WO2004010972A2 - Pellicle-resistant gelatin capsule - Google Patents
Pellicle-resistant gelatin capsule Download PDFInfo
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- WO2004010972A2 WO2004010972A2 PCT/US2003/024042 US0324042W WO2004010972A2 WO 2004010972 A2 WO2004010972 A2 WO 2004010972A2 US 0324042 W US0324042 W US 0324042W WO 2004010972 A2 WO2004010972 A2 WO 2004010972A2
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- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/485—Inorganic compounds
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- A61K31/18—Sulfonamides
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- A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
- 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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Definitions
- the present invention relates to gelatin capsules which exhibit reduced gelatin cross-linking. Such capsules are useful in, ter alia, the pharmaceutical, nutraceutical, and food industries.
- Gelatin a mixture of water-soluble proteins derived from collagen by hydrolysis, is widely used in the pharmaceutical and food industries, among others.
- One major application of gelatin is in preparation of both hard and soft gelatin capsules.
- Such capsules are desirable for, inter alia, their versatility (they may contain drug formulations in solid, semi-solid, or liquid form) and for their rapid dissolution characteristics.
- drug dosage forms containing gelatin in an outer layer e.g. liquid or powder filled into a gelatin capsule
- an outer layer e.g. liquid or powder filled into a gelatin capsule
- gelatin capsules could be prepared which are capable of providing a predictable and stable dissolution rate of a drug contained therein, even after storage of such capsules under stressed conditions, a significant advance in the oral delivery of drugs, particularly drugs of low water solubility or drugs whose absorption is dissolution- rate limited, would result.
- composition suitable for preparing a pharmaceutical capsule shell comprising gelatin and an amine agent that comprises at least one pharmaceutically acceptable primary or secondary amine.
- the amine agent is present in an amount effective to inhibit cross-linking of the gelatin and/or pellicle formation in a capsule shell prepared from the composition.
- a capsule shell of the instant composition There is further provided a capsule shell of the instant composition.
- a pharmaceutical dosage form comprising capsule shells of the instant composition, wherein the shells define a fill volume that is at least partially occupied by a fill material.
- the fill material preferably contains a drug, more preferably a drug of low water solubility.
- the drug is a selective cyclooxygenase-2 inhibitory drug.
- the composition and dosage form of the present invention are especially useful for liquid fill materials and for soft gelatin capsules.
- pellicle refers to a relatively water-insoluble membrane formed in a gelatin capsule shell. Such a membrane tends to be thin, tough, and rubbery. It is now understood that one mechanism underlying pellicle formation is gelatin cross- linking. Gelatin cross-linking and pellicle formation result in reduced dissolution rates. Accordingly, quantification of dissolution rate of a first capsule within a reasonably short time after capsule preparation and of a second capsule after storage under stressed conditions (e.g., four weeks at 40°C and 85% relative humidity in a closed container) as described herein provides one means of assessing pellicle formation and/or gelatin cross- linking.
- stressed conditions e.g., four weeks at 40°C and 85% relative humidity in a closed container
- pellicle-resistant herein means that a gelatin capsule so described has a reduced tendency to form, or exhibits slowed, delayed or reduced formation of a pellicle upon storage under stressed conditions.
- inhibitor of cross-linking herein means a slowed, delayed or reduced formation of gelatin cross-links (or pellicle formation) in a capsule by comparison with an otherwise similar capsule lacking only the amine agent as provided herein.
- Pharmaceutical dosage forms according to the present invention have been found to exhibit an unexpected and surprisingly substantial reduction in cross-linking of gelatin in the capsule shell and in pellicle formation. As a result, such dosage forms are capable of consistently meeting desired in vitro dissolution criteria, even after storage under stressed conditions. This invention represents a significant improvement over conventional dosage forms and conventional gelatin capsule shells.
- Figure 1 is a graph showing Tier I dissolution rate of Formulation 30 following storage at 25°C as described in Example 6.
- Figure 2 is a graph showing Tier I dissolution rate of Formulation 30 following storage at 40°C as described in Example 6.
- Figure 3 is a graph showing Tier II dissolution rate of Formulation 30 following storage at 25°C as described in Example 6.
- Figure 4 is a graph showing Tier II dissolution rate of Formulation 30 following storage at 40°C as described in Example 6.
- Figure 5 is a graph showing Tier I dissolution rate of Formulation 19 following storage at 25°C as described in Example 6.
- Figure 6 is a graph showing Tier I dissolution rate of Formulation 19 following storage at 40°C as described in Example 6.
- Figure 7 is a graph showing Tier II dissolution rate of Formulation 19 following storage at 40°C as described in Example 6.
- the present invention provides a composition suitable for preparation of a capsule shell.
- a composition suitable for preparation of a capsule shell.
- Such a composition comprises gelatin and an amine agent comprising at least one pharmaceutically acceptable primary or secondary amine present in an amount effective to inhibit cross-linking of the gelatin shell and/or pellicle formation upon storage.
- primary or secondary amine compound herein includes those primary and secondary amine compounds which are pharmaceutically acceptable excipients.
- primary and secondary amine compounds of the instant invention are not therapeutically or nutritionally active compounds.
- a liquid for example water
- a liquid for example water
- such a composition suitable for preparation of a capsule shell comprises gelatin, at least one primary or secondary amine compound, and water.
- water will be present in an amount such that the weight ratio of water to gelatin is about 0.8 to about 1.6, and preferably about 1 to about 1.3.
- gelatin is present in a composition of the invention in an amount of about 1% to about 99%, more preferably about 10% to about 80%, and still more preferably about 15% to about 90% of the composition on a dry weight basis. It should be understood that "on a dry weight basis" means total weight excepting water weight.
- Any pharmaceutically acceptable primary or secondary amine can be used in a composition of this embodiment.
- suitable primary amines include tris(hydroxymethyl)aminomethane (also known and/or referred to herein as tromethamine or Tris), ethanolamine, ethylenediamine, diethylamine, ethylene N-methyl- D-glucamine, and amino acids such as L-arginine, L-lysine, and guanidine.
- Non-limiting examples of suitable secondary amines include diethanolamine, benethamine (i.e., N- phenymethyl)benezeneethanamine), benzathine (i.e., N,N-dibenzylethylenediamine), piperazine, hydrabamine (i.e., N,N-bis(dehydroabietyl)ethylenediamine), and imidazole.
- the amine compound is preferably present in a composition of the invention in a total amount of not more than about 10%, for example about 0.01% to about 10%, preferably about 0.1% to about 5%, and more preferably about 0.1% to about 2% of the composition on a dry weight basis.
- a composition of the invention in addition to gelatin and a primary or secondary amine, preferably further comprises one or more pharmaceutically acceptable excipients.
- the composition preferably comprises at least one plasticizer in a total amount of about 2% to about 60%, preferably about 5% to about 45%, and more preferably about 10% to about 40% of the composition on a dry weight basis.
- the weight ratio of plasticizer (dry weight) to gelatin is about 0.3 to about 1.8 and preferably about 0.4 to about 0.75.
- Non-limiting examples of suitable plasticizers include poly-hydroxy-alcohols such as sorbitol, glycerol, and mannitol; dialkylphthalates; lower alkyl citrates wherein the lower alkyl has 1 - 6 carbon atoms; glycols and polyglycols including polyethylene glycols with a molecular weight range of about 200 to about 40,000, methoxyl-propylene-glycol, and 1,2-propylene glycol; esters of polyhydroxy-alcohols such as mono-, di-, and tri-acetate of glycerol; ricinoleic acid and esters thereof; and mixtures of the above.
- poly-hydroxy-alcohols such as sorbitol, glycerol, and mannitol
- dialkylphthalates lower alkyl citrates wherein the lower alkyl has 1 - 6 carbon atoms
- glycols and polyglycols including polyethylene glycols with a molecular
- a composition of the invention can further comprise one or more preservatives, opacifying agents (e.g. titanium dioxide), decomposition inhibitors (e.g. sulfur dioxide) color, flavor, etc.
- opacifying agents e.g. titanium dioxide
- decomposition inhibitors e.g. sulfur dioxide
- suitable preservatives include methylparaben, propylparaben, butylparaben, sorbic acid, benzoic acid, editic acid, phenolic acids, potassium sorbate, and sodium propionate.
- a composition of the invention further comprises at least one pharmaceutically acceptable sulfite compound.
- Illustrative pharmaceutically acceptable sulfite compounds include sodium metabisulfite, sodium bisulfite, and sodium thiosulfate (sodium hyposulfite).
- one or more sulfite compounds are preferably present in a composition of the invention in an amount of not more than about 10%, for example about 0.01% to about 5%, and preferably about 0.1% to about 2% of the composition on a dry weight basis.
- a composition suitable for preparation of a capsule wall can be in the form of a solid, a dry powder, a semi-solid, a liquid solution, or a liquid suspension.
- a suitable physical form (e.g. powder, liquid mixture, etc.) of a composition of the invention will, at least in part, be determined by the particular process, if any, which will be used to make capsules, and by the particular type of capsule being prepared (hard or soft).
- a composition of the invention can be used to prepare hard gelatin capsules according to any suitable process including but not limited to those processes described in the following patents and/or publications, each of which is hereby incorporated by reference.
- One preferred method for preparing hard gelatin capsules of the invention comprises the steps of (a) providing a composition suitable for preparation of a capsule shell (comprising gelatin and a primary or secondary amine compound) in dry powder form, (b) preparing a liquid solution or solution/suspension comprising water and the composition, (c) heating the liquid, (d) dipping stainless steel capsule-making pins in the heated liquid, (e) removing the dipped pins from the liquid to form coated pins, and (f) subjecting the coated pins to a drying process to produce a dry capsule half-shell. After drying, capsule half-shells are removed from the pins and trimmed to desired length.
- the capsule half-shells can next be filled with any desired fill material, brought together in a cooperative manner to form a capsule shell, and then capped.
- the cap can be spot welded, fused or banded with molten gelatin to provide a tamper-resistant product.
- the primary or secondary amine compound is preferably present in the composition suitable for making a capsule shell, and/or if desired, can also be added during steps (b), (c) and/or (d).
- Soft capsules [0045]
- Soft gelatin capsules of the invention can be prepared according to any suitable process including but not limited to the plate process, vacuum process, or the rotary die process. See, for example, (1) Ansel et al.
- the rotary die process is a presently preferred process by which to make soft gelatin capsules according to the present invention.
- a composition of the invention comprising gelatin and a primary or secondary amine compound is dissolved or suspended in water to form a flowable material and is then placed in an overhead tank.
- the flowable material from the overhead tank is formed into two continuous ribbons by a rotary die machine and the ribbons are then brought together by twin rotating dies.
- metered fill material is injected between ribbons at approximately the same moment that the dies form pockets of the ribbons. These pockets of fill-containing encapsulation material are then sealed by pressure and heat.
- Soft gelatin capsules can be manufactured in different shapes including round, oval, oblong, and tube-shape, among others. Additionally, by using two different ribbon colors, two-tone capsules can be produced.
- capsule shell and “gelatin capsule shell” embraces capsule half-shells (that can cooperate to form a whole capsule shell) and whole capsule shells (that define a fill volume). Such term also embraces soft gelatin capsule shells and hard gelatin capsules, irrespective of the process by which such shells are made.
- sealed capsule shell means to denote a whole capsule shell that defines a fill volume, that such fill volume can contain a fill material, that such fill material is enclosed in the whole capsule shell, and that such enclosure affords the fill material more than a de minimus amount of protection from the atmosphere outside of the whole capsule shell.
- Capsule shells according to the present invention define a fill volume and such fill volume can be occupied at least partially by any fill material.
- the fill material can comprise any active drug.
- the active drug is a drug of low water solubility, also referred to herein as a poorly water soluble drug.
- a "drug of low water solubility” or “poorly water solubility drug” herein refers to any drug or compound having a solubility in water, measured at 37°C, not greater than about 10 mg/ml, and preferably not greater than about 1 mg/ml. Particularly preferred drugs having a solubility in water, measured at 37°C, not greater than about 0.1 mg/ml.
- Solubility in water for many drugs can be readily determined from standard pharmaceutical reference books, for example The Merck Index, 11th ed., 1989 (published by Merck & Co., Inc., Rahway, NJ); the United States Pharmacopoeia, 24th ed. (USP 24), 2000; The Extra Pharmacopoeia, 29th ed., 1989 (published by Pharmaceutical Press, London); and the Physicians Desk Reference (PDR), 2001 ed. (published by Medical Economics Co., Montvale, NJ).
- individual drugs of low solubility as defined herein include those drugs categorized as “slightly soluble”, “very slightly soluble”, “practically insoluble” and “insoluble” in USP 24, pp. 2254-2298; and those drugs categorized as requiring 100 ml or more of water to dissolve 1 g of the drug, as listed in USP 24, pp. 2299-2304.
- suitable drugs of low water solubility include, without limitation, drugs from the following classes: abortifacients, ACE inhibitors, ⁇ - and ⁇ -adrenergic agonists, ⁇ - and ⁇ -adrenergic blockers, adrenocortical suppressants, adrenocorticotropic hormones, alcohol deterrents, aldose reductase inhibitors, aldosterone antagonists, anabolics, analgesics (including narcotic and non-narcotic analgesics), androgens, angiotensin II receptor antagonists, anorexics, antacids, anthelminthics, antiacne agents, antiallergics, antialopecia agents, antiamebics, antiandrogens, antianginal agents, antiarrhythmics, antiarteriosclerotics, antiarthritic/antirheumatic agents (including selective COX-2 inhibitors), antia
- Non-limiting illustrative examples of suitable drugs of low water solubility include acetohexamide, acetylsalicylic acid, alclofenac, allopurinol, atropine, benzthiazide, carprofen, celecoxib, chlordiazepoxide, chlorpromazine, clonidine, codeine, codeine phosphate, codeine sulfate, deracoxib, diacerein, diclofenac, diltiazem, estradiol, etodolac, etoposide, etoricoxib, fenbufen, fenclofenac, fenprofen, fentiazac, flurbiprofen, griseofulvin, haloperidol, ibuprofen, indomethacin, indoprofen, ketoprofen, lorazepam, medroxyprogesterone acetate,
- the amount of drug incorporated into fill material to be filled into a capsule of the invention can be selected according to known principles of pharmacy.
- a therapeutically effective amount of drug is specifically contemplated.
- the term "therapeutically and/or prophylactically effective amount” as used herein refers to an amount of drug that is sufficient to elicit the required or desired therapeutic and/or prophylactic response.
- the therapeutic agent is present in an amount of at least about 0.01%, preferably at least about 0.1%, more preferably at least about 1%, and still more preferably at least about 5%, by weight of the composition on a dry weight basis.
- the drug is a selective cyclooxygenase-2 inhibitory drug.
- a preferred selective cyclooxygenase-2 inhibitory drug useful herein, or to which a salt or prodrug useful herein is converted in vivo, is a compound of formula (I)
- A is a substituent selected from partially unsaturated or unsaturated heterocyclyl and partially unsaturated or unsaturated carbocyclic rings, preferably a heterocyclyl group selected from pyrazolyl, furanonyl, isoxazolyl, pyridinyl, cyclopentenonyl and pyridazinonyl groups;
- X is O, S or CH 2 ; n is O or 1;
- R 1 is at least one substituent selected from heterocyclyl, cycloalkyl, cycloalkenyl and aryl, and is optionally substituted at a substitutable position with one or more radicals selected from alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino, alkylamino, arylamino, nitro, alkoxyalkyl, alkylsulfinyl, halo, alkoxy and alkylthio;
- R 2 is methyl, amino or aminocarbonylalkyl;
- R is one or more radicals selected from hydrido, halo, alkyl, alkenyl, alkynyl, oxo, cyano, carboxyl, cyanoalkyl, heterocyclyloxy, alkyloxy, alkylthio, alkylcarbonyl, cycloalkyl, aryl, haloalkyl, heterocyclyl, cycloalkenyl, aralkyl, heterocyclylalkyl, acyl, alkylthioalkyl, hydroxyalkyl, alkoxycarbonyl, arylcarbonyl, aralkylcarbonyl, aralkenyl, alkoxyalkyl, arylthioalkyl, aryloxyalkyl, aralkylthioalkyl, aralkoxyalkyl, alkoxyaralkoxyalkyl, alkoxycarbonylalkyl
- compositions of the invention are especially useful for selective cyclooxygenase -2 inhibitory drugs having the formula (II):
- R > 5 i ⁇ s a methyl or amino group
- R is hydrogen or a C 1- alkyl or alkoxy group
- X' is N or CR 7 where R 7 is hydrogen or halogen
- Y and Z are independently carbon or nitrogen atoms defining adjacent atoms of a five- to six-membered ring that is optionally substituted at one or more positions with oxo, halo, methyl or halomethyl groups, or an isomer, tautomer, pharmaceutically-acceptable salt or prodrug thereof.
- Preferred such five- to six-membered rings are cyclopentenone, furanone, methylpyrazole, isoxazole and pyridine rings substituted at no more than one position.
- capsules of the invention are suitable for delivering celecoxib, deracoxib, valdecoxib, rofecoxib, etoricoxib, 2-(3,5-difluorophenyl)-3-[4-
- Capsules of the invention are also useful for compounds having the formula
- R 8 is lower haloalkyl
- R 9 is hydrogen or halogen
- R 10 is hydrogen, halogen, lower alkyl, lower alkoxy or haloalkoxy, lower aralkylcarbonyl, lower dialkylaminosulfonyl, lower alkylaminosulfonyl, lower aralkylaminosulfonyl, lower heteroaralkylaminosulfonyl, or 5- or 6-membered nitrogen-containing heterocyclosulfonyl
- R 11 and R 12 are independently hydrogen, halogen, lower alkyl, lower alkoxy, or aryl; and for pharmaceutically acceptable salts thereof.
- a particularly useful compound of formula (ITf) is (S)-6,8-dichloro-2- (trifluoromethyl)-2H-l-benzopyran-3-carboxylic acid, particularly in the form of a water- soluble salt thereof, for example the sodium salt.
- the invention is illustrated herein with particular reference to celecoxib, and it will be understood that any other selective COX-2 inhibitory drug can, if desired, be substituted in whole or in part for celecoxib in dosage forms herein described.
- dosage forms of the invention are suitable for formulation of valdecoxib, alone or in combination with celecoxib.
- the dosage form typically comprises celecoxib in a therapeutically and/or prophylactically effective total amount of about 10 mg to about 1000 mg per dose unit.
- the drug is a selective COX-2 inhibitory drug other than celecoxib
- the amount of the drug per dose unit is therapeutically equivalent to about 10 mg to about 1000 mg of celecoxib.
- a therapeutically and/or prophylactically effective amount of a drug for a subject is dependent inter alia on the body weight of the subject.
- a "subject" herein to which a therapeutic agent or composition thereof can be administered includes a human patient of either sex and of any age, and also includes any nonhuman animal, particularly a domestic or companion animal, illustratively a cat, dog or horse.
- an amount of celecoxib relatively low in the preferred range of about 10 mg to about 1000 mg is likely to be consistent with therapeutic effectiveness.
- an adult human or a large animal e.g., a horse
- therapeutic effectiveness is likely to require dose units containing a relatively greater amount of celecoxib.
- a therapeutically effective amount of celecoxib per dose unit in a dosage form of the present invention is typically about 10 mg to about 400 mg.
- Especially preferred amounts of celecoxib per dose unit are about 100 mg to about 200 mg, for example about 100 mg or about 200 mg.
- an amount of the drug per dose unit can be in a range known to be therapeutically effective for such drugs.
- the amount per dose unit is in a range providing therapeutic equivalence to celecoxib in the dose ranges indicated immediately above.
- a capsule of the invention is filled with a liquid fill material. More preferably, the fill material is self -emulsifying upon contact with simulated gastric fluid.
- Fill material according to this embodiment comprises at least one solvent which is preferably suitable for dissolving the drug and/or any additional ingredients or excipients present therein.
- Glycol solvents [0077]
- a preferred liquid solvent is a glycol or glycol ether. Suitable glycol ethers include those conforming to formula (X):
- Glycol ethers used as solvents in fill material typically have a molecular weight of about 75 to about 1000, preferably about 75 to about 500, and more preferably about 100 to about 300.
- the glycol ethers used in fill material of this embodiment must be pharmaceutically acceptable and must meet all other conditions prescribed herein.
- Non-limiting examples of glycol ethers that may be used in fill material of this embodiment include ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, ethylene glycol monoethyl ether, ethylene glycol diethyl ether, ethylene glycol monobutyl ether, ethylene glycol dibutyl ether, ethylene glycol monophenyl ether, ethylene glycol monobenzyl ether, ethylene glycol butylphenyl ether, ethylene glycol terpinyl ether, diethylene glycol monomethyl ether, diethylene glycol dimethyl ether, diethylene glycol monoethyl ether, diethylene glycol diethyl ether, diethylene glycol divinyl ether, ethylene glycol monobutyl ether, diethylene glycol dibutyl ether, diethylene glycol monoisobutyl ether, triethylene glycol dimethyl ether, triethylene glycol monoethyl ether, triethylene glycol monobutyl ether, t
- glycol ether solvent is diethylene glycol monoethyl ether, sometimes referred to in the art as DGME or ethoxydiglycol. It is available for example under the trademark TranscutolTM of Gattefosse Corporation.
- Glycols suitable as solvents in fill material include propylene glycol, 1,3- butanediol and polyethylene glycols.
- a presently preferred solvent is polyethylene glycol (PEG).
- any pharmaceutically acceptable PEG can be used.
- the PEG has an average molecular weight of about 100 to about 10,000, and more preferably about 100 to about 1,000. Still more preferably, the PEG is of liquid grade.
- PEGs that can be used in solvent liquids of this invention include PEG-200, PEG-350, PEG-400, PEG-540 and PEG-600. See for example Flick (1998), op. cit., p. 392.
- a presently preferred PEG has an average molecular weight of about 375 to about 450, as exemplified by PEG-400.
- Polyethylene glycols such as PEG-400 have many desirable properties as solvents for poorly water-soluble drugs.
- the drug can be dissolved or solubilized at a very high concentration in PEG-400, enabling formulation of a therapeutically effective dose in a very small volume of solvent liquid. This is especially important where the resulting solution is to be encapsulated, as capsules of a size convenient for swallowing can be prepared containing a therapeutically effective dose even of a drug such as celecoxib having a relatively high dose requirement for efficacy.
- ethanol, water, and other excipients identified as co-solvents hereinbelow or elsewhere can, if desired, be used as solvents in a fill material of the invention.
- one or more solvents will be present in a fill material in a total amount of about 5% to about 95%, preferably about 10% to about 90% and more preferably about 15% to about 85%, by weight of the fill material.
- Co-solvents [0083] A fill material of this embodiment optionally comprises one or more pharmaceutically acceptable co-solvents.
- Non-limiting examples of suitable co-solvents include additional glycols, alcohols, for example ethanol and n-butanol; oleic and linoleic acid triglycerides, for example soybean oil; caprylic/capric triglycerides, for example MiglyolTM 812 of Huls; caprylic/capric mono- and diglycerides, for example CapmulTM MCM of Abitec; polyoxyethylene caprylic/capric glycerides such as polyoxyethylene (8) caprylic/capric mono- and diglycerides, for example LabrasolTM of Gattefosse; propylene glycol fatty acid esters, for example propylene glycol laurate; polyoxyethylene (35) castor oil, for example CremophorTM EL of BASF; polyoxyethylene glyceryl trioleate, for example TagatTM TO of Goldschmidt; lower alkyl esters of fatty acids, for example ethyl butyrate, ethyl cap
- fill material placed into a capsule of the present invention can further comprise a sulfite compound.
- a sulfite compound In a preferred embodiment, at least about 40%, preferably at least about 50%, still more preferably at least about 55%, even more preferably at least about 60%, and yet more preferably at least about 70% of all sulfite compound present in a dosage unit of the invention is present in the fill material.
- fill material (which is placed into a capsule according to the present invention) can further comprise a primary or secondary amine compound.
- a primary or secondary amine compound preferably at least about 40%, preferably at least about 50%, still more preferably at least about 55%, even more preferably at least about 60%, and yet more preferably at least about 70% of all primary or secondary amine compound present in a dosage unit of the invention is present in the capsule shell.
- the capsule shell comprises at least one primary or secondary amine and optionally a sulfite compound.
- the fill material of the dosage form optionally comprises either (1) at least one primary or secondary amine, or (2) a sulfite compound; or (3) at least one primary or secondary amine and a sulfite compound.
- at least one primary or secondary amine contemplates the presence of one or more primary amines, one or more secondary amines, and combinations of primary and secondary amines.
- Fill material of the present invention optionally further comprises at least one pharmaceutically acceptable free radical-scavenging antioxidant.
- a free radical- scavenging antioxidant is to be contrasted with a "non-free radical-scavenging antioxidant", i.e., an antioxidant that does not possess free radical-scavenging properties.
- Non-limiting illustrative examples of suitable free radical-scavenging antioxidants include ⁇ -tocopherol (vitamin E), ascorbic acid (vitamin C) and salts thereof including sodium ascorbate and ascorbic acid palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), fumaric acid and salts thereof, hypophosphorous acid, malic acid, alkyl gallates, for example propyl gallate, octyl gallate and lauryl gallate, sodium sulfite, sodium bisulfite and sodium metabisulfite.
- Preferred free radical-scavenging antioxidants are alkyl gallates, vitamin E, BHA and BHT. More preferably the at least one free radical-scavenging antioxidant is propyl gallate.
- One or more free radical-scavenging antioxidants are optionally present in dosage forms of the invention in a total amount effective to substantially reduce formation of an addition compound, typically in a total amount of about 0.01% to about 5%, preferably about 0.01% to about 2.5%, and more preferably about 0.01% to about 1%, by weight of the fill material.
- Fill material according to the invention optionally comprises one or more pharmaceutically acceptable sweeteners.
- suitable sweeteners include mannitol, propylene glycol, sodium saccharin, acesulfame K, neotame and aspartame.
- a viscous sweetener such as sorbitol solution, syrup (sucrose solution) or high-fructose corn syrup can be used and, in addition to sweetening effects, can also be useful to increase viscosity and to retard sedimentation.
- Fill material of the invention optionally comprises one or more pharmaceutically acceptable preservatives other than free radical-scavenging antioxidants.
- Non-limiting examples of suitable preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, chlorobutanol, phenol, phenylethyl alcohol, phenylmercuric nitrate, thimerosal, etc.
- Fill material of the invention optionally comprises one or more pharmaceutically acceptable wetting agents.
- Surfactants, hydrophilic polymers and certain clays can be useful as wetting agents to aid in dissolution and/or dispersion of a hydrophobic drug such as celecoxib.
- Non-limiting examples of suitable surfactants include benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, dioctyl sodium sulfosuccinate, nonoxynol 9, nonoxynol 10, octoxynol 9, poloxamers, polyoxyethylene (8) caprylic/capric mono- and diglycerides (e.g., LabrasolTM of Gattefosse), polyoxyethylene (35) castor oil, polyoxyethylene (20) cetostearyl ether, polyoxyethylene (40) hydrogenated castor oil, polyoxyethylene (10) oleyl ether, polyoxyethylene (40) stearate, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80 (e.g., TweenTM 80 of ICI), propylene glycol laurate (e.g., LauroglycolTM of Gattefosse), sodium lauryl sulfate, sorbitan monolaurate, sorbitan monoole
- dosage forms of the invention optionally comprise one or more pharmaceutically acceptable buffering agents, flavoring agents, colorants, stabilizers and/or thickeners.
- Buffers can be used to control pH of a formulation and can thereby modulate drug solubility.
- Flavoring agents can enhance patient compliance by making the dosage form more palatable, and colorants can provide a product with a more aesthetic and/or distinctive appearance.
- suitable colorants include D&C Red No. 33, FD&C Red No. 3, FD&C Red No. 40, D&C Yellow No. 10, and C Yellow No. 6.
- gelatin cross-linking can result from a process by which amino acid residues of gelatin covalently bond to form an insoluble material.
- the process can be the result of low levels of aldehydes coming into contact with the gelatin.
- Cross-linking of a gelatin capsule can impact product performance by delaying the release of the formulation (containing the active compound) from the capsule shell. The delay in release can, in turn, affect the rate of absorption of the compound into the blood stream and clinical onset of action.
- “mild” cross- linking does not necessarily have a significant impact on release of the formulation from the dosage form
- severe cross-linking can have a significant impact. When cross- linking is severe, it can lead to a delay of release of formulation from the dosage form in humans, potential bioequivalence problems, and a potential delay in clinical onset of action.
- Capsules according to the present invention exhibit decreased gelatin cross- linking (and pellicle formation) and, therefore, when filled with a drug-containing composition and placed in an in vitro dissolution assay, are capable of advantageously exhibiting less dissolution rate change during storage under stressed conditions than conventional capsules. Capsules according to the present invention are also believed to exhibit more uniform inter-capsule drug dissolution rate than standard gelatin capsules.
- the fill material optionally comprises a drug and at least one substance that promotes cross-linking of gelatin when in contact therewith (the substance being the drug itself or an excipient substance, and the substance acting independently or in combination with one or more other substances to promote said cross-linking); (b) sealing the capsules; (c) immediately testing a first sealed capsule in a first in vitro dissolution assay; (d) storing a second sealed capsule in a closed container maintained at 40 °C and 75% relative humidity for a period of four weeks and, after said storage; (e) testing the second sealed capsule in a second in vitro dissolution assay which is identical to the first in vitro dissolution assay; the amount of drug dissolved at 45 minutes in the second dissolution assay is within ⁇ 15 percent and preferably within ⁇ 10 percent of the amount of drug dissolved at 45 minutes in the first dissolution assay.
- a gelatin capsule dosage form is placed in a USP apparatus II with a rotating paddle with a paddle speed of 50 rpm in 900 mL of 0.01N HC1 + 1% Tween 80. Samples are typically withdrawn at 15, 30, 45, 60 and 90 minutes and assayed for drug content by HPLC.
- the Tier II test employs the addition of the enzyme pepsin to the media .
- Pepsin in the human stomach digests cross-linked gelatin.
- the appropriate amount of pepsin added to the media (750,000 units/L) was determined and reported in Collaborative Development of Two-Tier Dissolution Testing for Gelatin Capsules and Gelatin-Coated Tablets using Enzyme-Containing Media, Stimuli to the Revision Process, Pharmacopeial Forum, Vol. 25, No. 5, Sept.-Oct. 1998.
- the Tier II drug release test designed in this way is expected to produce a drug release profile that is a reasonable approximation of the drug release profile in humans.
- An 'initial' drug release profile is determined for each dosage form within a reasonably short time after formation (i.e. dosage form before the formulation is exposed to conditions which might result in gelatin cross-linking, such as temperature or relative humidity).
- a subsequent profile is determined for samples pulled at subsequent time points.
- a change from initial to subsequent Tier I profile i.e. a delay in dissolution
- this reduction is deemed further evidence of gelatin cross-linking upon storage.
- a liquid fill formulation, F0 is prepared as shown in Table 1.
- compositions suitable for preparation of a capsule wall are prepared as shown in Tables 2 and 3 according to the following procedure.
- Gelatin and one or primary and/or secondary amines are admixed together to form a dry mixture.
- One or more plasticizers glycerol and/or sorbitol
- water are then added to the mixture to form a liquid mixture.
- the liquid mixture is melted at 80 °C for up to four hours to form a melt.
- the melt is cooled to 60 °C to form a flowable gelatin mix and is fed into the two spreader boxes of a rotary die soft gelatin capsule manufacturing machine, which controls the flow of said mix onto two air-cooled rotating drums, where two white opaque gelatin ribbons are cast and further processed to white opaque, soft gelatin capsules, at a rate of about 15,000 capsules per hour; capsules are filled with 1 ml of fill Formulation F0 of Example 1.
- the capsules are then dried in a tumbler dryer with an air blast at 21 C and 20% relative humidity, and are then brought to room temperature.
- capsules are stored 40 °C and 75% relative humidity for up to 24 weeks. After 24 weeks of storage, each of the capsules are analyzed for pellicle formation. Overall, capsules prepared from compositions Cl - C14 (comprising a primary amine) exhibit less pellicle formation than do capsules prepared from comparative compositions CC-1 - CC7 (no primary amine).
- FI - F3 Three fill formulations, FI - F3, were prepared as shown in Table 5. One ml of each fill formulation was filled into each of several standard (no primary or secondary amine) soft gelatin capsules (R.P. Scherer). Table 5. Composition of fill formulations FI - F3
- capsules containing fill formulation FI (comprising tromethamine in an amount of about 3% by weight of the fill material) exhibited no pellicle formation during storage for a period of six months.
- capsules containing Fill Formulation F2 (no primary or secondary amine compound) or F3 (0.5% tromethamine) exhibited pellicle formation by 15 and 30 days of storage, respectively.
- a composition of the invention is prepared by mixing in a vessel (a) 35% B grade, 150 Bloom strength, pharmaceutical grade gelatin; (b) 15% chilled glycerol; (c) 5% tromethamine; and (d) 45% chilled deionized water.
- the mixture is melted at 80 °C for up to four hours to form a melt.
- the melt is cooled to 60 °C to form a flowable gelatin mix and is fed into the two spreader boxes of a rotary die soft gelatin capsule manufacturing machine, which controls the flow of said mix onto two air-cooled rotating drums, where two white opaque gelatin ribbons are cast and further processed to white opaque, soft gelatin capsules, at a rate of about 15,000 capsules per hour.
- the capsules are then dried in a tumbler dryer with an air blast at 21 C° and 20% relative humidity, and are then brought to room temperature.
- compositions suitable for preparation of a capsule wall are prepared as shown in Tables 7, according to the procedure described in Examples 1 and 2.
- compositions C15 - C21 for preparing a capsule wall (% wt)
- Tier I drug release profile As early as 1 month of storage, there was a marked delay in the Tier I drug release profile at both temperature conditions. This delay increased with storage time.
- Tier I and Tier U results are very similar for this 6 month sample indicating that the change in drug release profile is not attributable to cross-linking.
- the change in the Tier ⁇ drug release profile i.e. reduced delay
- Tier I delayed release is the result of cross-linking for this formulation and further indicates that a significant delay in the drug release profile in humans would be likely.
- the Formulation 19, containing sodium metabisulfite exhibits no measurable cross-linking through 6 months at stringent (40°C / 75% RH) storage conditions.
- sodium metabisulfite is believed to inhibit cross-linking by a process in which sodium metabisulfite reacts with aldehydes forming a bisulfite addition product.
- sodium metabisulfite may effectively scavenges aldehydes making them unavailable to promote cross-linking in the gelatin.
- a dosage form (of Formulation X-60 set forth in Table 9) was prepared and stored under two different conditions as shown in Table 10. At the times indicated, capsules were removed and Tris content was quantified in the fill material and in the capsule. As shown in Table 10, upon storage with time, Tris content in the capsules increased and Tris content in the fill material decreased in comparison to the initial formulation.
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Abstract
Description
Claims
Priority Applications (6)
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JP2004524261A JP2005538993A (en) | 2002-07-31 | 2003-07-31 | Gelatin capsule that does not easily form a thin film |
EP03772159A EP1526844A2 (en) | 2002-07-31 | 2003-07-31 | Pellicle-resistant gelatin capsule |
BR0312875-0A BR0312875A (en) | 2002-07-31 | 2003-07-31 | Film-Resistant Gelatin Capsule |
MXPA05001166A MXPA05001166A (en) | 2002-07-31 | 2003-07-31 | Pellicle-resistant gelatin capsule. |
CA002494069A CA2494069A1 (en) | 2002-07-31 | 2003-07-31 | Pellicle-resistant gelatin capsule |
AU2003257981A AU2003257981A1 (en) | 2002-07-31 | 2003-07-31 | Pellicle-resistant gelatin capsule |
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PCT/US2003/024042 WO2004010972A2 (en) | 2002-07-31 | 2003-07-31 | Pellicle-resistant gelatin capsule |
PCT/US2003/024045 WO2004010974A2 (en) | 2002-07-31 | 2003-07-31 | Gelatin capsule exhibiting reduced cross-linking |
PCT/US2003/024043 WO2004010973A2 (en) | 2002-07-31 | 2003-07-31 | Pharmaceutical dosage form capable of maintaining stable dissolution profile upon storage |
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PCT/US2003/024045 WO2004010974A2 (en) | 2002-07-31 | 2003-07-31 | Gelatin capsule exhibiting reduced cross-linking |
PCT/US2003/024043 WO2004010973A2 (en) | 2002-07-31 | 2003-07-31 | Pharmaceutical dosage form capable of maintaining stable dissolution profile upon storage |
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CA (4) | CA2494069A1 (en) |
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US8895059B2 (en) | 2002-06-05 | 2014-11-25 | Ivax Pharmaceuticals S.R.O. | Reduction of cross-linking gelatin in gelatin capsules |
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EP1919882A2 (en) | 2005-02-17 | 2008-05-14 | Synta Pharmaceuticals Corporation | Isoxazole combretastatin derivatives for the treatment of proliferative disorders |
US7485323B2 (en) | 2005-05-31 | 2009-02-03 | Gelita Ag | Process for making a low molecular weight gelatine hydrolysate and gelatine hydrolysate compositions |
RU2406482C2 (en) | 2005-07-26 | 2010-12-20 | Никокс С.А. | Pharmaceutical composition of nitroxy derivative nonsteroid anti-inflammatory drugs |
JP5503939B2 (en) * | 2009-10-16 | 2014-05-28 | 東洋カプセル株式会社 | Azelastine hydrochloride-containing capsule |
JP6887456B2 (en) | 2018-07-04 | 2021-06-16 | キャプシュゲル・ベルジウム・エヌ・ヴィ | A film-forming composition containing a surfactant or a surfactant and a salt as a whitening agent. |
US11364478B2 (en) * | 2019-05-22 | 2022-06-21 | Mezzimatic, LLC | Method of manufacturing throwable paintballs and paintballs made therefrom |
MX2023005459A (en) * | 2020-12-01 | 2023-05-23 | Lg Chemical Ltd | Stable oral formulation containing 1-(3-cyano-1-isopropyl-indol-5 -yl)pyrazole-4-carboxylic acid. |
CN113230241A (en) * | 2021-06-11 | 2021-08-10 | 北京畅盛医药科技有限公司 | Application of tris (hydroxymethyl) aminomethane salt in medicine for treating cardiovascular and cerebrovascular diseases |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2204401A1 (en) * | 1972-11-01 | 1974-05-24 | Meiji Seika Co | |
FR2617047A1 (en) * | 1987-06-23 | 1988-12-30 | Sanofi Sa | Gelatin composition which withstands tanning, capsules based on this composition and their pharmaceutical application, in particular to fenofibrate |
EP0679395A1 (en) * | 1994-04-26 | 1995-11-02 | Bayer S.p.A. | Pharmaceutical compositions containing a ketoprofen solution in a soft gelatine capsule and method to produce them |
EP0695544A1 (en) * | 1994-08-05 | 1996-02-07 | Shionogi & Co., Ltd. | Hard gelatin capsules resistant to denaturation and the production thereof |
WO1996014365A2 (en) * | 1994-11-07 | 1996-05-17 | Warner-Lambert Company | Process for stabilizing gelatin products |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4349529A (en) * | 1980-04-14 | 1982-09-14 | E. R. Squibb & Sons, Inc. | Diagnostic and therapeutic capsules and method of producing |
US4590183A (en) * | 1985-04-22 | 1986-05-20 | Sterling Drug Inc. | Gastric cytoprotection with sodium thiosulfate in oral administration of aspirin |
JP2790659B2 (en) * | 1989-06-30 | 1998-08-27 | 帝国臓器製薬株式会社 | Gelatin capsule |
HUT71245A (en) * | 1994-03-15 | 1995-11-28 | Senju Pharma Co | Stable liquid preparation of pranoprofen |
US7115565B2 (en) * | 2001-01-18 | 2006-10-03 | Pharmacia & Upjohn Company | Chemotherapeutic microemulsion compositions of paclitaxel with improved oral bioavailability |
-
2003
- 2003-07-31 BR BR0313064-9A patent/BR0313064A/en not_active IP Right Cessation
- 2003-07-31 AU AU2003257103A patent/AU2003257103A1/en not_active Abandoned
- 2003-07-31 BR BR0313150-5A patent/BR0313150A/en not_active IP Right Cessation
- 2003-07-31 EP EP03772161A patent/EP1526846A2/en not_active Withdrawn
- 2003-07-31 BR BR0312875-0A patent/BR0312875A/en not_active IP Right Cessation
- 2003-07-31 EP EP03772160A patent/EP1526845A2/en not_active Withdrawn
- 2003-07-31 MX MXPA05001167A patent/MXPA05001167A/en unknown
- 2003-07-31 JP JP2004534259A patent/JP2006500389A/en not_active Withdrawn
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- 2003-07-31 WO PCT/US2003/024044 patent/WO2004022032A2/en active Application Filing
- 2003-07-31 CA CA002493974A patent/CA2493974A1/en not_active Abandoned
- 2003-07-31 EP EP03794452A patent/EP1526847A2/en not_active Withdrawn
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- 2003-07-31 MX MXPA05000862A patent/MXPA05000862A/en not_active Application Discontinuation
- 2003-07-31 JP JP2004524261A patent/JP2005538993A/en not_active Withdrawn
- 2003-07-31 CA CA002493980A patent/CA2493980A1/en not_active Abandoned
- 2003-07-31 AU AU2003257981A patent/AU2003257981A1/en not_active Abandoned
- 2003-07-31 AU AU2003257102A patent/AU2003257102A1/en not_active Abandoned
- 2003-07-31 WO PCT/US2003/024043 patent/WO2004010973A2/en active Application Filing
- 2003-07-31 BR BR0313149-1A patent/BR0313149A/en not_active IP Right Cessation
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2204401A1 (en) * | 1972-11-01 | 1974-05-24 | Meiji Seika Co | |
FR2617047A1 (en) * | 1987-06-23 | 1988-12-30 | Sanofi Sa | Gelatin composition which withstands tanning, capsules based on this composition and their pharmaceutical application, in particular to fenofibrate |
EP0679395A1 (en) * | 1994-04-26 | 1995-11-02 | Bayer S.p.A. | Pharmaceutical compositions containing a ketoprofen solution in a soft gelatine capsule and method to produce them |
EP0695544A1 (en) * | 1994-08-05 | 1996-02-07 | Shionogi & Co., Ltd. | Hard gelatin capsules resistant to denaturation and the production thereof |
WO1996014365A2 (en) * | 1994-11-07 | 1996-05-17 | Warner-Lambert Company | Process for stabilizing gelatin products |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8895059B2 (en) | 2002-06-05 | 2014-11-25 | Ivax Pharmaceuticals S.R.O. | Reduction of cross-linking gelatin in gelatin capsules |
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