dried using a fluid bed dryer.

可使用習知設備實現乾式研磨。舉例而言，可使用旋轉篩磨機研磨所有乾燥顆粒。 Dry grinding can be achieved using conventional equipment. For example, all dry particles can be ground using a rotary screen mill.

可使用習知設備實現頂噴製程。舉例而言，配備有頂噴或底噴(wurster)塗佈裝置之流化床乾燥器。 The top spray process can be implemented using conventional equipment. For example, a fluidized bed dryer equipped with a top spray or a wurster coating device.

可使用習知設備實現錠劑壓縮。舉例而言，可使用制錠機壓縮最終摻合物。可使用習知設備實現純度分析。舉例而言，HPLC。 Tablet compression can be achieved using conventional equipment. For example, a tablet machine can be used to compress the final blend. Purity analysis can be achieved using conventional equipment. For example, HPLC.

本發明提供一種單體錠劑包括：地瑞那韋或其生理學上之功能衍生物；以及利托那韋或其生理學上之功能衍生物。 The present invention provides a monomeric lozenge comprising: darunavir or a physiologically functional derivative thereof; and ritonavir or a physiologically functional derivative thereof.

較佳地，錠劑可為化學穩定的。 Preferably, the tablet can be chemically stable.

本發明之包括地瑞那韋及利托那韋之單體錠劑之總重量可為小於或等於約1.300g、小於或等於約1.200g、小於或等於約1.100g、小於或等於約1.000g、小於或等於約0.900g、小於或等於約0.700g、小於或等於0.600g或小於或等於約0.550g。在本發明之一個特定實施例中，錠劑重量在0.550g至約0.600g、至約0.700g、至約0.900g、至約1.000g、至約1.100g、至約1.200 g、至約1.300g之間，或在0.600g至約0.700g、至約0.900g、至約1.000g、至約1.100g、至約1.200g或至約1.300g之間，或在0.700g至約0.900g、至約1.000g、至約1.100g、至約1.300g之間，或在0.900g至約1.000g、至約1.100g、至約1.200g或至約1.300g之間，或在1.000g至約1.100g、至約1.200g、至約1.300g之間，或在1.100g至約1.200g或至約1.300g之間，或在1.200g至約1.300g之間。 The total weight of the monomeric lozenges of the present invention comprising darunavir and ritonavir may be less than or equal to about 1.300 g, less than or equal to about 1.200 g, less than or equal to about 1.100 g, less than or equal to about 1.000 g. Less than or equal to about 0.900 g, less than or equal to about 0.700 g, less than or equal to 0.600 g, or less than or equal to about 0.550 g. In a particular embodiment of the invention, the tablet weight ranges from 0.550 g to about 0.600 g, to about 0.700 g, to about 0.900 g, to about 1.000 g, to about 1.100 g, to about 1.200. g, to between about 1.300 g, or between 0.600 g to about 0.700 g, to about 0.900 g, to about 1.000 g, to about 1.100 g, to about 1.200 g or to about 1.300 g, or at 0.700 g to From about 0.900 g, to about 1.000 g, to about 1.100 g, to about 1.300 g, or between 0.900 g to about 1.000 g, to about 1.100 g, to about 1.200 g or to about 1.300 g, or at 1.000 g to between about 1.100 g, to about 1.200 g, to about 1.300 g, or between 1.100 g to about 1.200 g or to about 1.300 g, or between 1.200 g to about 1.300 g.

本發明之包括地瑞那韋及利托那韋之單體錠劑提供一種活性成分之化學穩定調配物，而且適合於以單一丸劑每日投與一次。有利地，所述劑量形式之尺寸及重量遠小於市售地瑞那韋800mg錠劑(普利司他，具有1048mg之總重量)及市售利托那韋100mg錠劑(諾韋，具有800mg之總重量)之合併尺寸/重量。 The monomeric lozenges of the present invention comprising darunavir and ritonavir provide a chemically stable formulation of the active ingredient and are suitable for administration once daily in a single bolus. Advantageously, the dosage form is of a size and weight much less than the commercially available darunavir 800 mg lozenge (prilistan, having a total weight of 1048 mg) and a commercial ritonavir 100 mg lozenge (Novi, with 800 mg) The combined weight/weight of the total weight).

包括地瑞那韋及利托那韋的本發明之醫藥調配物之最大直徑可為約22mm或小於22mm且深度可為小於約9mm；較佳地，最大直徑可在約20mm至約22mm之間且深度可在約6mm至約9mm之間；更佳地，最大直徑可在約20mm至約21mm之間且深度可在約8mm至約7mm之間，最佳地，最大直徑可為約21mm且深度可為約7mm。 The pharmaceutical formulations of the present invention comprising darunavir and ritonavir may have a maximum diameter of about 22 mm or less and a depth of less than about 9 mm; preferably, the largest diameter may range from about 20 mm to about 22 mm. And the depth may be between about 6 mm and about 9 mm; more preferably, the maximum diameter may be between about 20 mm and about 21 mm and the depth may be between about 8 mm and about 7 mm, and optimally, the maximum diameter may be about 21 mm and The depth can be about 7 mm.

舉例而言，本發明之錠劑包括約150mg至350mg反丁烯二酸泰諾福韋酯、約100mg至300mg恩曲他濱、約75mg至800mg地瑞那韋以及約100mg利托那韋。地瑞那韋之量可為75mg、150mg、300mg、400mg、600mg或800mg(對應於市售普利司他之劑量)。所述地瑞那韋可為地瑞那韋乙醇化物、水合物或任何其他結晶形態以及非晶形地瑞那韋。利托那韋之量可為100 mg利托那韋(對應於市售諾韋錠劑之劑量)。 For example, the tablet of the present invention comprises from about 150 mg to 350 mg of tenofovir disoproxil, from about 100 mg to 300 mg of emtricitabine, from about 75 mg to 800 mg of darunavir, and about 100 mg of ritonavir. The amount of darunavir may be 75 mg, 150 mg, 300 mg, 400 mg, 600 mg or 800 mg (corresponding to the dosage of commercially available prilistat). The darunavir may be darunavir ethanolate, hydrate or any other crystalline form and amorphous darunavir. The amount of ritonavir can be 100 Mg ritonavir (corresponding to the dosage of a commercially available Novo lozenge).

較佳地，本發明之錠劑包括約300mg反丁烯二酸泰諾福韋酯、約200mg恩曲他濱、約800mg地瑞那韋以及100mg利托那韋。 Preferably, the tablet of the present invention comprises about 300 mg of tenofovir, fumarate, about 200 mg of emtricitabine, about 800 mg of darunavir, and 100 mg of ritonavir.

在某些實施例中，本發明之包括地瑞那韋及利托那韋之單體錠劑包括約20重量%至約85重量%之以其總重量計的兩種醫藥學活性成分。本發明之錠劑包括約20重量%至約25重量%、至約30重量%、至約35重量%、至約40重量%、至約45重量%、至約50重量%、至約55重量%、至約60重量%、至約65重量%、至約70重量%、至約75重量%、至約80重量%或至約85重量%之以其總重量計的兩種醫藥學活性成分，或包括約25重量%至約30重量%、至約35重量%、至約40重量%、至約45重量%、至約50重量%、至約55重量%、至約60重量%、至約65重量%、至約70重量%、至約75重量%、至約80重量%或至約85重量%，或約30重量%至約35重量%、至約40重量%、至約45重量%、至約50重量%、至約55重量%、至約60重量%、至約65重量%、至約70重量%、至約75重量%、至約80重量%或至約85重量%，或約40重量%至約45重量%、至約50重量%、至約55重量%、至約60重量%、至約65重量%、至約70重量%、至約75重量%、至約80重量%或至約85重量%，或約45重量%至約50重量%、至約55重量%、至約60重量%、至約65重量%、至約70重量%、至約75重量%、至約80重量%或至約85重量%，或約50重量%至約55重量%、至約60重量%、至約65重量%、至約70重量%、至約75重量%、至約80重量%或至約85重量%，或約55重量% 至約60重量%、至約65重量%、至約70重量%、至約75重量%、至約80重量%或至約85重量%，或約60重量%至約65重量%、至約70重量%、至約75重量%、至約80重量%或約85重量%，或約65重量%至約70重量%、至約75重量%、至約80重量%或至約85重量%，或約70重量%至約75重量%、至約80重量%或至約85重量%，或約75重量%至約80重量%或至約85重量%，或約80重量%至約85重量%之兩種醫藥學活性成分。 In certain embodiments, the monomeric lozenges of the present invention comprising darunavir and ritonavir comprise from about 20% to about 85% by weight of two pharmaceutically active ingredients, based on their total weight. The tablet of the present invention comprises from about 20% by weight to about 25% by weight, to about 30% by weight, to about 35% by weight, to about 40% by weight, to about 45% by weight, to about 50% by weight, to about 55% by weight %, to about 60% by weight, to about 65% by weight, to about 70% by weight, to about 75% by weight, to about 80% by weight or to about 85% by weight, based on the total weight of the two pharmaceutically active ingredients Or including from about 25% by weight to about 30% by weight, to about 35% by weight, to about 40% by weight, to about 45% by weight, to about 50% by weight, to about 55% by weight, to about 60% by weight, to From about 65% by weight, to about 70% by weight, to about 75% by weight, to about 80% by weight or to about 85% by weight, or from about 30% to about 35% by weight, to about 40% by weight, to about 45% by weight %, to about 50% by weight, to about 55% by weight, to about 60% by weight, to about 65% by weight, to about 70% by weight, to about 75% by weight, to about 80% by weight or to about 85% by weight, Or from about 40% by weight to about 45% by weight, to about 50% by weight, to about 55% by weight, to about 60% by weight, to about 65% by weight, to about 70% by weight, to about 75% by weight, to about 80% % by weight or to about 85% by weight, or from about 45% by weight to about 50% by weight, to about 55% by weight, From about 60% by weight, to about 65% by weight, to about 70% by weight, to about 75% by weight, to about 80% by weight or to about 85% by weight, or from about 50% to about 55% by weight, to about 60% by weight %, to about 65% by weight, to about 70% by weight, to about 75% by weight, to about 80% by weight or to about 85% by weight, or about 55% by weight To about 60% by weight, to about 65% by weight, to about 70% by weight, to about 75% by weight, to about 80% by weight or to about 85% by weight, or from about 60% to about 65% by weight, to about 70% % by weight, to about 75% by weight, to about 80% by weight or about 85% by weight, or about 65% by weight to about 70% by weight, to about 75% by weight, to about 80% by weight or to about 85% by weight, or From about 70% by weight to about 75% by weight, to about 80% by weight or to about 85% by weight, or from about 75% by weight to about 80% by weight or to about 85% by weight, or from about 80% by weight to about 85% by weight Two pharmaceutically active ingredients.

包括地瑞那韋及利托那韋之上述單體錠劑可包含混合及壓縮為單層錠劑之兩種化合物/活性醫藥成分。所述單層可包含地瑞那韋及粒外型利托那韋或地瑞那韋及粒內型利托那韋。可向這些物質中添加至少一種潤滑劑(諸如硬脂醯反丁烯二酸鈉)以形成摻合物，隨後可將所述摻合物壓縮為錠劑核心。可隨後用膜衣材料包覆錠劑核心以產生膜衣錠劑。 The above monomeric lozenges, including darunavir and ritonavir, may comprise two compounds/active pharmaceutical ingredients which are mixed and compressed into a single layer tablet. The monolayer may comprise darunavir and extragranular ritonavir or darunavir and intragranular ritonavir. At least one lubricant (such as stearin fumarate) can be added to these materials to form a blend which can then be compressed into a tablet core. The tablet core can then be coated with a film coating material to produce a film-coated lozenge.

如上文所述，地瑞那韋及利托那韋不論是粒外型或粒內型，可在摻合之前加工。 As noted above, darinavir and ritonavir, whether of the extragranular or intragranular form, can be processed prior to blending.

根據一些實施例，本發明提供視情況可藉由分割溝分成兩個或多於兩個離散區段之錠劑。所述分割溝有助於將劑量分成對應片段且因此使得易於分成含有大致相同比例之活性物質之部分劑量。本發明之錠劑可例如具有一個至三個、較佳兩個位於頂表面及底表面上之側向擴展凹槽及一個位於側面上之小側向開口凹槽以便於容易地分開錠劑。 According to some embodiments, the present invention provides a lozenge that can be divided into two or more than two discrete segments by dividing the trench. The dividing groove helps to divide the dose into corresponding segments and thus makes it easy to divide into partial doses containing substantially the same proportion of active substance. The tablet of the present invention may, for example, have one to three, preferably two, lateral expansion grooves on the top and bottom surfaces and a small lateral opening groove on the side to facilitate easy separation of the tablet.

本發明之醫藥調配物可更包含一或多種如上文及下文所述的醫藥學上可接受之載劑或賦形劑。 The pharmaceutical formulations of the present invention may further comprise one or more pharmaceutically acceptable carriers or excipients as described above and below.

醫藥賦形劑之實例為填充劑、黏合劑、崩解劑、界面活 性劑、滑動劑以及潤滑劑。 Examples of pharmaceutical excipients are fillers, binders, disintegrants, and interface materials. Agents, slip agents and lubricants.

適合之填充劑(稀釋劑)包含例如水溶性聚合物、水不溶性聚合物、微晶纖維素(例如艾維素(Avicel)PH102具有或PH101)、各種形式之乳糖(例如乳糖USP、無水或經噴霧乾燥)、山梨糖醇、右旋糖、蔗糖、甘露醇、木糖醇、麥芽糖、多元醇、果糖、瓜爾豆膠、氫氧化鎂、磷酸二鈣、無水磷酸氫鈣、澱粉以及其類似物或任何組合。 Suitable fillers (diluents) include, for example, water soluble polymers, water insoluble polymers, microcrystalline cellulose (eg, Avicel PH 102 has or PH 101), various forms of lactose (eg, lactose USP, anhydrous or via Spray drying), sorbitol, dextrose, sucrose, mannitol, xylitol, maltose, polyol, fructose, guar gum, magnesium hydroxide, dicalcium phosphate, anhydrous calcium hydrogen phosphate, starch and the like Object or any combination.

適合之黏合劑包含例如纖維素聚合物(例如羥丙基甲基纖維素、羥丙基纖維素、甲基纖維素以及羥乙基纖維素)、聚乙烯吡咯啶酮、聚乙烯醇、澱粉或預膠凝化澱粉以及其類似物或任何組合。 Suitable binders include, for example, cellulosic polymers (such as hydroxypropyl methylcellulose, hydroxypropylcellulose, methylcellulose, and hydroxyethylcellulose), polyvinylpyrrolidone, polyvinyl alcohol, starch, or Pregelatinized starch and its analogs or any combination.

適合之潤滑劑包含例如硬脂醯反丁烯二酸鈉、硬脂酸、硬脂酸鎂、硬脂酸鈣、硬脂酸鋅、滑石、甘油二十二酸酯或氫化植物油以及其類似物或任何組合。 Suitable lubricants include, for example, sodium stearyl fumarate, stearic acid, magnesium stearate, calcium stearate, zinc stearate, talc, glyceryl behenate or hydrogenated vegetable oils and the like. Or any combination.

適合之滑動劑可用以改良流動性。適合之滑動劑包含例如膠態二氧化矽、矽膠、沈澱二氧化矽或滑石以及其類似物或任何組合。 Suitable slip agents can be used to improve flow. Suitable slip agents include, for example, colloidal cerium oxide, cerium, precipitated cerium oxide or talc, and the like or any combination thereof.

適合之崩解劑包含例如羧甲基澱粉鈉；交聯聚乙烯吡咯啶酮(交聯聚維酮)；羧甲基羥乙酸鈉(例如伊斯勞塔伯®(Explotab®))；交聯羧甲纖維素鈉；膨脹多醣，例如大豆多醣、角叉菜膠、瓊脂、果膠、澱粉及其衍生物；蛋白，例如甲醛-酪蛋白；碳酸氫鈉；離子交換樹脂以及其類似物或任何組合。 For the disintegrant comprises, for example, sodium carboxymethyl starch; crosslinked polyvinylpyrrolidone (crosslinked povidone); carboxymethylcellulose sodium glycolate (e.g.伊斯劳塔伯 ® (Explotab ®)); crosslinked Sodium carboxymethylcellulose; swollen polysaccharides such as soybean polysaccharide, carrageenan, agar, pectin, starch and derivatives thereof; proteins such as formaldehyde-casein; sodium bicarbonate; ion exchange resins and their analogues or any combination.

適合之界面活性劑為可降低兩相之間的界面張力，因此使得能夠或支持形成分散液或充當增溶劑之物質。適合之界面活 性劑包含例如烷基硫酸鹽(例如月桂基硫酸鈉)、烷基三甲基銨鹽、醇乙氧基化物、脫水山梨糖醇(例如脫水山梨糖醇月桂酸酯)、聚氧乙烯脫水山梨糖醇、聚氧甘油酯或聚氧乙烯蓖麻油衍生物。脫水山梨糖醇月桂酸酯及月桂基硫酸鈉為較佳界面活性劑。 Suitable surfactants are those which reduce the interfacial tension between the two phases, thus enabling or supporting the formation of a dispersion or acting as a solubilizing agent. Suitable interface The agent includes, for example, an alkyl sulfate (for example, sodium lauryl sulfate), an alkyltrimethylammonium salt, an alcohol ethoxylate, a sorbitan (such as sorbitan laurate), and a polyoxyethylene dehydrated pear. A sugar alcohol, polyoxyglyceride or polyoxyethylene castor oil derivative. Sorbitan laurate and sodium lauryl sulfate are preferred surfactants.

上述揭露的4種API之單位劑量調配物或上述2種API之單體錠劑可用作藥物。特定言之，本發明之調配物亦可用於治療HIV-1感染。 The unit dosage formulations of the above four APIs disclosed above or the monomeric tablets of the above two APIs can be used as a medicament. In particular, the formulations of the invention may also be used to treat HIV-1 infection.

本發明更提供一種治療HIV-1感染之方法，包括投與醫藥學上有效量之上述4種API之單位劑量調配物或上述2種API之單體錠劑。 The invention further provides a method of treating HIV-1 infection comprising administering a pharmaceutically effective amount of the above four API unit dose formulations or the above two API monomer tablets.

藉由以下實例說明本發明，所述實例並不意欲限制本發明之範疇。應瞭解，各種修改屬於本發明之精神及範疇內。 The invention is illustrated by the following examples which are not intended to limit the scope of the invention. It should be understood that various modifications are within the spirit and scope of the invention.

分析方法Analytical method 用於包括地瑞那韋及利托那韋之錠劑之檢定分析方法Analytical method for the determination of lozenges including darunavir and ritonavir

層析系統 Chromatography system

管柱及填料：菲羅門盧納(Phenomenex Luna)C18(2)5μm， 100A 250mm×4.6mm Column and packing: Phenomenex Luna C18(2) 5μm, 100A 250mm × 4.6mm

管柱溫度：30 Column temperature: 30

行動相：緩衝溶液(pH 3.2)：乙腈(40：60) Action phase: buffer solution (pH 3.2): acetonitrile (40:60)

流動速率：1.0mL/min. Flow rate: 1.0mL/min.

偵測器：240nm下之UV，10mm流槽路徑長度 Detector: UV at 240nm, 10mm flow path length

用於包括恩曲他濱、泰諾福韋、地瑞那韋、利托那韋之錠劑之分析方法：Analytical methods for lozenges including emtricitabine, tenofovir, darunavir, and ritonavir:

用於恩曲他濱/泰諾福韋/地瑞那韋之雜質及降解產物測定層析條件：For the determination of impurities and degradation products of emtricitabine / tenofovir / darunavir:

管柱：島津(Inertsil)ODS-3，150mm×4.6mm，3μm Column : Shimadzu (Inertsil) ODS-3, 150mm × 4.6mm, 3μm

管柱溫度：40℃ Column temperature : 40 ° C

行動相： Action phase :

溶液A：乙酸酯緩衝液pH 4.6：MeOH(95：5 v/v) Solution A: acetate buffer pH 4.6: MeOH (95: 5 v/v)

溶液B：乙腈(ACN) Solution B: acetonitrile (ACN)

梯度： Gradient :

流速：0.8mL/min Flow rate : 0.8mL/min

偵測器：262nm下之UV(根據PDA)，10mm流槽路徑長度 Detector : UV at 262 nm (according to PDA), 10 mm flow path length

檢定層析條件：Calibration chromatographic conditions:

管柱：非羅門盧納(Phenomenex Luna)C18(2)，250mm×4.6mm，5μm Column : Phenomenex Luna C18 (2), 250mm × 4.6mm, 5μm

管柱溫度：30℃ Column temperature : 30 ° C

行動相： Action phase :

溶液A：H2O(pH 3.2)：ACN(90：10 v/v) Solution A: H 2 O (pH 3.2): ACN (90: 10 v/v)

溶液B：ACN Solution B: ACN

梯度： Gradient :

偵測器：240nm下之UV，10mm流槽路徑長度 Detector : UV at 240nm, 10mm flow path length

利托那韋之雜質及降解產物測定層析條件：Determination of impurities and degradation products of ritonavir by chromatographic conditions:

管柱：阿奎提高效液相層析亞乙基橋雜化(ACQUITY UPLC BEH)C8 1.7μm，2.1mm×100mm Pipe column : Acqui Enhanced Liquid Chromatography Ethylene Bridge Hybrid (ACQUITY UPLC BEH) C8 1.7μm, 2.1mm×100mm

管柱溫度：50℃ Column temperature : 50 ° C

行動相： Action phase :

溶液A=緩衝劑：四氫呋喃(THF)：正丁醇(87：8：5 v/v) Solution A = Buffer: Tetrahydrofuran (THF): n-butanol (87:8:5 v/v)

溶液B=ACN：THF：正丁醇(87：8：5 v/v) Solution B = ACN: THF: n-butanol (87:8:5 v/v)

梯度： Gradient :

流速：0.6mL/min Flow rate: 0.6mL/min

偵測器：240nm下之UV(根據PDA)，10mm流槽路徑長度 Detector : UV at 240nm (according to PDA), 10mm flow path length

實例Instance 實例1：製備利托那韋預混物Example 1: Preparation of ritonavir premix

利托那韋及賦形劑溶解於乙醇中。蒸發乙醇以獲得乾燥粉末。隨後將粉末研磨為較低粒度。 Ritonavir and excipients are dissolved in ethanol. The ethanol was evaporated to obtain a dry powder. The powder is then ground to a lower particle size.

實例2：製備含有地瑞那韋-粒外型利托那韋之單體錠劑Example 2: Preparation of a monomeric tablet containing darunavir-granular ritonavir

地瑞那韋粒化-藉由頂噴製程使用羥丙甲纖維素(美多秀E-15)作為粒化溶液且使用純化水作為粒化液體對地瑞那韋進行濕式粒化。 Granulation of darunavir - Wet granulation of darunavir by using a hypromellose (Medodo E-15) as a granulation solution and using purified water as a granulation liquid by a top spray process.

隨後在流化床乾燥器中乾燥濕式粒化材料且研磨為較低粒度。 The wet granulated material is then dried in a fluid bed dryer and ground to a lower particle size.

混合地瑞那韋粒化物、利托那韋預混物(根據實例1製備)、交聯聚維酮、微晶纖維素(艾維素102)以及二氧化矽(埃羅希爾)且接著添加硬脂醯反丁烯二酸鈉以用於最終混合，且將混合物進一步壓縮為錠劑核心。 Mixed darunavir granulate, ritonavir premix (prepared according to Example 1), crospovidone, microcrystalline cellulose (Avicel 102) and cerium oxide (Erhiel) and then Sodium stearyl fumarate is added for final mixing and the mixture is further compressed into a tablet core.

隨後用膜衣材料塗佈錠劑核心以產生膜衣錠劑(約3%重量增加)。 The tablet core was then coated with a film coat material to produce a film-coated lozenge (about 3% weight gain).

實例3：製備含有地瑞那韋-利托那韋(粒內型)之單體錠劑Example 3: Preparation of a monomeric lozenge containing darunavir-ritonavir (intragranular)

地瑞那韋-利托那韋粒化-使用羥丙甲纖維素(美多秀E-15)作為粒化溶液及純化水作為粒化液體藉由頂噴製程使地瑞那韋與利托那韋預混物(根據實例1製備)進行濕式粒化。 Granulation of darunavir-ritonavir - using hypromellose (Medodo E-15) as granulation solution and purified water as granulating liquid to make darunavir and Lito by top spray process The Nave premix (prepared according to Example 1) was wet granulated.

隨後在流化床乾燥器中乾燥濕式粒化材料且研磨為較低粒度。 The wet granulated material is then dried in a fluid bed dryer and ground to a lower particle size.

混合地瑞那韋-利托那韋之粒化物、交聯聚維酮、微晶纖維素(艾維素102)以及二氧化矽(埃羅希爾)且接著添加硬脂醯反丁烯二酸鈉以用於最終混合，且將混合物進一步壓縮為錠劑核心。 Mixing darunavir-ritonavir granules, crospovidone, microcrystalline cellulose (Avicel 102) and cerium oxide (Erthir) followed by the addition of stearin antibutene Sodium is used for the final mixing and the mixture is further compressed into a tablet core.

隨後用膜衣材料塗佈錠劑核心以產生膜衣錠劑(約3%重量增加)。 The tablet core was then coated with a film coat material to produce a film-coated lozenge (about 3% weight gain).

實例4：製備恩曲他濱/泰諾福韋粒化物Example 4: Preparation of emtricitabine/tenofovir granulate

恩曲他濱/反丁烯二酸泰諾福韋酯藉由高剪切混合器與微晶纖維素(艾維素102)、單水合乳糖、預膠凝化澱粉以及交聯羧甲纖維素鈉(Ac-Di-Sol)進行濕式粒化。隨後藉由流化床乾燥器乾燥顆粒且研磨為較低粒度[參見上文評述]。隨後視情況添加交聯羧甲纖維素鈉作為粒外型崩解劑。 Emtricitabine/tenofovir fumarate by high shear mixer with microcrystalline cellulose (Avicel 102), lactose monohydrate, pregelatinized starch and croscarmellose Sodium (Ac-Di-Sol) was subjected to wet granulation. The granules were then dried by a fluid bed dryer and ground to a lower particle size [see review above] . Then, croscarmellose sodium is added as an extragranular disintegrator as the case may be.

實例5：製備恩曲他濱粒化物Example 5: Preparation of emtricitabine granulate

恩曲他濱與賦形劑混合且使用純化水中之聚維酮溶液進行濕式粒化。隨後在流化床乾燥器中乾燥潮濕粒化物。 Emtricitabine is mixed with excipients and wet granulated using a solution of povidone in purified water. The wet granulate is then dried in a fluid bed dryer.

實例5A：製備恩曲他濱粒化物Example 5A: Preparation of emtricitabine granulate

恩曲他濱與賦形劑混合且使用純化水中之聚維酮溶液進行濕式粒化。隨後在流化床乾燥器中乾燥潮濕粒化物。 Emtricitabine is mixed with excipients and wet granulated using a solution of povidone in purified water. The wet granulate is then dried in a fluid bed dryer.

實例6：製備反丁烯二酸泰諾福韋酯粒化物Example 6: Preparation of Tenofovir Fumarate Granules

反丁烯二酸泰諾福韋酯與賦形劑混合且使用純化水進行濕式粒化。隨後在流化床乾燥器中乾燥潮濕粒化物。 Tenofovir fumarate is mixed with an excipient and wet granulated using purified water. The wet granulate is then dried in a fluid bed dryer.

實例7：藉由乾燥混合製備反丁烯二酸泰諾福韋酯粒化物Example 7: Preparation of Tenofovir Fumarate Granules by Dry Mixing

泰諾福韋粒化藉由泰諾福韋酯連同賦形劑之乾燥混合製備產生。 Tenofovir granulation is produced by dry mixing of tenofovir and esters with excipients.

實例7A：製備反丁烯二酸泰諾福韋酯粒化物Example 7A: Preparation of Tenofovir Fumarate Granules

反丁烯二酸泰諾福韋酯與賦形劑混合且使用純化水進行濕式粒化。隨後在流化床乾燥器中乾燥潮濕粒化物。 Tenofovir fumarate is mixed with an excipient and wet granulated using purified water. The wet granulate is then dried in a fluid bed dryer.

實例8：製備含有恩曲他濱、泰諾福韋、地瑞那韋以及利托那韋(粒外型)之單體錠劑Example 8: Preparation of a monomeric lozenge containing emtricitabine, tenofovir, darunavir and ritonavir (extragranular)

根據實例4A或實例4B製備包含粒外型崩解劑之恩曲他濱/泰諾福韋粒化物。隨後添加根據實例2製備之地瑞那韋-利托那韋調配物。隨後，將最終混合物進一步壓縮為錠劑核心。 The emtricitabine/tenofovir granulate containing the extragranular disintegrant was prepared according to Example 4A or Example 4B. The darunavir-ritonavir formulation prepared according to Example 2 was then added. Subsequently, the final mixture is further compressed into a tablet core.

隨後用膜衣材料塗佈錠劑核心以產生膜衣錠劑(約3%重量增加)。 The tablet core was then coated with a film coat material to produce a film-coated lozenge (about 3% weight gain).

實例9：製備在第一層中含有恩曲他濱及泰諾福韋、在第二層中含有地瑞那韋及利托那韋(粒外型)之雙層錠劑Example 9: Preparation of a bilayer tablet containing emtricitabine and tenofovir in the first layer and darinavir and ritonavir (extragranular form) in the second layer

最終摻合物第1層： The final blend of the first layer:

根據實例4A製備包含粒外型崩解劑之恩曲他濱/泰諾福韋粒化物，隨後將其與硬脂酸鎂混合。 The emtricitabine/tenofovir granulate containing the extragranular disintegrant was prepared according to Example 4A, which was then mixed with magnesium stearate.

最終摻合物第2層： Final blend layer 2:

地瑞那韋-利托那韋調配物，根據實例2製備，不包括壓縮步驟。 The darunavir-ritonavir formulation, prepared according to Example 2, did not include a compression step.

隨後將兩種摻合物壓縮為錠劑核心。 The two blends are then compressed into a tablet core.

隨後用膜衣材料塗佈錠劑核心以產生膜衣錠劑(約3%重量增加)。 The tablet core was then coated with a film coat material to produce a film-coated lozenge (about 3% weight gain).

實例10：製備含有恩曲他濱、泰諾福韋、地瑞那韋以及利托那韋(粒內型)之單體錠劑Example 10: Preparation of a monomeric lozenge containing emtricitabine, tenofovir, darunavir, and ritonavir (intragranular)

根據實例4A或實例4B製備包含粒外型崩解劑之恩曲他濱/泰諾福韋粒化物。隨後添加根據實例3(不包括壓縮步驟)製備之地瑞那韋-利托那韋調配物。隨後，將最終混合物進一步壓縮為錠劑核心。 The emtricitabine/tenofovir granulate containing the extragranular disintegrant was prepared according to Example 4A or Example 4B. The darunavir-ritonavir formulation prepared according to Example 3 (excluding the compression step) was then added. Subsequently, the final mixture is further compressed into a tablet core.

隨後用膜衣材料塗佈錠劑核心以產生膜衣錠劑(約3%重量增加)。 The tablet core was then coated with a film coat material to produce a film-coated lozenge (about 3% weight gain).

實例11：製備在第一層中含有恩曲他濱及泰諾福韋、在第二層中含有地瑞那韋及利托那韋(粒內型)之雙層錠劑Example 11: Preparation of a bilayer tablet containing emtricitabine and tenofovir in the first layer and darinavir and ritonavir (intragranular form) in the second layer

最終摻合物第1層： The final blend of the first layer:

根據實例4A製備包含粒外型崩解劑之恩曲他濱/泰諾福韋粒化物，隨後將其與硬脂酸鎂混合。 The emtricitabine/tenofovir granulate containing the extragranular disintegrant was prepared according to Example 4A, which was then mixed with magnesium stearate.

最終摻合物第2層： Final blend layer 2:

地瑞那韋-利托那韋調配物，根據實例3製備，不包括壓縮步驟。 The darunavir-ritonavir formulation, prepared according to Example 3, did not include a compression step.

隨後將兩種摻合物壓縮為錠劑核心。 The two blends are then compressed into a tablet core.

隨後用膜衣材料塗佈錠劑核心以產生膜衣錠劑(約3%重量增加)。 The tablet core was then coated with a film coat material to produce a film-coated lozenge (about 3% weight gain).

Claims (140)

一種呈單位劑量形式之醫藥調配物，包括：(a)泰諾福韋或其生理學上之功能衍生物；(b)恩曲他濱或其生理學上之功能衍生物；(c)地瑞那韋或其生理學上之功能衍生物；以及(d)利托那韋或其生理學上之功能衍生物。 A pharmaceutical formulation in unit dosage form comprising: (a) tenofovir or a physiologically functional derivative thereof; (b) emtricitabine or a physiologically functional derivative thereof; (c) Rinavir or a physiologically functional derivative thereof; and (d) ritonavir or a physiologically functional derivative thereof. 如申請專利範圍第1項所述之呈單位劑量形式之醫藥調配物，其中(b)-(d)之情況下，所述生理學上之功能衍生物為醫藥學上可接受之衍生物，其選自於由鹽類、對映異構體、固態形式(結晶、半結晶或非晶形)、多晶型物、溶劑合物、代謝物或前藥所構成的族群，較佳地，其中所述前藥為酯，或所述對映異構體、固態形式、多晶型物、溶劑合物、代謝物或前藥(諸如酯)之醫藥學上可接受之鹽。 The pharmaceutical formulation in unit dosage form as described in claim 1 wherein, in the case of (b)-(d), the physiologically functional derivative is a pharmaceutically acceptable derivative, It is selected from the group consisting of salts, enantiomers, solid forms (crystalline, semi-crystalline or amorphous), polymorphs, solvates, metabolites or prodrugs, preferably wherein The prodrug is an ester, or a pharmaceutically acceptable salt of the enantiomer, solid form, polymorph, solvate, metabolite or prodrug such as an ester. 如申請專利範圍中前述任一項所述之呈單位劑量形式之醫藥調配物，其中所述泰諾福韋酯以反丁烯二酸鹽形式呈現。 A pharmaceutical formulation in unit dosage form as described in any one of the preceding claims, wherein the tenofovir disoproxil is presented as a fumarate salt. 如申請專利範圍中前述任一項所述之呈單位劑量形式之醫藥調配物，其中所述地瑞那韋以地瑞那韋乙醇化物、水合物或任何其他結晶形態呈現以及非晶形地瑞那韋形式呈現，較佳為水合物。 A pharmaceutical formulation in unit dosage form according to any of the preceding claims, wherein the darunavir is presented as darunavir ethanolate, hydrate or any other crystalline form and amorphous rena The form of wei is present, preferably a hydrate. 如申請專利範圍中前述任一項所述之呈單位劑量形式之醫藥調配物，其中所述利托那韋以其結晶形態呈現以及非晶形利托那韋形式呈現。 A pharmaceutical formulation in unit dosage form as described in any one of the preceding claims, wherein the ritonavir is present in its crystalline form and in the form of an amorphous ritonavir. 如申請專利範圍中前述任一項所述之呈單位劑量形式之醫藥調配物，其以固體單位劑量形式呈現。 A pharmaceutical formulation in unit dosage form as described in any one of the preceding claims, which is presented as a solid unit dosage form. 如申請專利範圍中前述任一項所述之呈單位劑量形式之醫藥調配物，其經口投與。 A pharmaceutical formulation in unit dosage form as described in any one of the preceding claims, which is administered orally. 如申請專利範圍中前述任一項所述之呈單位劑量形式之醫藥調配物，以膠囊(諸如硬膠囊或軟膠囊)、錠劑(諸如包覆或未包覆包衣、起泡、可溶、口內崩散、腸溶或緩釋錠劑或糖衣錠劑)、顆粒、丸粒、丸劑、散劑、片劑以及其醫藥調配物形式呈現。 A pharmaceutical formulation in unit dosage form as described in any one of the preceding claims, in capsules (such as hard or soft capsules), lozenges (such as coated or uncoated, foamed, soluble) , in-oral disintegration, enteric or sustained-release tablets or dragees), granules, pellets, pills, powders, tablets, and pharmaceutical formulations thereof. 如申請專利範圍中前述任一項所述之呈單位劑量形式之醫藥調配物，以錠劑或膠囊形式呈現。 A pharmaceutical formulation in unit dosage form as described in any one of the preceding claims is presented in the form of a lozenge or capsule. 如申請專利範圍中前述任一項所述之呈單位劑量形式之醫藥調配物，以膜衣錠劑形式呈現。 A pharmaceutical formulation in unit dosage form as described in any one of the preceding claims is presented as a film-coated tablet. 如申請專利範圍中前述任一項所述之呈單位劑量形式之醫藥調配物，其中所述醫藥劑量形式為錠劑，其可為單體(單層)或可包括兩層(雙層)或多於兩層(多層)。 A pharmaceutical formulation in unit dosage form as described in any one of the preceding claims, wherein the pharmaceutical dosage form is a tablet, which may be a monomer (single layer) or may comprise two layers (double layer) or More than two layers (multilayer). 如申請專利範圍中前述任一項所述之呈單位劑量形式之醫藥調配物，以單體錠劑形式呈現。 A pharmaceutical formulation in unit dosage form as described in any one of the preceding claims is presented in the form of a monomeric lozenge. 如申請專利範圍中前述任一項所述之呈單位劑量形式之醫藥調配物，其以每天投與一次之單一單位劑量形式呈現。 A pharmaceutical formulation in unit dosage form as described in any one of the preceding claims, which is presented as a single unit dosage form administered once daily. 如申請專利範圍中前述任一項所述之呈單位劑量形式之醫藥調配物，其中相比於以獨立單位劑量形式投與所述活性成分(a)至所述活性成分(d)，其達到所述活性成分(a)至所述活性成分(d)中之每一者之峰值血漿濃度。 A pharmaceutical formulation in unit dosage form as described in any one of the preceding claims, wherein the administration of the active ingredient (a) to the active ingredient (d) is achieved in a separate unit dosage form. Peak plasma concentration of each of the active ingredient (a) to the active ingredient (d). 如申請專利範圍中前述任一項所述之呈單位劑量形式之醫藥調配物，其為化學穩定的。 A pharmaceutical formulation in unit dosage form as described in any one of the preceding claims, which is chemically stable. 如申請專利範圍中前述任一項所述之呈單位劑量形式之 醫藥調配物，其中所述單位劑量形式具有總重量約2.800g、小於或等於約2.600g、小於或等於約2.500g、小於或等於約2.400g、小於或等於約2.300g、小於或等於約2.200g、小於或等於約1.900g或小於或等於約1.800g、或小於或等於約1.700g、或小於或等於約1.600g、或小於或等於約1.500g。 Unit dosage form as described in any one of the preceding claims A pharmaceutical formulation wherein the unit dosage form has a total weight of about 2.800 g, less than or equal to about 2.600 g, less than or equal to about 2.500 g, less than or equal to about 2.400 g, less than or equal to about 2.300 g, less than or equal to about 2.200. g, less than or equal to about 1.900 g or less than or equal to about 1.800 g, or less than or equal to about 1.700 g, or less than or equal to about 1.600 g, or less than or equal to about 1.500 g. 如申請專利範圍中前述任一項所述之呈單位劑量形式之醫藥調配物，其中所述單位劑量形式具有總重量介於約1.500g至約1.600g、至約1.700g、至約1.800g、至約1.900g、至約2.000g、至約2.200g、至約2.300g、至約2.400g、至約2.500g、至約2.600g、至約2.800g之間。 A pharmaceutical formulation in unit dosage form as described in any one of the preceding claims, wherein the unit dosage form has a total weight of from about 1.500 g to about 1.600 g, to about 1.700 g, to about 1.800 g, To between about 1.900 g, to about 2.000 g, to about 2.200 g, to about 2.300 g, to about 2.400 g, to about 2.500 g, to about 2.600 g, to about 2.800 g. 如申請專利範圍中前述任一項所述之呈單位劑量形式之醫藥調配物，其中所述單位劑量形式具有總重量介於約1.600g至約1.700g、至約1.800g、至約1.900g、至約2.000g、至約2.200g、至約2.300g、至約2.400g、至約2.500g、至約2.600g、至約2.800g之間。 A pharmaceutical formulation in unit dosage form as described in any one of the preceding claims, wherein the unit dosage form has a total weight of from about 1.600 g to about 1.700 g, to about 1.800 g, to about 1.900 g, To between about 2.000 g, to about 2.200 g, to about 2.300 g, to about 2.400 g, to about 2.500 g, to about 2.600 g, to about 2.800 g. 如申請專利範圍中前述任一項所述之呈單位劑量形式之醫藥調配物，其中所述單位劑量形式具有總重量介於約1.700g至約1.800g、至約1.900g、至約2.000g、至約2.200g、至約2.300g、至約2.400g、至約2.500g、至約2.600g、至約2.800g之間。 A pharmaceutical formulation in unit dosage form as described in any one of the preceding claims, wherein the unit dosage form has a total weight of from about 1.700 g to about 1.800 g, to about 1.900 g, to about 2.000 g, To between about 2.200 g, to about 2.300 g, to about 2.400 g, to about 2.500 g, to about 2.600 g, to about 2.800 g. 如申請專利範圍中前述任一項所述之呈單位劑量形式之醫藥調配物，其中所述單位劑量形式具有總重量介於約1.800g至約1.900g、至約2.000g、至約2.200g、至約2.300g、至約2.400g、至約2.500g、至約2.600g、至約2.800g之間。 A pharmaceutical formulation in unit dosage form as described in any one of the preceding claims, wherein the unit dosage form has a total weight of from about 1.800 g to about 1.900 g, to about 2.000 g, to about 2.200 g, To between about 2.300 g, to about 2.400 g, to about 2.500 g, to about 2.600 g, to about 2.800 g. 如申請專利範圍中前述任一項所述之呈單位劑量形式之 醫藥調配物，其中所述單位劑量形式具有總重量介於約1.900g至約2.000g、至約2.200g、至約2.300g、至約2.400g、至約2.500g、至約2.600g、至約2.800g之間。 Unit dosage form as described in any one of the preceding claims A pharmaceutical formulation wherein the unit dosage form has a total weight of from about 1.900 g to about 2.000 g, to about 2.200 g, to about 2.300 g, to about 2.400 g, to about 2.500 g, to about 2.600 g, to about Between 2.800g. 如申請專利範圍中前述任一項所述之呈單位劑量形式之醫藥調配物，其中所述單位劑量形式具有總重量介於約2.000g至約2.200g、至約2.300g、至約2.400g、至約2.500g、至約2.600g、至約2.800g之間。 A pharmaceutical formulation in unit dosage form as described in any one of the preceding claims, wherein the unit dosage form has a total weight of from about 2.000 g to about 2.200 g, to about 2.300 g, to about 2.400 g, Up to about 2.500 g, to about 2.600 g, to about 2.800 g. 如申請專利範圍中前述任一項所述之呈單位劑量形式之醫藥調配物，其中所述單位劑量形式具有總重量介於約2.200g至約2.300g、至約2.400g、至約2.500g、至約2.600g、至約2.800g之間。 A pharmaceutical formulation in unit dosage form as described in any one of the preceding claims, wherein the unit dosage form has a total weight of from about 2.200 g to about 2.300 g, to about 2.400 g, to about 2.500 g, It is between about 2.600 g and about 2.800 g. 如申請專利範圍中前述任一項所述之呈單位劑量形式之醫藥調配物，其中所述單位劑量形式具有總重量介於約2.300g至約2.400g、至約2.500g、至約2.600g、至約2.800g之間。 A pharmaceutical formulation in unit dosage form as described in any one of the preceding claims, wherein the unit dosage form has a total weight of from about 2.300 g to about 2.400 g, to about 2.500 g, to about 2.600 g, Up to about 2.800g. 如申請專利範圍中前述任一項所述之呈單位劑量形式之醫藥調配物，其中所述單位劑量形式具有總重量介於約2.400g至約2.500g、至約2.600g、至約2.800g之間。 A pharmaceutical formulation in unit dosage form as described in any one of the preceding claims, wherein the unit dosage form has a total weight of from about 2.400 g to about 2.500 g, to about 2.600 g, to about 2.800 g. between. 如申請專利範圍中前述任一項所述之呈單位劑量形式之醫藥調配物，其中所述單位劑量形式具有總重量介於約2.500g至約2.600g、至約2.800g之間，或約2.600g至約2.800g之間。 A pharmaceutical formulation in unit dosage form as described in any one of the preceding claims, wherein the unit dosage form has a total weight of between about 2.500 g to about 2.600 g, to about 2.800 g, or about 2.600. g to between about 2.800g. 如申請專利範圍中前述任一項所述之呈單位劑量形式之醫藥調配物，其中包括4種API之本發明之所述錠劑之最大直徑為約27mm或小於27mm且深度為小於約12.5mm；較佳地，所述最大直徑在約26mm至約27mm之間且所述深度在約12.5mm 至約10mm之間。 A pharmaceutical formulation in unit dosage form as described in any one of the preceding claims, wherein the tablet of the invention comprising four APIs has a maximum diameter of about 27 mm or less and a depth of less than about 12.5 mm. Preferably, the maximum diameter is between about 26 mm and about 27 mm and the depth is about 12.5 mm. It is between about 10mm. 如申請專利範圍中前述任一項所述之呈單位劑量形式之醫藥調配物，其中包括所述4種API之本發明之所述錠劑之硬度可為約75科布強度單位(Strong-Cobb Unit；SCU)至約20SCU，較佳約55SCU至約25SCU。 A pharmaceutical formulation in unit dosage form as described in any one of the preceding claims, wherein the tablet of the present invention comprising the four APIs has a hardness of about 75 cob strength units (Strong-Cobb Unit; SCU) to about 20 SCU, preferably about 55 SCU to about 25 SCU. 如申請專利範圍中前述任一項所述之呈單位劑量形式之醫藥調配物，其中所述單位劑量形式包括：(a)約150mg至約350mg泰諾福韋酯；(b)約100mg至約300mg恩曲他濱；(c)約75mg至約800mg地瑞那韋；以及(d)約100mg利托那韋。 A pharmaceutical formulation in unit dosage form as described in any one of the preceding claims, wherein the unit dosage form comprises: (a) from about 150 mg to about 350 mg of tenofovir disoproxil; (b) from about 100 mg to about 300 mg of emtricitabine; (c) from about 75 mg to about 800 mg of darunavir; and (d) about 100 mg of ritonavir. 如申請專利範圍中前述任一項所述之呈單位劑量形式之醫藥調配物，其中所述單位劑量形式包括：(a)約300mg泰諾福韋酯；(b)約200mg恩曲他濱；(c)約800mg地瑞那韋；以及(d)約100mg利托那韋。 A pharmaceutical formulation in unit dosage form according to any of the preceding claims, wherein the unit dosage form comprises: (a) about 300 mg of tenofovir disoproxil; (b) about 200 mg of emtricitabine; (c) about 800 mg of darunavir; and (d) about 100 mg of ritonavir. 如申請專利範圍中前述任一項所述之呈單位劑量形式之醫藥調配物，其中所述單位劑量形式包括約20重量%至約85重量%之活性成分(a)至活性成分(d)。 A pharmaceutical formulation in unit dosage form as described in any one of the preceding claims, wherein the unit dosage form comprises from about 20% to about 85% by weight of active ingredient (a) to active ingredient (d). 如申請專利範圍中前述任一項所述之呈單位劑量形式之醫藥調配物，其中所述單位劑量形式包括約20重量%至約25重量%、至約30重量%、至約35重量%、至約40重量%、至約45重量%、至約50重量%、至約55重量%、至約60重量%、至約65 重量%、至約70重量%、至約75重量%、至約80重量%或至約85重量%之活性成分(a)至活性成分(d)。 A pharmaceutical formulation in unit dosage form as described in any one of the preceding claims, wherein the unit dosage form comprises from about 20% to about 25% by weight, to about 30% by weight, to about 35% by weight, To about 40% by weight, to about 45% by weight, to about 50% by weight, to about 55% by weight, to about 60% by weight, to about 65 The active ingredient (a) to the active ingredient (d) is % by weight, to about 70% by weight, to about 75% by weight, to about 80% by weight or to about 85% by weight. 如申請專利範圍中前述任一項所述之呈單位劑量形式之醫藥調配物，其中所述單位劑量形式包括約25重量%至約30重量%、至約35重量%、至約40重量%、至約45重量%、至約50重量%、至約55重量%、至約60重量%、至約65重量%、至約70重量%、至約75重量%、至約80重量%或至約85重量%之活性成分(a)至活性成分(d)。 A pharmaceutical formulation in unit dosage form as described in any one of the preceding claims, wherein the unit dosage form comprises from about 25% to about 30% by weight, to about 35% by weight, to about 40% by weight, To about 45% by weight, to about 50% by weight, to about 55% by weight, to about 60% by weight, to about 65% by weight, to about 70% by weight, to about 75% by weight, to about 80% by weight or to about 85 % by weight of active ingredient (a) to active ingredient (d). 如申請專利範圍中前述任一項所述之呈單位劑量形式之醫藥調配物，其中所述單位劑量形式包括約30重量%至約35重量%、至約40重量%、至約45重量%、至約50重量%、至約55重量%、至約60重量%、至約65重量%、至約70重量%、至約75重量%、至約80重量%或至約85重量%之活性成分(a)至活性成分(d)。 A pharmaceutical formulation in unit dosage form as described in any one of the preceding claims, wherein the unit dosage form comprises from about 30% to about 35% by weight, to about 40% by weight, to about 45% by weight, Up to about 50% by weight, to about 55% by weight, to about 60% by weight, to about 65% by weight, to about 70% by weight, to about 75% by weight, to about 80% by weight or to about 85% by weight of active ingredient (a) to the active ingredient (d). 如申請專利範圍中前述任一項所述之呈單位劑量形式之醫藥調配物，其中所述單位劑量形式包括約40重量%至約45重量%、至約50重量%、至約55重量%、至約60重量%、至約65重量%、至約70重量%、至約75重量%、至約80重量%或至約85重量%之活性成分(a)至活性成分(d)。 A pharmaceutical formulation in unit dosage form as described in any one of the preceding claims, wherein the unit dosage form comprises from about 40% to about 45% by weight, to about 50% by weight, to about 55% by weight, Up to about 60% by weight, to about 65% by weight, to about 70% by weight, to about 75% by weight, to about 80% by weight or to about 85% by weight of active ingredient (a) to active ingredient (d). 如申請專利範圍中前述任一項所述之呈單位劑量形式之醫藥調配物，其中所述單位劑量形式包括約45重量%至約50重量%、至約55重量%、至約60重量%、至約65重量%、至約70重量%、至約75重量%、至約80重量%或至約85重量%之活性成分(a)至活性成分(d)。 A pharmaceutical formulation in unit dosage form as described in any one of the preceding claims, wherein the unit dosage form comprises from about 45% to about 50% by weight, to about 55% by weight, to about 60% by weight, Up to about 65% by weight, to about 70% by weight, to about 75% by weight, to about 80% by weight or to about 85% by weight of active ingredient (a) to active ingredient (d). 如申請專利範圍中前述任一項所述之呈單位劑量形式之醫藥調配物，其中所述單位劑量形式包括約50重量%至約55重量%、至約60重量%、至約65重量%、至約70重量%、至約75重量%、至約80重量%或至約85重量%之活性劑(a)至活性成分(d)。 A pharmaceutical formulation in unit dosage form as described in any one of the preceding claims, wherein the unit dosage form comprises from about 50% to about 55% by weight, to about 60% by weight, to about 65% by weight, Up to about 70% by weight, to about 75% by weight, to about 80% by weight or to about 85% by weight of active agent (a) to active ingredient (d). 如申請專利範圍中前述任一項所述之呈單位劑量形式之醫藥調配物，其中所述單位劑量形式包括約55重量%至約60重量%、至約65重量%、至約70重量%、至約75重量%、至約80重量%或至約85重量%之活性成分(a)至活性成分(d)。 A pharmaceutical formulation in unit dosage form as described in any one of the preceding claims, wherein the unit dosage form comprises from about 55% to about 60% by weight, to about 65% by weight, to about 70% by weight, Up to about 75% by weight, up to about 80% by weight or up to about 85% by weight of active ingredient (a) to active ingredient (d). 如申請專利範圍中前述任一項所述之呈單位劑量形式之醫藥調配物，其中所述單位劑量形式包括約60重量%至約65重量%、至約70重量%、至約75重量%、至約80重量%或至約85重量%之活性成分(a)至活性成分(d)。 A pharmaceutical formulation in unit dosage form as described in any one of the preceding claims, wherein the unit dosage form comprises from about 60% to about 65% by weight, to about 70% by weight, to about 75% by weight, Up to about 80% by weight or up to about 85% by weight of active ingredient (a) to active ingredient (d). 如申請專利範圍中前述任一項所述之呈單位劑量形式之醫藥調配物，其中所述單位劑量形式包括約65重量%至約70重量%、至約75重量%、至約80重量%或至約85重量%之活性成分(a)至活性成分(d)。 A pharmaceutical formulation in unit dosage form as described in any one of the preceding claims, wherein the unit dosage form comprises from about 65% to about 70% by weight, to about 75% by weight, to about 80% by weight or Up to about 85% by weight of active ingredient (a) to active ingredient (d). 如申請專利範圍中前述任一項所述之呈單位劑量形式之醫藥調配物，其中所述單位劑量形式包括約70重量%至約75重量%、至約80重量%或至約85重量%之活性成分(a)至活性成分(d)。 A pharmaceutical formulation in unit dosage form as described in any one of the preceding claims, wherein the unit dosage form comprises from about 70% to about 75% by weight, to about 80% by weight or to about 85% by weight. Active ingredient (a) to active ingredient (d). 如申請專利範圍中前述任一項所述之呈單位劑量形式之醫藥調配物，其中所述單位劑量形式包括約75重量%至約80重量%或至約85重量%，或約80重量%至約85重量%之活性成分(a)至活性成分(d)。 A pharmaceutical formulation in unit dosage form as described in any one of the preceding claims, wherein the unit dosage form comprises from about 75% to about 80% by weight or to about 85% by weight, or about 80% by weight to About 85% by weight of active ingredient (a) to active ingredient (d). 如申請專利範圍中前述任一項所述之呈單位劑量形式之 醫藥調配物，其以單體錠劑形式呈現，其中所述活性成分(a)至所述活性成分(d)經混合及壓縮為單層(單體)錠劑。 Unit dosage form as described in any one of the preceding claims A pharmaceutical formulation is presented in the form of a monomeric lozenge wherein the active ingredient (a) to the active ingredient (d) are mixed and compressed into a single layer (monomeric) lozenge. 如申請專利範圍第43項所述之呈單位劑量形式之醫藥調配物，其中所述單層包括：(a)下述者之混雜物：地瑞那韋與粒外型利托那韋或地瑞那韋與粒內型利托那韋(亦即地瑞那韋-利托那韋之粒化物)、恩曲他濱顆粒及泰諾福韋顆粒(較佳泰諾福韋酯，且更佳反丁烯二酸泰諾福韋酯)顆粒；或(b)下述者之混雜物：地瑞那韋與粒外型利托那韋或地瑞那韋與粒內型利托那韋(亦即地瑞那韋-利托那韋之粒化物)以及包括恩曲他濱及泰諾福韋二者之顆粒。 The pharmaceutical formulation in unit dosage form as described in claim 43 wherein the monolayer comprises: (a) a mixture of: darinavir and extragranular ritonavir or diatom Renavir and intragranular ritonavir (also known as granules of darunavir-ritonavir), emtricitabine granules and tenofovir granules (preferably tenofovir), and better Granules of tenofovir disoproxil); or (b) a mixture of darunavir and extragranular ritonavir or darunavir with intragranular ritonavir ( That is, granules of darunavir-ritonavir and granules including both emtricitabine and tenofovir. 如申請專利範圍中前述任一項所述之呈單位劑量形式之醫藥調配物，更包括一或多種醫藥學上可接受之賦形劑。 A pharmaceutical formulation in unit dosage form as described in any one of the preceding claims, further comprising one or more pharmaceutically acceptable excipients. 如申請專利範圍第45項所述之呈單位劑量形式之醫藥調配物，其中所述醫藥學上可接受之賦形劑是選自於由崩解劑、填充劑以及潤滑劑所構成的族群。 A pharmaceutical formulation in unit dosage form as described in claim 45, wherein the pharmaceutically acceptable excipient is selected from the group consisting of a disintegrant, a filler, and a lubricant. 一種用於製備如申請專利範圍中前述任一項所述之呈單位劑量形式之醫藥調配物之方法，其中所述醫藥調配物為錠劑、較佳單體錠劑，所述方法包括：(a)摻合包括泰諾福韋酯、恩曲他濱、地瑞那韋、利托那韋以及視情況存在之一或多種醫藥學上可接受之賦形劑之混合物；(b)將所述摻合物壓縮為錠劑核心；以及(c)視情況在所述錠劑核心上塗覆一或多個塗層。 A method for the preparation of a pharmaceutical formulation in unit dosage form as described in any one of the preceding claims, wherein the pharmaceutical formulation is a tablet, preferably a monomeric tablet, the method comprising: a) blending a mixture comprising tenofovir, emtricitabine, darunavir, ritonavir, and optionally one or more pharmaceutically acceptable excipients; (b) The blend is compressed into a tablet core; and (c) one or more coatings are applied to the tablet core as appropriate. 一種用於製備如申請專利範圍第1項至第47項中任一項 所述之呈單位劑量形式之醫藥調配物之方法，包括視情況在一或多種醫藥學上可接受之賦形劑存在下合併：(a)地瑞那韋與粒外型利托那韋或地瑞那韋與粒內型利托那韋(亦即地瑞那韋-利托那韋之粒化物)；(b)恩曲他濱顆粒；以及(c)泰諾福韋(較佳泰諾福韋酯，且更佳反丁烯二酸泰諾福韋酯)顆粒而形成摻合物。 One for preparing any one of items 1 to 47 as claimed in the patent application The method of providing a pharmaceutical formulation in unit dosage form comprising combining, where appropriate, one or more pharmaceutically acceptable excipients: (a) darunavir and extragranular ritonavir or Darunavir and intragranular ritonavir (ie, granulation of darunavir-ritonavir); (b) emtricitabine granules; and (c) tenofovir (better Tylenol) The fumarate, and more preferably the tenofovir disoproxil granules, form a blend. 一種用於製備如申請專利範圍第1項至第47項中任一項所述之呈單位劑量形式之醫藥調配物之方法，包括視情況在一或多種醫藥學上可接受之賦形劑存在下合併：(a)地瑞那韋與粒外型利托那韋或地瑞那韋與粒內型利托那韋(亦即地瑞那韋-利托那韋之粒化物)；(b)包括恩曲他濱及泰諾福韋二者之顆粒而形成摻合物。 A method for the preparation of a pharmaceutical formulation in unit dosage form according to any one of claims 1 to 47, which comprises the presence of one or more pharmaceutically acceptable excipients as appropriate Lower combination: (a) darunavir with extragranular ritonavir or darunavir and intragranular ritonavir (ie granules of darunavir-ritonavir); (b A pellet comprising both emtricitabine and tenofovir to form a blend. 如申請專利範圍第47項至第49項所述之方法，其中所述醫藥學上可接受之賦形劑包括至少一種選自填充劑(較佳微晶纖維素)、崩解劑(較佳交聯聚維酮)、滑動劑(較佳二氧化矽)以及潤滑劑(較佳硬脂醯反丁烯二酸鈉)之賦形劑。 The method of claim 47, wherein the pharmaceutically acceptable excipient comprises at least one member selected from the group consisting of a filler (preferably microcrystalline cellulose) and a disintegrating agent. An excipient for crospovidone, a slip agent (preferably cerium oxide), and a lubricant (preferably stearic acid succinimide). 如申請專利範圍第50項所述之方法，其中所述醫藥學上可接受之賦形劑包括微晶纖維素、交聯聚維酮、二氧化矽以及硬脂醯反丁烯二酸鈉。 The method of claim 50, wherein the pharmaceutically acceptable excipient comprises microcrystalline cellulose, crospovidone, cerium oxide, and sodium stearyl fumarate. 如申請專利範圍第47項至第51項中任一項所述之方法，更包括加工所述摻合物以提供固體劑量形式。 The method of any one of claims 47 to 51, further comprising processing the blend to provide a solid dosage form. 如申請專利範圍第47項至第52項中任一項所述之方法，包括壓縮所述摻合物以形成錠劑，及視情況用膜衣材料塗佈 所述錠劑以形成膜衣錠劑。 The method of any one of claims 47 to 52, comprising compressing the blend to form a tablet, and optionally coating the film material The tablet is used to form a film-coated tablet. 如申請專利範圍第53項所述之方法，其中所述摻合物在壓縮為錠劑之前視情況與一或多種醫藥學上可接受之賦形劑組合。 The method of claim 53, wherein the blend is combined with one or more pharmaceutically acceptable excipients prior to compression into a tablet. 如申請專利範圍第48項至第54項中任一項所述之方法，其中所述地瑞那韋-利托那韋之粒化物藉由地瑞那韋之濕式粒化製備，透過頂噴製程將溶解於適合液體(較佳水)中之至少一種黏合劑(較佳羥丙甲纖維素)噴於對地瑞那韋上之，接著乾燥濕顆粒及研磨乾燥顆粒。 The method of any one of claims 48 to 54, wherein the granulation of the darunavir-ritonavir is prepared by wet granulation of darunavir, through the top The spraying process sprays at least one binder (preferably hypromellose) dissolved in a suitable liquid (preferably water) onto darunavir, followed by drying the wet granules and grinding the dried granules. 如申請專利範圍第48項至第55項中任一項所述之方法，其中所述地瑞那韋顆粒與利托那韋預混物、至少一種填充劑(較佳微晶纖維素)、至少一種崩解劑(較佳交聯聚維酮)以及至少一種滑動劑(較佳二氧化矽)混合，接著添加至少一種潤滑劑(較佳硬脂醯反丁烯二酸鈉)至所獲得之混合物中以獲得地瑞那韋-利托那韋之最終摻合物(較佳為地瑞那韋與粒外型利托那韋)。 The method of any one of claims 48 to 55, wherein the darunavir granules are mixed with a ritonavir premix, at least one filler (preferably microcrystalline cellulose), Mixing at least one disintegrant (preferably crospovidone) and at least one slip agent (preferably cerium oxide), followed by addition of at least one lubricant (preferably stearic acid succinimide) to obtain The mixture is obtained in a final blend of darunavir-ritonavir (preferably darunavir and extragranular ritonavir). 如申請專利範圍第48項至第57項中任一項所述之方法，其中所述地瑞那韋-利托那韋之粒化物藉由地瑞那韋與利托那韋預混物之濕式粒化製備，透過頂噴製程將溶解於適合液體(較佳水)中之至少一種黏合劑(較佳羥丙甲纖維素)噴於對地瑞那韋及利托那韋之混合物上，接著乾燥濕顆粒及研磨乾燥顆粒。 The method of any one of claims 48 to 57, wherein the granule of darunavir-ritonavir is premixed with darunavir and ritonavir. Wet granulation preparation, spraying at least one binder (preferably hypromellose) dissolved in a suitable liquid (preferably water) onto a mixture of darunavir and ritonavir by a top spray process Then, the wet granules are dried and the dried granules are ground. 如申請專利範圍第48項至第54項中任一項所述之方法，其中所述地瑞那韋-利托那韋之粒化物與至少一種填充劑(較佳微晶纖維素)、至少一種崩解劑(較佳交聯聚維酮)以及至少一種滑動劑(較佳二氧化矽)混合，接著添加至少一種潤滑劑(較 佳硬脂醯反丁烯二酸鈉)至所獲得之混合物中以獲得地瑞那韋-利托那韋之最終摻合物(較佳為地瑞那韋與粒內型利托那韋)。 The method of any one of claims 48 to 54 wherein the granulation of darunavir-ritonavir is at least one filler (preferably microcrystalline cellulose), at least a disintegrant (preferably crospovidone) and at least one slip agent (preferably ceria) mixed, followed by at least one lubricant (more The stearyl sulfonium fumarate is added to the obtained mixture to obtain a final blend of darunavir-ritonavir (preferably darunavir and intragranular ritonavir) . 如申請專利範圍第47項至第58項中任一項所述之方法，其中所述利托那韋為非晶形利托那韋。 The method of any one of claims 47 to 58 wherein the ritonavir is amorphous ritonavir. 如申請專利範圍第47項至第59項中任一項所述之方法，其中所述利托那韋呈預混物形式，其中利托那韋預混物為利托那韋與至少一種醫藥學上可接受之賦形劑之共沈澱物，所述預混物藉由在溶劑(較佳乙醇)中混合利托那韋與至少一種賦形劑(較佳載劑，且更佳共聚維酮)以形成溶液及蒸發所述溶劑製備。 The method of any one of claims 47 to 59, wherein the ritonavir is in the form of a premix, wherein the ritonavir premix is ritonavir and at least one drug a coprecipitate of a permissible acceptable excipient by mixing ritonavir with at least one excipient (preferably a carrier, and a better copolymerization) in a solvent, preferably ethanol The ketone) is prepared by forming a solution and evaporating the solvent. 如申請專利範圍第60項所述之方法，其中利托那韋預混物之製備透過在溶劑(較佳乙醇)中混合利托那韋與至少一種賦形劑(較佳載劑且更佳共聚維酮)、視情況與至少一種增溶劑(較佳脫水山梨糖醇月桂酸酯)以及至少一種滑動劑(較佳二氧化矽)，接著藉由蒸發移除所述溶劑以形成固體，以及視情況研磨所得固體。 The method of claim 60, wherein the preparation of the ritonavir premix is carried out by mixing ritonavir with at least one excipient (preferably a carrier and preferably) in a solvent (preferably ethanol). Copolyvidone), optionally with at least one solubilizer (preferably sorbitan laurate) and at least one slip agent (preferably cerium oxide), followed by removal of the solvent by evaporation to form a solid, and The resulting solid was milled as appropriate. 如申請專利範圍第48項至第49項中任一項或申請專利範圍第55項至第72項中任一項所述之方法，其中所述恩曲他濱顆粒之製備透過與至少一種醫藥學上可接受之賦形劑摻合以形成混合物，以及對所述混合物進行粒化，例如藉由乾式粒化或藉由濕式粒化，接著乾燥所述濕顆粒。 The method according to any one of claims 48 to 49, wherein the preparation of the emtricitabine particles is at least one medicine The acceptable excipients are blended to form a mixture, and the mixture is granulated, for example by dry granulation or by wet granulation, followed by drying of the wet granules. 如申請專利範圍第62項所述之方法，其中所述恩曲他濱顆粒與至少一種填充劑(較佳乳糖)及至少一種崩解劑(較佳交聯聚維酮)混合以提供混合物、合併所述混合物與黏合劑溶液(較佳聚維酮水溶液)而形成濕顆粒，乾燥所述濕顆粒。 The method of claim 62, wherein the emtricitabine particles are mixed with at least one filler (preferably lactose) and at least one disintegrant (preferably crospovidone) to provide a mixture, The mixture is combined with a binder solution (preferably an aqueous povidone solution) to form wet granules, and the wet granules are dried. 如申請專利範圍第62項所述之方法，其中所述恩曲他濱顆粒之製備透過合併恩曲他濱與至少一種填充劑(較佳微晶纖維素及/或預膠凝化澱粉)及至少一種崩解劑(較佳交聯羧甲纖維素鈉)以獲得混合物、合併所述混合物與黏合劑溶液(較佳聚維酮水溶液)而形成濕顆粒，乾燥所述濕顆粒。 The method of claim 62, wherein the preparation of the emtricitabine particles is carried out by combining emtricitabine with at least one filler (preferably microcrystalline cellulose and/or pregelatinized starch) and At least one disintegrant (preferably croscarmellose sodium) is obtained to obtain a mixture, and the mixture is combined with a binder solution (preferably aqueous povidone) to form wet granules, and the wet granules are dried. 如申請專利範圍第47項至第48項中任一項或申請專利範圍第49項至第64項中任一項所述之方法，其中所述泰諾福韋顆粒之製備藉由乾式混合，或藉由濕式粒化、接著乾燥泰諾福韋與至少一種醫藥學上可接受之賦形劑之混合物。 The method of any one of claims 47 to 48, wherein the preparation of the tenofovir particles is by dry mixing, Or by wet granulation followed by drying a mixture of tenofovir with at least one pharmaceutically acceptable excipient. 如申請專利範圍第65項所述之方法，其中泰諾福韋與至少一種填充劑[較佳微晶纖維素(例如艾維素®(Avicel®)]及至少一種崩解劑/黏合劑(較佳預膠凝化澱粉)乾式混合。 The method of claim 65, wherein tenofovir and at least one filler [preferably microcrystalline cellulose (such as Avicel®) and at least one disintegrant/adhesive ( Preferably pregelatinized starch) is dry blended. 如申請專利範圍第65項所述之方法，其中泰諾福韋與至少一種填充劑(較佳乳糖)、至少一種崩解劑(較佳交聯聚維酮)及至少一種黏合劑(較佳聚維酮)及視情況存在之至少一種潤滑劑(較佳硬脂酸鎂)以及粒化液體(較佳水)濕式粒化而提供濕顆粒，乾燥所述濕顆粒。 The method of claim 65, wherein the tenofovir is at least one filler (preferably lactose), at least one disintegrant (preferably crospovidone), and at least one binder (preferably). The povidone) and optionally at least one lubricant (preferably magnesium stearate) and the granulated liquid (preferably water) are wet granulated to provide wet granules which are dried. 如申請專利範圍第65項所述之方法，其中泰諾福韋與至少一種填充劑(較佳微晶纖維素及/或預膠凝化澱粉)以及粒化液體(較佳水)濕式粒化而提供濕顆粒，乾燥所述濕顆粒。 The method of claim 65, wherein the tenofovir is mixed with at least one filler (preferably microcrystalline cellulose and/or pregelatinized starch) and granulated liquid (preferably water) wet granules. The wet granules are provided to dry the wet granules. 如申請專利範圍第47項至第48項中任一項或申請專利範圍第49項至第68項中任一項所述之方法，其中包括恩曲他濱及泰諾福韋二者之所述顆粒之製備透過合併恩曲他濱與泰諾福韋以及至少一種醫藥學上可接受之賦形劑以及濕式粒化而形成濕顆 粒，接著乾燥。 The method of any one of claims 47 to 48, or the method of any one of claims 49 to 68, which includes both emtricitabine and tenofovir Preparation of granules by combining emtricitabine with tenofovir and at least one pharmaceutically acceptable excipient and wet granulation to form wet granules Granules, followed by drying. 如申請專利範圍第69項所述之方法，其中所述恩曲他濱及泰諾福韋與至少一種填充劑(較佳乳糖)、至少一種崩解劑(較佳交聯聚維酮)、至少一種黏合劑(較佳預膠凝化澱粉或聚維酮)合併以獲得混合物，用水粒化所述混合物以及乾燥所述顆粒。 The method of claim 69, wherein the emtricitabine and tenofovir are combined with at least one filler (preferably lactose), at least one disintegrant (preferably crospovidone), At least one binder (preferably pregelatinized starch or povidone) is combined to obtain a mixture, the mixture is granulated with water and the granules are dried. 如申請專利範圍第11項或申請專利範圍第13項至第40項中任一項所述之醫藥調配物，其以包括第一層及第二層之雙層錠劑形式呈現。 A pharmaceutical formulation according to any one of claims 13 to 40, or a pharmaceutical composition comprising the first layer and the second layer. 如申請專利範圍第71項所述之醫藥調配物，其中所述第一層包括恩曲他濱及泰諾福韋且所述第二層包括地瑞那韋及利托那韋。 The pharmaceutical formulation of claim 71, wherein the first layer comprises emtricitabine and tenofovir and the second layer comprises darunavir and ritonavir. 如申請專利範圍第71項或申請專利範圍第72項所述之醫藥調配物，其中所述第一層包括恩曲他濱顆粒及泰諾福韋顆粒之混合物，或包括恩曲他濱、泰諾福韋之混合物之顆粒，且所述第二層包括地瑞那韋與粒外型利托那韋或地瑞那韋與粒內型利托那韋(亦即地瑞那韋-利托那韋之粒化物)。 The pharmaceutical formulation of claim 71, or the pharmaceutical composition of claim 72, wherein the first layer comprises a mixture of emtricitabine particles and tenofovir particles, or includes emtricitabine, Thai a particle of a mixture of norfovir, and the second layer comprises darunavir and extragranular ritonavir or darunavir with intragranular ritonavir (ie, darunavir-lito) Nawei's granules). 如申請專利範圍第71項至第73項中任一項所述之醫藥調配物，其中所述第一層更包含至少一種醫藥學上可接受之賦形劑。 The pharmaceutical formulation of any one of claims 71 to 73, wherein the first layer further comprises at least one pharmaceutically acceptable excipient. 如申請專利範圍第70項至第74項所述之醫藥調配物，其中所述第一層包括至少一種崩解劑(較佳交聯羧甲纖維素鈉)及至少一種潤滑劑(較佳硬脂酸鎂)以形成所述第一層之摻合物。 The pharmaceutical formulation according to any one of claims 70 to 74, wherein the first layer comprises at least one disintegrant (preferably croscarmellose sodium) and at least one lubricant (preferably hard) Magnesium oleate) to form a blend of the first layer. 如申請專利範圍第71項至第75項中任一項所述之醫藥調配物，其中所述雙層錠劑之形成藉由壓縮而形成具有兩個相異 層之錠劑，且視情況用膜衣材料塗佈所述錠劑。 The pharmaceutical formulation according to any one of claims 71 to 75, wherein the formation of the bilayer tablet is formed by compression to have two differences The tablet is coated and the tablet is coated with a film coating material as appropriate. 一種用於製備呈如申請專利範圍第71項至第76項中任一項所述之呈雙層錠劑形式之醫藥調配物之方法，包括：(a)提供兩個摻合物層；其中：(i)第一層包括恩曲他濱顆粒及泰諾福韋顆粒之混合物，或包括恩曲他濱及泰諾福韋之混合物之顆粒；(ii)第二層包括地瑞那韋與粒外型利托那韋或地瑞那韋與粒內型利托那韋(亦即地瑞那韋-利托那韋之粒化物)；(b)將所述兩個摻合物層壓縮為錠劑；以及(c)視情況在所述錠劑核心上塗覆一或多個塗層。 A method for the preparation of a pharmaceutical formulation in the form of a bilayer tablet according to any one of claims 71 to 76, comprising: (a) providing two blend layers; : (i) the first layer comprises a mixture of emtricitabine particles and tenofovir particles, or a mixture comprising emtricitabine and tenofovir; and (ii) the second layer comprises darunavir and Extragranular ritonavir or darunavir with intragranular ritonavir (ie, granules of darunavir-ritonavir); (b) compression of the two blend layers a tablet; and (c) optionally coating one or more coatings on the tablet core. 如申請專利範圍第77項所述之方法，其中所述利托那韋以根據申請專利範圍第60項至第61項中任一項所述之方法製備的預混物形式呈現。 The method of claim 77, wherein the ritonavir is present in the form of a premix prepared according to the method of any one of claims 60 to 61. 如申請專利範圍第77項至第78項中任一項所述之方法，其中地瑞那韋-利托那韋之粒化物根據申請專利範圍第55項至第58項中之任一項所述之方法製備。 The method according to any one of claims 77 to 78, wherein the granulation of darunavir-ritonavir is according to any one of items 55 to 58 of the patent application scope. Prepared by the method described. 如申請專利範圍第77項至第79項中任一項所述之方法，其中恩曲他濱顆粒根據申請專利範圍第62項至第64項中之任一項所述之方法製備。 The method of any one of the preceding claims, wherein the emtricitabine granules are prepared according to the method of any one of claims 62 to 64. 如申請專利範圍第77項至第80項中任一項所述之方法，其中泰諾福韋顆粒根據申請專利範圍第65項至第68項中之任一項所述之方法製備。 The method of any one of claims 77 to 80, wherein the tenofovir granules are prepared according to the method of any one of claims 65 to 68. 如申請專利範圍第77項至第81項中任一項所述之方法，其中包括恩曲他濱、泰諾福韋之混合物之顆粒根據申請專利 範圍第69項或申請專利範圍第70項所述之方法製備。 The method according to any one of claims 77 to 81, wherein the granules comprising a mixture of emtricitabine and tenofovir are claimed Prepared by the method described in Section 69 or Patent Application No. 70. 如申請專利範圍第77項至第82項中任一項所述之方法，更包括壓縮所述兩個摻合物層以形成錠劑，及視情況用膜衣材料塗佈所述錠劑以形成膜衣錠劑。 The method of any one of clauses 77 to 82, further comprising compressing the two blend layers to form a tablet, and optionally coating the tablet with a film coating material A film-coated lozenge is formed. 如申請專利範圍第1項至第44項及第71項至第76項中任一項所述之醫藥調配物，其用作藥物。 The pharmaceutical formulation according to any one of claims 1 to 44 and 71 to 76, which is used as a medicament. 如申請專利範圍第1項至第44項及第71項至第76項中任一項所述之醫藥調配物，其用於治療HIV-1感染。 The pharmaceutical formulation according to any one of claims 1 to 44, and the method of claim 71, wherein the pharmaceutical preparation is for treating HIV-1 infection. 一種用於治療HIV-1感染之方法，包括投與醫藥學上有效量之如申請專利範圍第1項至第44項及第71項至第76項中任一項所述之醫藥調配物。 A method for treating an HIV-1 infection, comprising administering a pharmaceutically effective amount of a pharmaceutical formulation according to any one of claims 1 to 44 and 71 to 76. 一種單體錠劑，包括：(a)地瑞那韋或其生理學上之功能衍生物(較佳為地瑞那韋水合物或地瑞那韋乙醇化物)；以及(b)利托那韋或其生理學上之功能衍生物。 A monomeric lozenge comprising: (a) darunavir or a physiologically functional derivative thereof (preferably darunavir hydrate or darunavir ethanolate); and (b) ritona Wei or its physiologically functional derivative. 如申請專利範圍第87項所述之單體錠劑，其為化學穩定的。 A monomer tablet as described in claim 87, which is chemically stable. 如申請專利範圍第87項至第88項中任一項所述之單體錠劑，其中總錠劑重量為1.300g或小於1.300g、約1.200g或小於1.200g、約1.100g或小於1.100g、約1.000g或小於1.000g、約0.900g或小於0.900g、約0.700g或小於0.700g、0.600g或小於0.600g、約0.550g或小於0.550g。 The monomer tablet according to any one of claims 87 to 88, wherein the total tablet weight is 1.300 g or less than 1.300 g, about 1.200 g or less than 1.200 g, about 1.100 g or less than 1.100. g, about 1.000 g or less than 1.000 g, about 0.900 g or less than 0.900 g, about 0.700 g or less than 0.700 g, 0.600 g or less than 0.600 g, about 0.550 g or less than 0.550 g. 如申請專利範圍第87項至第89項中任一項所述之單體錠劑，其中所述總錠劑重量為約0.550g至約0.600g、約0.550g 至約0.700g、約0.550g至約0.900g、約0.550g至約1.000g、約0.550g至約1.100g，或約0.550g至約1.200g，或約0.550g至約1.300g。 The monomer tablet according to any one of claims 87 to 89, wherein the total tablet weight is from about 0.550 g to about 0.600 g, about 0.550 g. To about 0.700 g, from about 0.550 g to about 0.900 g, from about 0.550 g to about 1.000 g, from about 0.550 g to about 1.100 g, or from about 0.550 g to about 1.200 g, or from about 0.550 g to about 1.300 g. 如申請專利範圍第87項至第90項中任一項所述之單體錠劑，其中所述總錠劑重量為約0.600g至約0.700g、約0.600g至約0.900g、約0.600g至約1.000g、約0.600g至約1.100g或約0.600g至約1.200g，或約0.600g至約1.300g。 The monomer tablet of any one of clauses 87 to 90, wherein the total tablet weight is from about 0.600 g to about 0.700 g, from about 0.600 g to about 0.900 g, about 0.600 g. To about 1.000 g, from about 0.600 g to about 1.100 g or from about 0.600 g to about 1.200 g, or from about 0.600 g to about 1.300 g. 如申請專利範圍第87項至第91項中任一項所述之單體錠劑，其中所述總錠劑重量為約0.700g至約0.900g、約0.700g至約1.000g、約0.700g至約1.100g，或約0.700g至約1.200g，或約0.700g至約1.300g。 The monomer tablet according to any one of claims 87 to 91, wherein the total tablet weight is from about 0.700 g to about 0.900 g, from about 0.700 g to about 1.000 g, about 0.700 g. To about 1.100 g, or from about 0.700 g to about 1.200 g, or from about 0.700 g to about 1.300 g. 如申請專利範圍第87項至第92項中任一項所述之單體錠劑，其中所述總錠劑重量為約0.900g至約1.000g、約0.900g至約1.100g，或約0.900g至約1.200g，或約0.900g至約1.300g。 The monomer tablet of any one of clauses 87 to 92, wherein the total tablet weight is from about 0.900 g to about 1.000 g, from about 0.900 g to about 1.100 g, or about 0.900 g to about 1.200 g, or from about 0.900 g to about 1.300 g. 如申請專利範圍第87項至第93項中任一項所述之單體錠劑，其中所述總錠劑重量為約1.000g至約1.100g，或約1.000g至約1.200g，或約1.000g至約1.300g。 The monomer tablet of any one of clauses 87 to 93, wherein the total tablet weight is from about 1.000 g to about 1.100 g, or from about 1.000 g to about 1.200 g, or about 1.000 g to about 1.300 g. 如申請專利範圍第87項至第94項中任一項所述之單體錠劑，其中所述總錠劑重量為約1.100g至約1.200g，或約1.100g至約1.300g。 The monomer tablet of any one of clauses 87 to 94, wherein the total tablet weight is from about 1.100 g to about 1.200 g, or from about 1.100 g to about 1.300 g. 如申請專利範圍第87項至第95項中任一項所述之單體錠劑，其中所述總錠劑重量為約1.100g至約1.300g。 The monomer tablet according to any one of claims 87 to 95, wherein the total tablet weight is from about 1.100 g to about 1.300 g. 如申請專利範圍第87項至第96項中任一項所述之單體錠劑，其中包括地瑞那韋及利托那韋之本發明之所述醫藥調配物 之最大直徑可為約22mm或小於22mm且深度可為小於約9mm；較佳地，最大直徑可在約20mm至約22mm之間且深度可在約6mm至約9mm之間。 A monomer tablet according to any one of claims 87 to 96, which comprises the pharmaceutical formulation of the present invention comprising darinavir and ritonavir. The largest diameter may be about 22 mm or less and the depth may be less than about 9 mm; preferably, the largest diameter may be between about 20 mm and about 22 mm and the depth may be between about 6 mm and about 9 mm. 如申請專利範圍第87項至第97項中任一項所述之單體錠劑，其包括約75mg至800mg地瑞那韋及約100mg利托那韋。 The monomer tablet according to any one of claims 87 to 97, which comprises about 75 mg to 800 mg of darunavir and about 100 mg of ritonavir. 如申請專利範圍第87項至第98項中任一項所述之單體錠劑，其包括約800mg地瑞那韋及約100mg利托那韋。 The monomer tablet of any one of claims 87 to 98, which comprises about 800 mg of darunavir and about 100 mg of ritonavir. 如申請專利範圍第87項至第99項中任一項所述之單體錠劑，其中所述地瑞那韋以地瑞那韋乙醇化物、水合物或任何其他結晶形態呈現以及非晶形地瑞那韋形式呈現，較佳為水合物。 The monomer tablet according to any one of claims 87 to 99, wherein the darunavir is present in darunavir ethanolate, hydrate or any other crystalline form and is amorphous The rinavir form is present, preferably a hydrate. 如申請專利範圍第87項至第100項中任一項所述之單體錠劑，其中利托那韋為非晶形利托那韋。 The monomer tablet according to any one of claims 87 to 100, wherein the ritonavir is amorphous ritonavir. 如申請專利範圍第87項至第101項中任一項所述之單體錠劑，其包括約20重量%至約85重量%之地瑞那韋及利托那韋。 The monomer tablet according to any one of claims 87 to 101, which comprises from about 20% by weight to about 85% by weight of darunavir and ritonavir. 如申請專利範圍第87項至第102項中任一項所述之單體錠劑，其包括以重量計約20重量%至約25重量%、約20重量%至約30重量%、約20重量%至約35重量%、約20重量%至約40重量%、約20重量%至約45重量%、約20重量%至約50重量%、約20重量%至約55重量%、約20重量%至約60重量%、約20重量%至約65重量%、約20重量%至約70重量%、約20重量%至約75重量%、約20重量%至約80重量%或約20重量%至約85重量%之地瑞那韋及利托那韋。 The monomer tablet according to any one of claims 87 to 102, which comprises from about 20% by weight to about 25% by weight, from about 20% by weight to about 30% by weight, and about 20% by weight. From wt% to about 35 wt%, from about 20 wt% to about 40 wt%, from about 20 wt% to about 45 wt%, from about 20 wt% to about 50 wt%, from about 20 wt% to about 55 wt%, from about 20 wt% From wt% to about 60% by weight, from about 20% to about 65% by weight, from about 20% to about 70% by weight, from about 20% to about 75% by weight, from about 20% to about 80% by weight or about 20% 5% by weight to about 85% by weight of darunavir and ritonavir. 如申請專利範圍第87項至第103項中任一項所述之單體錠劑，其包括約25重量%至約30重量%、約25重量%至約35 重量%、約25重量%至約40重量%、約25重量%至約45重量%、約25重量%至約50重量%、約25重量%至約55重量%、約25重量%至約60重量%、約25重量%至約65重量%、約25重量%至約70重量%、約25重量%至約75重量%、約25重量%至約80重量%或約25重量%至約85重量%之地瑞那韋及利托那韋。 The monomer tablet according to any one of claims 87 to 103, which comprises from about 25% by weight to about 30% by weight, from about 25% by weight to about 35. % by weight, from about 25% by weight to about 40% by weight, from about 25% by weight to about 45% by weight, from about 25% by weight to about 50% by weight, from about 25% by weight to about 55% by weight, from about 25% by weight to about 60% by weight % by weight, from about 25% by weight to about 65% by weight, from about 25% by weight to about 70% by weight, from about 25% by weight to about 75% by weight, from about 25% by weight to about 80% by weight or from about 25% by weight to about 85. 3% by weight of darunavir and ritonavir. 如申請專利範圍第87項至第104項中任一項所述之單體錠劑，其包括約30重量%至約35重量%、約30重量%至約40重量%、約30重量%至約45重量%、約30重量%至約50重量%、約30重量%至約55重量%、約30重量%至約60重量%、約30重量%至約65重量%、約30重量%至約70重量%、約30重量%至約75重量%、約30重量%至約80重量%或約30重量%至約85重量%之地瑞那韋及利托那韋。 The monomer tablet according to any one of claims 87 to 104, which comprises from about 30% by weight to about 35% by weight, from about 30% by weight to about 40% by weight, and about 30% by weight to About 45 wt%, about 30 wt% to about 50 wt%, about 30 wt% to about 55 wt%, about 30 wt% to about 60 wt%, about 30 wt% to about 65 wt%, about 30 wt% to About 70% by weight, about 30% by weight to about 75% by weight, about 30% by weight to about 80% by weight or about 30% by weight to about 85% by weight of darunavir and ritonavir. 如申請專利範圍第87項至第105項中任一項所述之單體錠劑，其包括約40重量%至約45重量%、約40重量%至約50重量%、約40重量%至約55重量%、約40重量%至約60重量%、約40重量%至約65重量%、約40重量%至約70重量%、約40重量%至約75重量%、約40重量%至約80重量%或約40重量%至約85重量%之地瑞那韋及利托那韋。 The monomer tablet according to any one of claims 87 to 105, which comprises from about 40% by weight to about 45% by weight, from about 40% by weight to about 50% by weight, and about 40% by weight to About 55 wt%, about 40 wt% to about 60 wt%, about 40 wt% to about 65 wt%, about 40 wt% to about 70 wt%, about 40 wt% to about 75 wt%, about 40 wt% to About 80% by weight or about 40% by weight to about 85% by weight of darunavir and ritonavir. 如申請專利範圍第87項至第106項中任一項所述之單體錠劑，其包括約45重量%至約50重量%、約45重量%至約55重量%、約45重量%至約60重量%、約45重量%至約65重量%、約45重量%至約70重量%、約45重量%至約75重量%、約45重量%至約80重量%或約45重量%至約85重量%之地瑞那韋及利托那韋。 The monomer tablet according to any one of claims 87 to 106, which comprises from about 45% by weight to about 50% by weight, from about 45% by weight to about 55% by weight, and about 45% by weight to About 60% by weight, about 45% by weight to about 65% by weight, about 45% by weight to about 70% by weight, about 45% by weight to about 75% by weight, about 45% by weight to about 80% by weight or about 45% by weight to About 85% by weight of darunavir and ritonavir. 如申請專利範圍第87項至第107項中任一項所述之單體錠劑，其包括約50重量%至約55重量%、約50重量%至約60重量%、約50重量%至約65重量%、約50重量%至約70重量%、約50重量%至約75重量%、約50重量%至約80重量%或約50重量%至約85重量%之地瑞那韋及利托那韋。 The monomer tablet according to any one of claims 87 to 107, which comprises from about 50% by weight to about 55% by weight, from about 50% by weight to about 60% by weight, and about 50% by weight to About 65% by weight, about 50% to about 70% by weight, about 50% to about 75% by weight, about 50% to about 80% by weight or about 50% to about 85% by weight of darunavir and Ritonavir. 如申請專利範圍第87項至第108項中任一項所述之單體錠劑，其包括約55重量%至約60重量%、約55重量%至約65重量%、約55重量%至約70重量%、約55重量%至約75重量%、約55重量%至約80重量%或約55重量%至約85重量%之地瑞那韋及利托那韋。 The monomer tablet according to any one of claims 87 to 108, which comprises from about 55% by weight to about 60% by weight, from about 55% by weight to about 65% by weight, and about 55% by weight to About 70% by weight, about 55% to about 75% by weight, about 55% to about 80% by weight or about 55% to about 85% by weight of darunavir and ritonavir. 如申請專利範圍第87項至第109項中任一項所述之單體錠劑，其包括約60重量%至約65重量%、約60重量%至約70重量%、約60重量%至約75重量%、約60重量%至約80重量%或約60重量%至約85重量%之地瑞那韋及利托那韋。 The monomer tablet according to any one of claims 87 to 109, which comprises from about 60% by weight to about 65% by weight, from about 60% by weight to about 70% by weight, and about 60% by weight to About 75% by weight, about 60% to about 80% by weight or about 60% to about 85% by weight of darunavir and ritonavir. 如申請專利範圍第87項至第110項中任一項所述之單體錠劑，其包括約65重量%至約70重量%、約65重量%至約75重量%、約65重量%至約80重量%或約65重量%至約85重量%之地瑞那韋及利托那韋。 The monomer tablet according to any one of claims 87 to 110, which comprises from about 65% by weight to about 70% by weight, from about 65% by weight to about 75% by weight, and about 65% by weight to About 80% by weight or about 65% by weight to about 85% by weight of darunavir and ritonavir. 如申請專利範圍第87項至第111項中任一項所述之單體錠劑，其包括約70重量%至約75重量%、約70重量%至約80重量%或約70重量%至約85重量%之地瑞那韋及利托那韋。 The monomer tablet according to any one of claims 87 to 111, which comprises from about 70% by weight to about 75% by weight, from about 70% by weight to about 80% by weight or about 70% by weight to About 85% by weight of darunavir and ritonavir. 如申請專利範圍第87項至第112項中任一項所述之單體錠劑，其包括約75重量%至約80重量%或約75重量%至約85重量%之地瑞那韋及利托那韋。 The monomer tablet according to any one of claims 87 to 112, which comprises from about 75% by weight to about 80% by weight or from about 75% by weight to about 85% by weight of darunavir and Ritonavir. 如申請專利範圍第87項至第113項中任一項所述之單體錠劑，其包括約80重量%至約85重量%之地瑞那韋及利托那韋。 The monomer tablet according to any one of claims 87 to 113, which comprises from about 80% by weight to about 85% by weight of darunavir and ritonavir. 如申請專利範圍第87項至第114項中任一項所述之單體錠劑，其中所述利托那韋以預混物形式呈現。 The monomer tablet of any one of claims 87 to 114, wherein the ritonavir is present as a premix. 如申請專利範圍第87項至第115項中任一項所述之單體錠劑，更包括至少一種潤滑劑(較佳硬脂醯反丁烯二酸鈉)以形成摻合物，所述摻合物隨後壓縮為錠劑核心。 The monomer tablet according to any one of claims 87 to 115, further comprising at least one lubricant (preferably stearin/sodium fumarate) to form a blend, The blend is then compressed into a tablet core. 如申請專利範圍第87項至第116項中任一項所述之錠劑核心，其中所述錠劑經膜衣材料塗佈以產生膜衣錠劑。 A tablet core according to any one of claims 87 to 116, wherein the tablet is coated with a film coating material to produce a film-coated tablet. 一種用於製備如申請專利範圍第87項至第117項中任一項所述之單體錠劑之方法，包括視情況在一或多種醫藥學上可接受之賦形劑存在下合併地瑞那韋與粒外型利托那韋或地瑞那韋與粒內型利托那韋(亦即地瑞那韋-利托那韋之粒化物)以形成摻合物。 A method for the preparation of a monomer tablet according to any one of claims 87 to 117, which comprises, if appropriate, in the presence of one or more pharmaceutically acceptable excipients Navir and extragranular ritonavir or darunavir with intragranular ritonavir (i.e., granules of darunavir-ritonavir) to form a blend. 如申請專利範圍第118項所述之方法，其中所述醫藥學上可接受之賦形劑包括至少一種選自填充劑(較佳微晶纖維素)、崩解劑(較佳交聯聚維酮)、滑動劑(較佳二氧化矽)以及潤滑劑(較佳硬脂醯反丁烯二酸鈉)之賦形劑。 The method of claim 118, wherein the pharmaceutically acceptable excipient comprises at least one member selected from the group consisting of a filler (preferably microcrystalline cellulose) and a disintegrant (preferably cross-linked poly-dimensional). Excipients for ketones, slip agents (preferably cerium oxide) and lubricants (preferably stearic acid succinimide). 如申請專利範圍第119項所述之方法，其中所述醫藥學上可接受之賦形劑包括微晶纖維素、交聯聚維酮、二氧化矽以及硬脂醯反丁烯二酸鈉。 The method of claim 119, wherein the pharmaceutically acceptable excipient comprises microcrystalline cellulose, crospovidone, cerium oxide, and sodium stearyl fumarate. 如申請專利範圍第118項至第119項中任一項所述之方法，更包括加工所述摻合物以提供固體劑量形式。 The method of any one of claims 118 to 119, further comprising processing the blend to provide a solid dosage form. 如申請專利範圍第118項至第119項中任一項所述之方 法，包括壓縮所述摻合物以形成錠劑，及視情況用膜衣材料塗佈所述錠劑以形成膜衣錠劑。 As stated in any one of claims 118 to 119 of the patent application scope The method comprises compressing the blend to form a tablet, and optionally coating the tablet with a film coating material to form a film-coated tablet. 如申請專利範圍第118項至第122項所述之方法，其中所述摻合物在壓縮為錠劑之前視情況與一或多種醫藥學上可接受之賦形劑組合。 The method of claim 118, wherein the blend is combined with one or more pharmaceutically acceptable excipients prior to compression into a tablet. 如申請專利範圍第118項至第123項中任一項所述之方法，其中所述地瑞那韋之顆粒與利托那韋預混物、至少一種填充劑(較佳微晶纖維素)、至少一種崩解劑(較佳交聯聚維酮)以及至少一種滑動劑(較佳二氧化矽)混合，接著添加至少一種潤滑劑(較佳硬脂醯反丁烯二酸鈉)至所獲得之混合物中以獲得地瑞那韋-利托那韋之最終摻合物(較佳為地瑞那韋與粒外型利托那韋)。 The method of any one of the preceding claims, wherein the graninavir granules and the ritonavir premix, at least one filler (preferably microcrystalline cellulose) Mixing at least one disintegrant (preferably crospovidone) and at least one slip agent (preferably cerium oxide), followed by adding at least one lubricant (preferably stearic acid succinimide) to the The resulting mixture is obtained to obtain a final blend of darunavir-ritonavir (preferably darunavir and extragranular ritonavir). 如申請專利範圍第118項至第124項中任一項所述之方法，其中所述地瑞那韋-利托那韋之粒化物藉由地瑞那韋之濕式粒化製備，經由頂噴製程將溶解於適合液體(較佳水)中之至少一種黏合劑(較佳羥丙甲纖維素)噴於對地瑞那韋上之，接著乾燥濕顆粒及研磨乾燥顆粒。 The method of any one of the preceding claims, wherein the granulation of the darunavir-ritonavir is prepared by wet granulation of darunavir, via a top The spraying process sprays at least one binder (preferably hypromellose) dissolved in a suitable liquid (preferably water) onto darunavir, followed by drying the wet granules and grinding the dried granules. 如申請專利範圍第118項至第125項中任一項所述之方法，其中所述地瑞那韋-利托那韋之粒化物藉由地瑞那韋與利托那韋預混物之濕式粒化製備，經由頂噴製程將溶解於適合液體(較佳水)中之至少一種黏合劑(較佳羥丙甲纖維素)噴於對地瑞那韋及利托那韋之混合物，接著乾燥所述濕顆粒及研磨所述乾燥顆粒。 The method of any one of the preceding claims, wherein the granulation of darunavir-ritonavir is by a premix of darunavir and ritonavir. Wet granulation preparation, spraying at least one binder (preferably hypromellose) dissolved in a suitable liquid (preferably water) to a mixture of darunavir and ritonavir via a top spray process. The wet granules are then dried and the dried granules are ground. 如申請專利範圍第118項至第126項中任一項所述之方 法，其中所述地瑞那韋-利托那韋之粒化物與至少一種填充劑(較佳微晶纖維素)、至少一種崩解劑(較佳交聯聚維酮)以及至少一種滑動劑(較佳二氧化矽)混合，接著添加至少一種潤滑劑(較佳硬脂醯反丁烯二酸鈉)至所獲得之混合物中以獲得地瑞那韋-利托那韋之最終摻合物(較佳地瑞那韋與粒內型利托那韋)。 As stated in any one of claims 118 to 126 of the patent application scope a method wherein the granulation of darunavir-ritonavir is combined with at least one filler (preferably microcrystalline cellulose), at least one disintegrant (preferably crospovidone), and at least one slip agent (preferably cerium oxide) is mixed, followed by adding at least one lubricant (preferably stearic acid succinimide) to the obtained mixture to obtain a final blend of darunavir-ritonavir (preferably rinavir and intragranular ritonavir). 如申請專利範圍第118項至第127項中任一項所述之方法，其中所述利托那韋為非晶形的。 The method of any one of clauses 118 to 127, wherein the ritonavir is amorphous. 如申請專利範圍第118項至第128項中任一項所述之方法，其中所述利托那韋以預混物形式呈現，其中利托那韋預混物之製備透過在溶劑(較佳乙醇)中混合利托那韋與至少一種賦形劑(較佳載劑，且更佳共聚維酮)以形成溶液，及蒸發所述溶劑。 The method of any one of the preceding claims, wherein the ritonavir is presented as a premix, wherein the preparation of the ritonavir premix is in a solvent (preferably The ritonavir is mixed with at least one excipient (preferably a carrier, and more preferably a copolyvidone) to form a solution, and the solvent is evaporated. 如申請專利範圍第129項所述之方法，其中利托那韋預混物之製備透過在溶劑(較佳乙醇)中混合利托那韋與至少一種賦形劑(較佳載劑且更佳共聚維酮)、視情況與至少一種增溶劑(較佳脫水山梨糖醇月桂酸酯)以及至少一種滑動劑(較佳二氧化矽)，接著藉由蒸發移除所述溶劑以形成固體，以及視情況研磨所得固體。 The method of claim 129, wherein the preparation of the ritonavir premix is carried out by mixing ritonavir with at least one excipient (preferably carrier and preferably) in a solvent (preferably ethanol). Copolyvidone), optionally with at least one solubilizer (preferably sorbitan laurate) and at least one slip agent (preferably cerium oxide), followed by removal of the solvent by evaporation to form a solid, and The resulting solid was milled as appropriate. 如申請專利範圍第87項至第117項中任一項所述之單體錠劑，其用作藥物。 A monomer tablet according to any one of claims 87 to 117, which is used as a medicament. 如申請專利範圍第87項至第117項中任一項所述之單體錠劑，其用於治療HIV-1感染。 A monomer tablet according to any one of claims 87 to 117, which is for use in the treatment of HIV-1 infection. 一種用於治療HIV-1感染之方法，包括投與醫藥學上有效量之如申請專利範圍第87項至第117項中任一項所述之單體錠劑。 A method for treating an HIV-1 infection comprising administering a pharmaceutically effective amount of a monomeric lozenge according to any one of claims 87 to 117. 如申請專利範圍中前述任一項所述之醫藥調配物、單體錠劑或方法，更包括一或多種醫藥學上可接受之賦形劑，較佳由填充劑、黏合劑、崩解劑、界面活性劑、滑動劑以及潤滑劑所構成的族群中之一或多者中選出。 The pharmaceutical formulation, monomer tablet or method of any of the preceding claims, further comprising one or more pharmaceutically acceptable excipients, preferably a filler, a binder, a disintegrant One or more of the groups consisting of surfactants, slip agents, and lubricants are selected. 如申請專利範圍第134項所述之醫藥調配物、單體錠劑或方法，其中所述填充劑(稀釋劑)是由水溶性聚合物、水不溶性聚合物、微晶纖維素(例如艾維素PH102具有或PH101)、各種形式之乳糖(例如乳糖USP、無水或噴霧乾燥)、山梨糖醇、右旋糖、蔗糖、甘露醇、木糖醇、麥芽糖、多元醇、果糖、瓜爾豆膠、氫氧化鎂、磷酸二鈣、無水磷酸氫鈣、澱粉以及其類似物或任何組合所構成的族群中之一或多者中選出。 The pharmaceutical formulation, monomer tablet or method of claim 134, wherein the filler (diluent) is a water-soluble polymer, a water-insoluble polymer, or a microcrystalline cellulose (eg, Aiwei) PH102 has or PH101), various forms of lactose (such as lactose USP, anhydrous or spray dried), sorbitol, dextrose, sucrose, mannitol, xylitol, maltose, polyol, fructose, guar gum One or more of the group consisting of magnesium hydroxide, dicalcium phosphate, anhydrous calcium hydrogen phosphate, starch, and the like or any combination thereof. 如申請專利範圍第134項或申請專利範圍第135項所述之醫藥調配物、單體錠劑或方法，其中所述黏合劑是由纖維素聚合物(例如羥丙基甲基纖維素、羥丙基纖維素、甲基纖維素以及羥乙基纖維素)、聚乙烯吡咯啶酮、聚乙烯醇、澱粉或預膠凝化澱粉以及其類似物或任何組合所構成的族群中之一或多者中選出。 The pharmaceutical formulation, monomer tablet or method of claim 134, or the pharmaceutical composition of claim 135, wherein the binder is a cellulose polymer (eg, hydroxypropyl methylcellulose, hydroxy One or more of a group of propyl cellulose, methyl cellulose, and hydroxyethyl cellulose), polyvinylpyrrolidone, polyvinyl alcohol, starch or pregelatinized starch, and analogs or any combination thereof Selected among those. 如申請專利範圍第134項至第136項中任一項所述之醫藥調配物、單體錠劑或方法，其中所述潤滑劑是由硬脂醯反丁烯二酸鈉、硬脂酸、硬脂酸鎂、硬脂酸鈣、硬脂酸鋅、滑石、甘油二十二酸酯或氫化植物油以及其類似物或任何組合所構成的族群中之一或多者中選出。 The pharmaceutical formulation, monomer tablet or method of any one of claims 134 to 136, wherein the lubricant is sodium stearate, stearic acid, One or more of the group consisting of magnesium stearate, calcium stearate, zinc stearate, talc, glyceryl behenate or hydrogenated vegetable oil, and analogs or any combination thereof. 如申請專利範圍第134項至第137項中任一項所述之醫藥調配物、單體錠劑或方法，其中所述滑動劑是由膠態二氧化矽、矽膠、沈澱二氧化矽或滑石及其類似物或任何組合所構成的族群 中之一或多者中選出。 The pharmaceutical formulation, monomer tablet or method of any one of claims 134 to 137, wherein the slip agent is a colloidal cerium oxide, cerium gel, precipitated cerium oxide or talc a group of analogues or any combination thereof One or more of them are selected. 如申請專利範圍第134項至第138項中任一項所述之醫藥調配物、單體錠劑或方法，其中所述崩解劑是由羧甲基澱粉鈉；交聯聚乙烯吡咯啶酮(交聯聚維酮)；羧甲基羥乙酸鈉(例如伊斯勞塔伯®(Explotab®)；交聯羧甲纖維素；膨脹多醣，例如大豆多醣、角叉菜膠、瓊脂、果膠、澱粉及其衍生物；蛋白質，例如甲醛-酪蛋白；碳酸氫鈉；離子交換樹脂以及其類似物或任何組合所構成的族群中之一或多者中選出。 The pharmaceutical formulation, monomer tablet or method of any one of claims 134 to 138, wherein the disintegrant is sodium carboxymethyl starch; crosslinked polyvinylpyrrolidone (cross-linked povidone); sodium carboxymethyl glycolate (eg, Inlotta®®; croscarmellose; expanded polysaccharides such as soybean polysaccharide, carrageenan, agar, pectin And one or more of the group consisting of starch, its derivatives, and proteins, such as formaldehyde-casein; sodium bicarbonate; ion exchange resins and analogs or any combination thereof. 如申請專利範圍第134項至第139項中任一項所述之醫藥調配物、單體錠劑或方法，其中所述界面活性劑是由烷基硫酸鹽(特定言之月桂基硫酸鈉)、烷基三甲基銨鹽、醇乙氧基化物、脫水山梨糖醇(特定言之脫水山梨糖醇月桂酸酯)、聚氧乙烯脫水山梨糖醇、聚氧甘油酯或聚氧乙烯蓖麻油衍生物所構成的族群中之一或多者中選出，且較佳其中所述界面活性劑是由脫水山梨糖醇月桂酸酯及月桂基硫酸鈉中之一或多者中選出。 The pharmaceutical formulation, monomer tablet or method of any one of claims 134 to 139, wherein the surfactant is an alkyl sulfate (specifically, sodium lauryl sulfate) , alkyl trimethyl ammonium salt, alcohol ethoxylate, sorbitan (specifically, sorbitan laurate), polyoxyethylene sorbitan, polyoxyglyceride or polyoxyethylene castor oil One or more of the groups of derivatives are selected, and preferably wherein the surfactant is selected from one or more of sorbitan laurate and sodium lauryl sulfate.
TW103129876A 2013-08-29 2014-08-29 Unit dosage form comprising emtricitabine, tenofovir, darunavir and ritonavir and a monolithic tablet comprising darunavir and ritonavir TW201542212A (en)

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