WO2008140460A1 - Forme solide - Google Patents

Forme solide Download PDF

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Publication number
WO2008140460A1
WO2008140460A1 PCT/US2007/011762 US2007011762W WO2008140460A1 WO 2008140460 A1 WO2008140460 A1 WO 2008140460A1 US 2007011762 W US2007011762 W US 2007011762W WO 2008140460 A1 WO2008140460 A1 WO 2008140460A1
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WO
WIPO (PCT)
Prior art keywords
solid form
active material
form according
active
actives
Prior art date
Application number
PCT/US2007/011762
Other languages
English (en)
Inventor
Dzenana Cengic
Olivia Darmuzey
Graeme Macleod
Original Assignee
Fmc Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Fmc Corporation filed Critical Fmc Corporation
Priority to PCT/US2007/011762 priority Critical patent/WO2008140460A1/fr
Publication of WO2008140460A1 publication Critical patent/WO2008140460A1/fr

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Classifications

    • 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
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4833—Encapsulating processes; Filling of capsules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds

Definitions

  • This invention relates to a solid form comprising a film enrobing a matrix of a compacted fill material and a method of producing the solid form.
  • Active ingredients for example pharmaceutical, agrochemical and detergent active ingredients may be delivered through a wide range of solid forms including tablets and capsules.
  • Conventional tablets generally are highly compacted and have relatively high densities.
  • the active ingredient is generally compacted with other components in a blend to provide the requisite structural integrity for the tablet. Delivery of the active ingredient in use may however be unsatisfactory due to the compaction level and it is known to add excipients to the formulation to aid disintegration or dissolution of the tablet to improve delivery, aid compaction, increase strength and increase robustness of the solid form.
  • Capsules generally include the active ingredient in a relatively non-compacted form.
  • the lack of compaction together with the void space inherent within capsules mean that for a given large dose of active, the volume of the final solid form is greater than for more compacted solid forms. Increasing the size of the capsule to accommodate the required dose is undesirable for the user.
  • capsules require a relatively high level of disintegrant to provide adequate disintegration of the solid form.
  • Capsule shells may also be sensitive to moisture and present problems as regards storage and product shelf-life.
  • WO 03/096963 discloses solid forms and processes utilizing films to enrobe a fill material to a degree of compaction less than that generally used to make a tablet. It is specifically disclosed therein that because of the nature of the capsule produced that certain ancillary ingredients necessary in conventional tablet production may be omitted.
  • a solid form having a compacted fill material in the form of a matrix with a particular combination of characteristics in which the components are less compacted than in a tablet but more than in a capsule formulation provides beneficial delivery of the active ingredient at acceptable dose levels and with fewer or lower quantities of excipients typically employed in capsules or tablets.
  • the invention provides in a first aspect a solid form comprising at least one film enrobing a compacted fill material wherein: i) said compacted fill material comprises at least one active material; ii) said solid form shows a weight loss that is less than 1% during a 30 minutes USP friability test United States Pharmacopeia (USP) 29 Test Number 1216
  • said compacted fill material has a density of at least 0.5 g/ml based on the total solid volume of the solid form and a tensile strength less than 0.9 MPa; iv) the compacted fill material comprises particles comprising the at least one of said active material contained within a matrix; and v) the active material exhibits controlled release.
  • matrix is known in the art and is employed in its known sense and is taken to mean herein a continuum of the compacted fill material which contains discrete particles of active material wherein the continuum and discrete particles form a single monolithic entity.
  • the matrix may have pores or capillaries through which components of the compacted fill material, for example the active material may pass in use so as to effect controlled release of the active material from the solid form.
  • controlled release refers to a solid form characterized by slower active release kinetics, compared to an immediate release solid form.
  • immediate release is employed herein in accordance with its meaning known in the art and refers to a solid form in which the active material is released rapidly after administration.
  • a typical release rate for an "immediate release" active material in a solid form is suitably not less than 85% active material release in 60 minutes, preferably in 45 minutes and especially in 30 minutes in the test specified in United States Pharmacopeia (USP) Edition 29 Test Number 711 at page 2673 for said active material when said active material is placed in a dissolution medium as specified in the USP dissolution specification or selected from dissolution media specified in the USP according to the solubility properties of the active material.
  • USP United States Pharmacopeia
  • the active material is not a pharmaceutical active
  • water is used as the dissolution medium to determine whether the active in the solid form exhibits a controlled release. This is referred to in the United States Pharmacopeia (USP) as "Q" time.
  • immediate release includes “fast release”.
  • the solid form suitably comprises an active material which exhibits immediate release.
  • the solid form may additionally comprise an active material which does not exhibit immediate release. If desired, the solid form may comprise an active material which exhibits immediate release and be free of an active material which does not exhibit immediate release.
  • the solid form preferably comprises an active material exhibiting a fast release.
  • a typical release rate for a "controlled release" active material is suitably less than 85% active material release in 60 minutes, preferably less than 85% in 2 hours, especially less than 85% in 4 hours and desirably 85% in 6 or more hours.
  • the solid form comprises an active material exhibiting controlled release.
  • the solid form comprises a further active material which does not exhibit controlled release.
  • the solid form does not contain an active material which does not exhibit a controlled release.
  • the active material is a pharmaceutical active
  • at least one of said active material exhibits a controlled release in a United States Pharmacopeia (USP) dissolution test specified in USP Edition 29 Test Number 711 at page 2673 for said active material when said active material is placed in a dissolution medium as specified in the USP dissolution specification or selected from dissolution media specified in the USP according to the solubility properties of the active material.
  • USP United States Pharmacopeia
  • water is used as the dissolution medium to determine whether the active in the solid form exhibits a controlled release.
  • a dissolution medium is specified in the USP for an active material, this is suitably employed in the dissolution test. Where there is either: i) no USP test for the active material; ii) more than one test for the active material; or iii) the active does not meet the USP specification with the specified medium; the skilled person will select the most appropriate medium for the dissolution test from the USP dissolution media specified in the USP having regard to the dissolution characteristics of the active material and the desired release profile of the active from the solid form.
  • Examples of media in which the dissolution test may be carried out include: (i) the medium specified in the United States Pharmacopeia preferably for said at least one active material, (ii) water, (iii) 0.1 M HCI or (iv) phosphate buffer having a pH between 5.8 and 8.0.
  • Suitable active materials include a pharmaceutical active, food component or product, veterinary active, cosmetic component or product, an appetite suppressant, detergent component or product or nutraceutical component or product.
  • the solid form comprises at least one film enrobing a compacted fill material wherein the compacted fill material comprises at least one active material and the compacted fill material is selected from a pharmaceutical product, a food product, a veterinary product, a cosmetic, an appetite suppressant, a detergent product and a nutraceutical product, the said solid form shows a weight loss that is less than 1% during a 30 minutes USP friability test United States Pharmacopeia (USP) 29 Test Number 1216 (page 3046) and the compacted fill material comprises particles comprising the at least one of said active material contained within a matrix.
  • USP United States Pharmacopeia
  • controlled release may be secured from the solid form with the compacted fill material having a low density as compared to known product forms which provide controlled release.
  • the objective of controlled release solid forms is to obtain a controlled, preferably constant, level of active in the plasma and to reduce the frequency of dose administration.
  • the film enrobing the compacted fill material is preferably a water-soluble film. Desirably, the film is in intimate contact with the compacted fill material.
  • the matrix of the compacted fill material comprises a polymer.
  • the matrix may be soluble in aqueous medium such that in use the matrix swells and then dissolves whereby the active material is released.
  • the matrix may be insoluble such that in use a solvent for example water enters the matrix and on reaching particles of the active, dissolves the active material in the dissolution medium.
  • the matrix is suitably a hydrophilic matrix and is preferably a water-swellable hydrophilic polymer.
  • the matrix is suitably capable of swelling by gel formation, followed by erosion and dissolution in aqueous media.
  • an insoluble matrix suitably comprises a hydrophobic polymer, for example a lipid.
  • the active material is contained in the hydrophobic matrix which preferably remains intact during release of the active material.
  • the matrix may comprise capillaries or may be porous.
  • the matrix may comprise a soluble channelling agent distributed through the matrix which upon contact with aqueous solution leaches out of the matrix so leaving a porous matrix with tortuous capillaries.
  • the active material may be released via dissolution and diffusion through the capillaries.
  • the insoluble matrix may be inert to gastrointestinal fluids.
  • the release rate of the active material within the matrix may be tailored by controlling the porosity of capillary pathways in the matrix.
  • the present invention advantageously provides a solid form which is able to provide release of the active material in a controlled manner, desirably with zero order kinetics that is where the rate of release of the active material is independent of time.
  • a soluble matrix may show two different mechanisms for release of the active material: firstly, hydration of the soluble polymer to form a gel layer which acts as a barrier both to further uptake of water and also to release of active material from the inner "dry" part of the solid form and so slows the release of the active material as compared to an immediate release profile.
  • erosion of the gel layer to release further active from within the eroded gel layer is another mechanism of a controlled release.
  • the relative contributions of swelling and dissolution on the one hand and erosion on the other provide the controlled release of the active material.
  • the gel layer thickness is constant and zero-order release of the active material may be observed and non-linear release is obtained when this is not the case.
  • the solid form of the present invention enables the achievement of zero order release mechanism using simple formulations for the compacted fill of the solid form.
  • the compacted fill density is relatively low in comparison with conventional solid forms such as tablets, it is higher than for the powder in hard capsules and sufficient to enable gel formation at an early stage of the solid form dissolution, while keeping the integrity of the solid form over a prolonged period of time.
  • the solid form of the present invention reduces some drawbacks of conventional solid forms, for example an initial burst of the active being released.
  • a lower or no burst effect from the solid form of the present invention may advantageously be achieved and a wide range of polymers may be employed without the need to employ pore formers to achieve zero order controlled release due to the low density level of the compacted fill of the solid form.
  • the enrobed solid form of the present invention having an active material within a matrix provides a means of tailoring the release profile of the active avoiding the use of complex formulations.
  • the compacted fill material including the matrix is formed by a compaction step.
  • the compaction process is preferably carried out at lower compaction force than conventionally applied in producing tablets. Varying the compression force provides a means of tailoring the porosity of the matrix so as to alter the release profile of the active material. Generally a more rigid and less porous matrix will release the active material more slowly than a less consolidated matrix.
  • lower compaction pressure in producing the solid form allows it to be formulated without a Filter if desired. This has the further practical advantage of simplifying processing and reducing the time required to formulate the product.
  • a gel modifier or a channelling agent compound for example soluble salts, sugars or polyols, may be included in the matrix.
  • the compacted fill material has a density of less than 1.1g/ml and more preferably less than 1.05g/ml.
  • the density of the compacted fill material is suitably at least 0.55g/ml.
  • the density of the compacted fill material is from 0.55 to
  • the density of the solid form is suitably higher than that for conventional capsules and as the density contributes to the release profile of the solid form, this may be optimized by the formulator according to the release profile required.
  • the compacted fill material suitably has a tensile strength of less than 0.9MPa, preferably less than 0.5MPa, especially less than 0.2MPa and particularly less than 0.1 MPa.
  • the compacted fill has sufficient tensile strength to retain the physical integrity of the compacted fill material and is preferably at least 0.05MPa.
  • the robustness of the solid form is suitably provided by the enrobing film rather than by the compacted fill material.
  • the solid form of the present invention has excellent robustness or physical strength.
  • the robustness of a solid form may suitably be defined by measuring the weight loss of 10 solid forms when rotated in a USP friability apparatus. This test is as set out in USP 29 ⁇ 1216> p 3046.
  • the solid form of the present invention shows a weight loss of less than 1% when tested for a 30 minutes in a friability drum.
  • conventional solid forms such as coated tablets are considered to be robust when the weight loss after 4 minutes of friability testing is less than 1% measured according to USP 29 ⁇ 1216> p 3046, the solid form of the present invention is especially robust.
  • the density of the compacted fill material of the solid form of the present invention refers to the total weight of the fill material divided by the total volume of the solid form within the film material. This is typically referred to as the apparent density of solid forms.
  • the apparent density of a conventional tablet is typically greater than 1 g/ml as disclosed in, Pharmaceutical Technology, 27 (4), 67-80.
  • the fill material is lightly tamped so as to form a very weak slug that breaks up in the capsule shell, due to the air space above it
  • the density of the fill material is therefore similar to the bulk density of the loose powder.
  • the latter is typically less than 0.5 g/ml as disclosed in, Pharmaceutical Technology, 27 (4), 67-80.
  • the density of the compacted fill material of the present invention is at least 0.5g/ml and preferably at least 0.55 g/ml based on the total solid form volume.
  • a typical method for determining the density D of the fill material in the present invention is to determine the fill weight W (1), the fill volume V, which depends on the size of the tooling used to manufacture the solid forms and to calculate D using equation (2) .
  • W Wt-Wf (g), where Wt is the weight of the total enrobed solid form and Wf is the weight of the film enrobing the solid form.
  • V (212.7+110.8t)/1000 (ml), where t is the sidewall thickness of the solid form (mm), typically measured using a micrometer.
  • t is the sidewall thickness of the solid form (mm), typically measured using a micrometer.
  • V [ ⁇ (13/2) 2 t]/1000 (ml), where t is the tablet thickness (mm), typically measured using a micrometer.
  • Conventiontal tablets are considered robust when the tensile strength of the compacted fill material is at least 1.0 MPa for example as disclosed in Pharmaceutical Technology, p52-62, April 2005 (Douglas McCormick, - Evolutions in Direct Compression).
  • a typical method for determining the tensile strength for round flat faced cylinder shapes is to measure the crushing force (also called hardness) of compacts on a tablet hardness tester and calculate the tensile strength ⁇ using equation
  • the said solid form has a tensile strength of at least 1.3 MPa
  • the present invention is also directed to a method of making the solid form of the present invention.
  • the invention in a further aspect provides for the use of a solid form according to the invention in a method of treatment of the human or animal body by therapy.
  • the invention also provides a solid form according to the invention for use in a method of treatment of the human or animal body by therapy.
  • a wide range of active materials having widely differing solubility characteristics may be employed in the present invention.
  • the active material may have a solubility in water of 1 g in less than 1 g water, 1 g in 1 to 10 g water, 1 g active in 10 to 30 g water, 1 g active in 30 to 100 g water, 1 g active in 100 to 1 ,000 g water, 1 g active in 1,000 to 10,000 g water, and 1 g active in more than 10,000 g water.
  • suitable classes of pharmaceutical actives include an analgesic, antiangina, antianaemia, antibiotic, antiarrhythmic, antidiarrheal, antidiuretic, antidepressant, antiemetic, antifungal, antirheumatic, antiviral, antiprotozoal, antihistamine, antihypertensive, anti-inflammatory, antimigraine, antinausea, antispasmodic, anxiolytic, beta blocker, calcium channel blocker, sedative, hypnotic, antipsychotic, bronchodilator, decongestant, cough expectorant, cough suppressant, antiasthma drug, corticosteroid, actives for treatment of cough or common cold, muscle relaxant, erectile dysfunction active, motion sickness active, anti-HIV, anti-malaria actives, anti-cholesterol actives, respiratory actives, gastrointestinal actives, cardiovascular actives, antidiabetes actives, central nervous system actives, anti- infection actives, mucolytics, proton
  • Suitable actives include paracetamol, pseudoephedrine, acravastine, lamivudine, abacavir, pravastatin, Roziglitazone, ezetimibe, Clavulanate, sulfamethoxazole, benazepril, Valsartan, Irbesartan, Losartan, Dutasteride, tamsolusin, Atazanavir, ritonavir, propoxyphene, Hydrocodone, Metocarbamol, Memantine, Donepezil, Glyburide, Pioglytazone, Glimepiride, Benazepril, Torcetrapib, Eprosartan, Telmisartan, Olmesartan, Lopinavir, Emtricitabine, Tenofovir, Amprenavir, Tipranavir, Atovaquone, Proguanil, 5-aminosalicylic acid, 4-aminophthalic acid, Bismuth citrate,
  • the two or more actives may be from the same class or may be from different classes.
  • combinations of active materials from different classes include an antibiotic in combination with one of a decongestant, an anti-inflammatory, a cough expectorant, a cough suppressant or an active for treatment of cough or common cold, a proton pump inhibitor, anti-hypertension and anti-cholesterol actives.
  • classes where two or more active materials from one class may suitably be employed include respiratory actives, gastronintestinal actives, cardiovascular actives, antidiabetes actives, central nervous system actives, anti- infection actives, anti-viral actives, analgesics, anti-inflammatory actives, antibiotics, cough suppressants, expectorants, mucolytics, and nasal decongestants, anti-HIV , anti- malaria actives.
  • Examples of particular combinations of active materials include: Paracetamol and Caffeine; Aspirin and paracetamol; Paracetamol and pseudoephedrine; Paracetamol and phenylephrine; lbuprofen and codeine; lbuprofen and pseudoephedrine; Paracetamol and diphenhydramine; Acravistine and pseudoephedrine; Paracetamol and dextromethorphan; Parcetamol and guaphenesin; Paracetamol, caffeine, aspirin; Aspirin and caffeine; Zidovudine, lamivudine and abacavir; Pravastatin and aspirin; Lamivudine and zidovudine; Roziglitazone and Metformin; Ezetimibe and fenofibrate; Amoxicillin and Clavulanate; Trimetoprim and sulfamethoxazole; Amlodipine and benazepril; Valsartan and Hydro
  • the compacted fill material preferably comprises a moderate to high amount of the active material and this will be selected according to the particular active material and the intended use of the product.
  • the compacted fill material suitably comprises active material at a level of 60 to 95%.
  • a moderate level of active material is suitably at least 30% and suitably up to 75%.
  • a high level of active material is suitably at least 75%, preferably at least 95%, for example 95 to 98% provided that a matrix may be formed in which the active material is contained.
  • the at least one active material may be in any form although in a preferred embodiment, the at least one active is a powder.
  • the active material of the present invention is preferably a powder and this suitably incfudes such powders as granules, micronized powders, spray-dried powders, freeze-dried powders and pellets.
  • the compacted fill material may contain at least one material from which the matrix is formed, herein referred to as a "matrix former".
  • suitable hydrophilic matrix formers include hydroxypropylmethyl cellulose, sodium carboxymethyl cellulose, alginates, carrageenans, xanthan gum, locust bean gum, carbopol, guar gum, hydroxypropyl cellulose, methyl cellulose, polyethylene oxide, polymethacrylates, mannitol, polyvinyl alcohol.
  • the hydrophilic matrix former suitably has a viscosity in the range of 80-120,000 cPs. A 2% w/v aqueous solution of the matrix former at 20°C is typically used to measure the viscosity.
  • a suitable insoluble matrix former examples include hydrogenated vegetable oils, microcrystalline wax and camauba wax, ethylcellulose, polyamide, polyethylene, polyvinyl acetate, cetyl alcohol, glyceryl monostearate, glyceryl behe ⁇ ate, glyceryl monooleate, glyceryl palmitostearate, polacrilin potassium, stearic acid, stearyl alcohol, yellow wax, zein, hydrogenated castor oil.
  • the compacted fill may contain at least one filler.
  • suitable fillers include excipients such as glidants, binders, pore formers and lubricants.
  • suitable fillers include microcrystalline cellulose, dicalcium phosphate, lactose, calcium carbonate, calcium phosphate dibasic anhydrous, calcium phosphate dibasic dehydrate, calcium phosphate tribasic, powdered cellulose, silicified microcrystalline cellulose, cellulose acetate, compressible sugar, confectioners sugar, dextrin, dextrose, ethylcellulose, fructose, lactitol, starch, pregelatinized starch, sucrose, talc, xylitol, maltodextrin, magnesium carbonate, maltose, mannitol, polydextrose, sodium alginate, sodium chloride, sorbitol, sucrose, sugar spheres, acacia, carrageenan, carbomer, chitosan, hydroxypropy
  • a filler When a filler is present, it may be present in an amount of less than 70% by weight of the compacted fill material, less than 60% by weight of the compacted fill material, less than 50% by weight, less than 40%, less than 30% by weight of the compacted fill material, from 1 to 25%, from 1 to 10% and suitably from 1 to 5% by weight of the compacted fill material.
  • the enrobed solid form of the present invention may contain no filler (except where the filler is a matrix former) in the compacted fill material.
  • the film to be used to enrobe the present invention may be any film capable of enrobing the compacted fill material without adversely impacting the desired dissolution profile.
  • the film to be used may comprise water soluble components, water insoluble components or may comprise soluble and insoluble components in combination.
  • the compacted fill material is enrobed by a film comprising at least one water soluble polymer.
  • Films generally useful in the present invention include those that are thermo formable and generally have dissolution rates appropriate for the preparation of rapid release, preferably immediate release, solid forms of the invention.
  • water soluble polymers examples include cellulosic materials such as hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose; polyvinyl alcohol; hydrocolloids such as carrageenan, alginate and pectin; and water soluble acrylates.
  • water insoluble polymers examples include ethylcellulose, methacrylates and cellulose acetate.
  • the films used in the invention may be gelatin free.
  • the films may contain plasticizers such as lactic acid, citric acid, polyethylene glycol, sorbitol, glycerine, triethylcitrate, propylene glycol, phthalates, triglycerides, triacetin, tributylcitrate, etc.
  • WO 2004/026284, WO 02/083779 and WO 03/095548 disclose further examples of films that may be used in the invention and such are incorporated herein by reference.
  • films that may be used in the present invention are available under the trade name XGEL UNO from BioTec Films LLC, Tampa, Florida, US. Films for use in the present invention may be made in a conventional manner. If desired, an adhesive and use thereof can be used to aid in sealing the films together. Suitable adhesive compositions include those set forth in WO 04/10337 and WO 04/103338 - both of which are incorporated herein by reference.
  • solid forms of the present invention may be enrobed and prepared in accordance with the methods disclosed in WO 03/096963, WO 05/030115, WO 05/030116 and PCT/GB2005/001077 — all of which are incorporated herein by reference.
  • the invention provides a method of making a solid form comprising at least one film enrobing a compacted fill comprising: i) providing a first film shaped to define an interior volume for holding a compacted fill material and having an open end; ii) depositing via the open end a fill material comprising an active material and a matrix former iii) applying pressure to the fill material so as to compact the fill material; iv) applying a second film over the said open end to close the said open end; and v) sealing the first and second films together to enrobe the compacted fill material and provide the solid form.
  • the invention also provides for the use of a solid form according to the invention in which the active material comprises a pharmaceutical active for use in the manufacture of a medicament for treatment of the human or animal body by therapy.
  • a further aspect of the invention provides a solid form according to the invention in which the active material comprises a pharmaceutical active for use in a method of treatment of the human or animal body by therapy.
  • Figure 1 shows the theophylline dissolution profile of of Examples 1 and 2 and Comparative Example 3.
  • Figure 2 shows the theophylline dissolution profile of Examples 1, 4, 5 and 6.
  • Figure 3 shows the theophylline dissolution profile of Examples 2 and 7.
  • the theohylline was sieved through a 24 mesh screen (710 microns) prior to weighing. Powders were weighed and blended for 15 to 20 minutes in a Turbula TF2 shaker mixer, a PharmaTech V-blender or in a Speedmixer DAC150FVZ-
  • the powder fill material was stored in a plastic bottle or double plastic bags until use.
  • Theophylline is slightly soluble in water (1 g in 100-1000 g water). Tablets were prepared with a manual single punch press Specac with 13 mm flat punches. 500 mg powder was weighed and poured in the die and was compressed with a 15 kN force approximately.
  • Enrobed solid form Soluble films known as XGEL UNO and supplied by Bio Tec Films LLC were cut into strips 6 centimeters by 20 centimeters approximately. The lower and upper films had a thickness of about 120 microns.
  • the lower film was heated sufficiently to thermoform under vacuum into dose cups about 3 millimeters in height to conform to cavities (7.5 millimeters width by 16.75 length millimeters) with the cavity depth determined by height-adjustable dose-shaped lower pistons within the stainless steef die.
  • the film strip was placed over the die and brought in contact with a heated TEFLON® coated surface by means of upward vacuum.
  • the film was then drawn into the stainless steel die cavities by inverting the vacuum to form a strip of twelve thermoformed dose cups with 3.0 millimeters separation between adjacent dose cups. Some unused portion of the filmstrip was cut and removed.
  • the fill composition was dosed (by volume) into the dose cups, though a paper funnel. Then the powder fill was lightly compacted in the dose cups with upper pistons, and the lower film was cut to separate the individual solid forms. The solid forms were then lifted by the lower pistons to expose a portion of the solid form sidewalls for application of the upper film to complete the enrobing of the solid form.
  • Dissolution was according to United States Pharmacopeia USP 29 with dissolution apparatus 1 , baskets, for the enrobed solid forms and according to United States Pharmacopeia USP 24 with dissolution apparatus 2, paddles and sinkers for tablets.
  • the solid forms were tested using 900 ml of simulated gastric fluid without enzymes according to USP 29 for 1 hour and 900 ml of simulated intestinal fluid without enzymes according to USP 29 thereafter. Examples 1 and 2 and Comparative Example 3
  • Solid forms of the present invention were composed of the following materials: 1) a blend made of 80% Theophylline and 20% Methocel K4M (medium viscosity HPMC grade for sustained release), and 2) a blend of 80% Theophylline and 20% Methocel K15M (high viscosity HPMC grade for sustained release).
  • the tablets 3) were prepared for comparative purposes and were made of a blend of 60% Theophylline, 20% Methocel K4M and 20% Avicel PH102 (used to aid compaction) The solid forms were compacted at approximately 15 kN.
  • Table I shows the mean weights of the dosage forms and their components (the fill materials), the Theophylline release in the dissolution test.
  • the release of Theophylline from the enrobed dosage forms of the present invention was prolonged, reaching a full release in approximately 24 hours of dissolution.
  • the release of Theophylline from the enrobed dosage forms made with the lower viscosity grade of HPMC was faster after two hours of dissolution than the enrobed dosage forms made with the higher viscosity grade of HPMC.
  • the active release profile was linear for both enrobed dosage forms of the invention, hence defining a zero order type of release.
  • the comparative tablets showed a release profile that is non-linear, proportional to the square root of time, typical of tableted HPMC.
  • Another typical characteristic of active release from HPMC tablets is the initial burst release and the subsequent decrease in release rate, which is shown by the tablets here and avoided using the enrobed solid dosage form of the present invention.
  • Example 1 and 2 The active release curves of Examples 1 and 2 and Comparative Example 3 are shown in Figurei .
  • Examples 1 and 2 are within the scope of the invention.
  • Example 3 is a comparative example.
  • the solid forms were composed of the following materials: 4) and 6) a blend made of 60% Theophylline and 40% Methoce! K4M, and 5) a blend of 80% Theophylline and 20% Methocel K4M.
  • Table Il shows the mean weights of the solid forms and their components (the compacted fill material) and the rate of Theophylline release in the dissolution test.
  • the active release rate was decreased with an increase in the HPMC content.
  • the difference in fill density did not generate significant difference in release rate of the Theophylline at high HPMC content but an increase of fill density generated slower release at lower HPMC content.
  • the active release profile was linear for all enrobed dosage forms of the invention, hence defining a zero order type of release.
  • Table H Theophylline release from Matrix enrobed dosage forms of the present invention
  • the solid forms were composed of the following materials: 7) a blend made of 60% Theophylline and 40% Methocel K15M.
  • Table III shows the mean weights of the dosage forms and their components (the fill materials), the Theophylline release in the dissolution test.
  • the active release rate was decreased with increase in the HPMC content.
  • the active release profile was linear for both enrobed dosage forms of the invention, hence defining a zero order type of release.
  • the active release curves of Examples 2 and 7 are shown in Figure 3.
  • Table III Theophylline release from Matrix enrobed dosage forms of the present invention

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Abstract

L'invention concerne une forme solide comprenant au moins un film enrobant un matériau de charge compacté. Ledit matériau comporte au moins un matériau actif contenu dans une matrice et dont la friabilité est faible, la densité d'au moins 0,5 g/ml du volume solide total de la forme solide et la déformation due à la traction inférieure à 0,9 Mpa. Le matériau présente un profil de libération contrôlée permettant la libération du matériau actif et l'obtention d'une libération d'ordre 0.
PCT/US2007/011762 2007-05-16 2007-05-16 Forme solide WO2008140460A1 (fr)

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WO2009066325A1 (fr) * 2007-11-23 2009-05-28 Lupin Limited Compositions pharmaceutiques de prégabaline à libération contrôlée
WO2009024889A3 (fr) * 2007-08-21 2009-07-09 Ranbaxy Lab Ltd Composition pharmaceutique comprenant un inhibiteur de réductase hmg-coa et un ézétimibe
EP2343055A1 (fr) 2009-12-22 2011-07-13 Sanovel Ilac Sanayi ve Ticaret A.S. Compositions pharmaceutiques de prégabaline
WO2011117313A1 (fr) * 2010-03-23 2011-09-29 Bioalliance Pharma Systèmes d'administration de médicaments à dissolution rapide
EP2377526A1 (fr) * 2010-03-23 2011-10-19 BioAlliance Pharma Systèmes d'administration de médicaments à dissolution rapide
EP2389935A1 (fr) 2010-05-25 2011-11-30 Sanovel Ilac Sanayi ve Ticaret A.S. Formulations orales liquides de prégabaline à libération contrôlée
EP2389934A1 (fr) 2010-05-25 2011-11-30 Sanovel Ilac Sanayi ve Ticaret A.S. Formulations de prégabaline en comprimé à libération prolongée
EP2389933A1 (fr) 2010-05-25 2011-11-30 Sanovel Ilac Sanayi ve Ticaret A.S. Compositions comprenant de la prégabaline à libération contrôlée
KR101137466B1 (ko) * 2009-06-12 2012-04-20 안국약품 주식회사 염산 알푸조신 함유 서방성 정제
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US8637540B2 (en) 2003-11-26 2014-01-28 Acura Pharmaceuticals Compositions for deterring abuse of opioid containing dosage forms
US8901113B2 (en) 2009-09-30 2014-12-02 Acura Pharmaceuticals, Inc. Methods and compositions for deterring abuse
US8920838B2 (en) 2006-08-03 2014-12-30 Horizon Pharma Ag Delayed-release glucocorticoid treatment of rheumatoid disease
US8927025B2 (en) 2010-05-11 2015-01-06 Cima Labs Inc. Alcohol-resistant metoprolol-containing extended-release oral dosage forms
US8951555B1 (en) 2000-10-30 2015-02-10 Purdue Pharma L.P. Controlled release hydrocodone formulations
CN104382896A (zh) * 2014-11-04 2015-03-04 万全万特制药江苏有限公司 含有依折麦布和辛伐他汀的药物组合物
US8975273B2 (en) 1999-10-29 2015-03-10 Purdue Pharma L.P. Controlled release hydrocodone formulations
US9101636B2 (en) 2012-11-30 2015-08-11 Acura Pharmaceuticals, Inc. Methods and compositions for self-regulated release of active pharmaceutical ingredient
US9492444B2 (en) 2013-12-17 2016-11-15 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
US9707184B2 (en) 2014-07-17 2017-07-18 Pharmaceutical Manufacturing Research Services, Inc. Immediate release abuse deterrent liquid fill dosage form
CN107921042A (zh) * 2015-08-20 2018-04-17 东生华制药股份有限公司 包含氨氯地平和右美沙芬的药物组合物
US9974751B2 (en) 2006-09-15 2018-05-22 Cima Labs Inc. Abuse resistant drug formulation
CN108685862A (zh) * 2018-06-05 2018-10-23 山东华辰制药有限公司 一种阿莫西林克拉维酸钾口腔崩解片及其制备方法
US10172797B2 (en) 2013-12-17 2019-01-08 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
US10179130B2 (en) 1999-10-29 2019-01-15 Purdue Pharma L.P. Controlled release hydrocodone formulations
US10195153B2 (en) 2013-08-12 2019-02-05 Pharmaceutical Manufacturing Research Services, Inc. Extruded immediate release abuse deterrent pill
CN110917164A (zh) * 2019-12-17 2020-03-27 南京康川济医药科技有限公司 一种苯磺酸米洛巴林缓释片及其制备方法
US10959958B2 (en) 2014-10-20 2021-03-30 Pharmaceutical Manufacturing Research Services, Inc. Extended release abuse deterrent liquid fill dosage form
US11103581B2 (en) 2015-08-31 2021-08-31 Acura Pharmaceuticals, Inc. Methods and compositions for self-regulated release of active pharmaceutical ingredient
US11179331B1 (en) 2020-04-21 2021-11-23 Cure Pharmaceutcai Holding Corp Oral soluble film containing sildenafil citrate

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US9492443B2 (en) 2003-11-26 2016-11-15 Acura Pharmaceuticals, Inc. Abuse deterrent compositions and methods of making same
US8920838B2 (en) 2006-08-03 2014-12-30 Horizon Pharma Ag Delayed-release glucocorticoid treatment of rheumatoid disease
US9504699B2 (en) 2006-08-03 2016-11-29 Hznp Limited Delayed-release glucocorticoid treatment of rheumatoid disease
US9216176B2 (en) 2006-09-15 2015-12-22 Cima Labs Inc. Abuse resistant drug formulation
US9974751B2 (en) 2006-09-15 2018-05-22 Cima Labs Inc. Abuse resistant drug formulation
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US8445018B2 (en) 2006-09-15 2013-05-21 Cima Labs Inc. Abuse resistant drug formulation
WO2009024889A3 (fr) * 2007-08-21 2009-07-09 Ranbaxy Lab Ltd Composition pharmaceutique comprenant un inhibiteur de réductase hmg-coa et un ézétimibe
WO2009066325A1 (fr) * 2007-11-23 2009-05-28 Lupin Limited Compositions pharmaceutiques de prégabaline à libération contrôlée
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