MXPA05001166A - Pellicle-resistant gelatin capsule. - Google Patents

Abstract

The present invention relates to compositions suitable for use in preparing gelatin capsules, to gelatin capsules exhibiting reduced cross-linking, and to methods of preparing such gelatin capsules.

Description

FILM RESISTANT GELATIN CAPSULE FIELD OF THE INVENTION The present invention relates to gelatin capsules exhibiting a reduced gelatin crosslinking. Said capsules are useful in, among others, the pharmaceutical, nutraceutical and food industries.

BACKGROUND OF THE INVENTION Gelatin, a mixture of hydrosoluble proteins derived from collagen by hydrolysis, is widely used in the pharmaceutical and food industries, among others. A fundamental application of gelatin is in the preparation of both hard and soft gelatin capsules. Such capsules are desirable for, among other things, their versatility (they may contain pharmacological formulations in solid, semi-solid or liquid form) and for their dissolution characteristics fast Unfortunately, it is known that pharmacological dosage forms containing gelatin in an outer layer (eg, gelatin capsule filled with liquid or powder) exhibit a decrease in the dissolution rate over time. This decrease in the rate of dissolution can lead to undesirable and unacceptable alterations in the in vitro dissolution profile and in bioavailability, in particular for drugs with low water solubility or whose absorption is limited by the rate of dissolution. It is thought that such changes in the dissolution profile result from the cross-linking of gelatin that occurs in the capsule shells. Singh et al., Alteration in Dissolution Characteristics of Gelatin-Containing Formulations, Pharmaceutical Technology, April 2002, incorporated herein by reference but not admitted as prior art, describe reports suggesting that several agents, including glycerin, glycine and hydroxylamine hydrochloride , when incorporated into the gelatin capsule filling contents m can limit the crosslinking of the gelatin. Unfortunately, existing procedures addressing the problem of gelatin crosslinking in capsule shells are unsatisfactory, particularly in situations where a longer shelf-life and storage life are desired in real life, as well as good handling and shipping conditions; therefore it is desirable to search for suitable solutions to the problem of the crosslinking of the gelatin capsules If gelatin capsule could be prepared capable of providing a predictive and stable dissolution rate of a drug contained therein, even after the storage of such capsules under stressful conditions, there would be a significant advance in the oral release of drugs, in particular of low water solubility drugs or drugs whose absorption is limited by the dissolution BRIEF DESCRIPTION OF THE INVENTION A suitable composition for preparing a capsule capsule is currently provided, wherein the composition containing gelatin and an amine agent comprising at least one primary or secondary pharmaceutically acceptable amine. It is desirable that the amine agent be present in an amount effective to inhibit crosslinking of the gelatin and / or film formation in a capsule shell prepared from the composition. In addition, a capsule shell of the present composition is provided. In addition, a pharmaceutical dosage form comprising capsule caps of the present composition is also provided, wherein the covers define a filling volume that is at least partially occupied by a filling material. Preferably, the filling material contains a drug, more preferably a low water solubility drug. In one embodiment, the drug is a selective inhibitor drug of cyclooxygenase 2. The composition and dosage form of the present invention are especially useful for liquid filling materials and soft gelatin capsules. The term "film" in the present specification is refers to a relatively water-insoluble membrane formed in a gelatin capsule shell. Such membrane has to be thin, rough and rubbery. It is now understood that a mechanism underlying film formation is the crosslinking of gelatin. The crosslinking of gelatin and film formation results in a reduction in dissolution rates. Accordingly, the quantification of a dissolution rate of a first capsule in a reasonably short time after preparation of the capsule and a second capsule after storage under stressful conditions (for example, four weeks at 40 ° C and 85% relative humidity in a closed container), as described herein, provides a means to assess film formation and / or cross-linking of gelatin. The term "in a reasonably short time after the formation of the capsule" means in such a period that it is unlikely that substantial crosslinking and / or film formation has occurred, for example within a week, depending on the storage conditions during this period. The term "film resistant" in the present specification means that a gelatin capsule thus described has a reduced tendency to form, or exhibit a slowed, delayed or reduced formation of a film after storage under stressful conditions. Similarly, "inhibition of crosslinking" (or "inhibition of film formation") in the present specification means a slowed, delayed or reduced formation of gelatin crosslinks (or film formation) in a capsule by comparison with a capsule, otherwise similar, that lacks only the amine agent as provided in the present specification. It has been found that the pharmaceutical dosage forms according to the present invention exhibit an unexpected and surprisingly substantial reduction in the crosslinking of gelatin in the capsule shell and in film formation. As a result, such dosage forms are able to consistently meet the desired in vitro dissolution criteria, even after storage under stressful conditions. This invention represents a significant improvement over conventional dosage forms and covers of conventional gelatin capsules.

BRIEF DESCRIPTION OF THE FIGURES Figure 1 is a graph showing the Tier I dissolution rate of formulation 30 after storage at 25 ° C as described in Example 6. Figure 2 is a graph showing the Tier I dissolution rate of formulation 30 after storage at 40 ° C as described in example 6. Figure 3 is a graph showing the Tier II dissolution rate of formulation 30 after storage at 25 ° C as described in Example 6. Figure 4 is a graph showing the Tier II dissolution rate of the formulation 30 after storage at 40 ° C as described in Example 6. Figure 5 is a graph showing the Tier I dissolution rate of formulation 19 after storage at 25 ° C as described in example 6. Figure 6 is a graph showing the Tier I dissolution rate of formulation 19 after storage at 40 ° C as described in example 6. 7 is a graph showing the Tier II dissolution rate of formulation 19 after storage at 40 ° C as described in example 6.

DETAILED DESCRIPTION OF THE INVENTION Composition suitable for the preparation of a capsular shell In one embodiment, the present invention provides a composition suitable for the preparation of a capsular shell. Such a composition according to the present invention comprises gelatin and an amine agent comprising at least one pharmaceutically acceptable primary or secondary amine present in an amount effective to inhibit the cross-linking of the gelatin shell and / or film formation after storage. The primary or secondary amine compound term of the present specification includes the primary and secondary amine compounds which are pharmaceutically acceptable excipients. Preferably, the primary and secondary amine compounds of the present invention are not therapeutic or nutritionally active compounds.

Before using such a composition in the preparation of gelatin capsule shells, the composition typically adds a liquid, for example water, to form an aqueous mixture. In one embodiment, such a composition suitable for the preparation of a capsule shell comprises gelatin, at least one primary or secondary amine compound and water. Preferably, the water will be present in an amount such that the weight ratio between water and gelatin is from about 0.8 to about 1.6, and preferably from about 1 to about 1.3. Preferably, the gelatin is present in a composition of the invention in an amount from about 1% to about 99%, more preferably from about 10% to about 80%, and still more preferably from about 15% to about 90% of the composition in dry weight. It should be understood that "dry weight" means the total weight minus the weight of the water.

Amines of the Composition Any pharmaceutically acceptable primary or secondary amine may be used in a composition of this embodiment. Non-limiting examples 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 such amino acids cone L-arginine, L-lysine and guanidine. . Non-limiting examples suitable secondary amines include diethanolamine, benetamine (ie, N-phenylmethyl) benezenetanamine), benzathine (ie, N, N-dibenclylethylene diamine), piperazine, hydrabamine (ie, N, N- bis (dehydroabiethyl) ethylenediamine) and imidazole. Preferably, the amine compound is 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 from about 0.1% to about 5%, and more preferably about 0.1% to about 2% of the composition in dry weight.

Optional Excipients of the Composition A composition of the invention, in addition to gelatin and the primary or secondary amine, preferably further comprises one or more pharmaceutically acceptable excipients. For example, when a composition of the invention is to be used to prepare gelatin capsules soft, the composition preferably comprises at least one plasticizer in a total amount of from about 2% to about 60%, preferably from about 5% to about 45% and more preferably from about 10% to about 40% of the composition by weight dry. When a plasticizer is present, the weight ratio between the plasticizer (dry weight) and the gelatin is from about 0.3 to about 1.8 and preferably from about 0.4 to about 0.75. Non-limiting examples of suitable plasticizers include polyhydroxy alcohols such as sorbitol, glycerol and mannitol; dialkyl phthalates; lower alkyl citrates in which the lower alkyl has from 1 to 6 carbon atoms; glycols and polyglycols, including polyethylene glycols with a molecular weight ranging from about 200 to about 400,000, methoxyl-propylene glycol and 1,2-propylene glycol; esters of polyhydroxyalcohols such as glycerol mono-, di and triacetate; ricinoleic acid and its esters; and mixtures of the above. A composition of the invention may further comprise one or more preservatives, opacifying agents (for example titanium dioxide), decomposition inhibitors (for example sulfur dioxide), color, taste etc. Illustrative non-limiting examples suitable preservatives include methylparaben, propylparaben, butylparaben, sorbic acid, benzoic acid, editic acid, phenolic acids, potassium sorbate and sodium propionate.

Optionally, 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). If present, 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 from about 0.01% to about 5%, and preferably from about 0.1% to about 2% of the composition in dry weight. A composition suitable for the preparation of a capsular shell may be in the form of a solid, a liquid powder, a semi-solid, a liquid solution or a liquid suspension. It is important that a suitable physical form (eg powder, liquid mixture, etc.) of a composition of the invention will be determined, at least in part, by the particular procedure, if any, that will be used to prepare capsules, and for the particular type of capsule to be prepared (hard or soft). One of ordinary skill in the art will readily select a suitable physical form for a composition of the invention taking into account these and torso factors.

Process for preparing capsules of the invention i. Hard Capsules A composition of the invention can be used to prepare hard gelatin capsules according to any suitable method, including but not limited to, the methods described in the following patents and / or publications, each of which is incorporated herein as reference. U.S. Patent No. 3,656,997 to CORDES, U.S. Patent No. 4,231, 211 to Strampfer et al. U.S. Patent No. 4,263,251 to VoeglE. U.S. Patent No. 4,403,461 to Goutard et al, U.S. Patent No. 4,705,658 to Lukas, U.S. Patent No. 4,720,924 to Hradecky et al, U.S. Patent No. 4,756,920 Harvey et al., U.S. Patent No. 4,884,602 to Yamamoto et al. U.S. Patent No. 4,892,766 to Jones, U.S. Patent No. 6,350,468 to Sanso, International Patent Publication No. WO 84 / 00919 of Mackie International Patent Publication No. WO 85/04100 of Kalidindi. A person of ordinary skill in the art will easily adapt the procedures described in the above documents in light of the present disclosure for the purpose of preparing capsules comprising an amine compound according to the present invention. A preferred process for preparing gelatin hard capsules of the invention comprises the steps of (a) providing a composition suitable for the preparation of a capsular shell (comprising gelatin and a primary or secondary amine compound) in the form of dry powder, ( b) preparing a liquid solution or a solution / suspension comprising water and the composition, (c) heating the liquid, (d) immersing stainless steel PINS forming capsules in the hot liquid, (e) removing the PINS from the liquid submerged for coated PINS forms; and (f) subjecting the coated OINS to a drying procedure to produce a dry capsular half shell. After drying, the capsular half-shells are removed from the PINS and trimmed to the desired length. Next, the capsular half-shells can be filled with any desired filling material, put together in a cooperative fashion to form a capsular cover and then cover. Optionally, the lid can be welded at a point, fused or bonded with melted gelatin to provide a tamper-resistant product. According to this method, the primary or secondary amine compound is preferably in the composition suitable for preparing a capsular shell and / or, if desired, may also be added during stages (b), (c) and / or (d) ).

II. Soft Capsules The soft gelatin capsules of the invention can be prepared by any suitable method, including, but not limited to, the plate process, the vacuum procedure or the rotary die process. See, for example, (1) Ansel et al. (1995) in Pharmaceutical Dosage Forms and Drug Delivery Systems, 6th ed., Williams &; Wilkins, Baltimore, MD, pages 176-182 and (2) Remington: The Science and Practice of Pharmacy, 19 ed., Mack Publishing Co., Easton, PA, pages 1646-1647, the pages cited above are incorporated herein descriptive memory as reference. The rotary die-cutting process is a currently preferred process by which gelatin capsules according to the invention are prepared. According to the rotary die-cutting process, a composition of the invention comprising gelatin and a primary amine compound or secondary is dissolved or suspended in water to form a fluid material that is then introduced into an air tank. The fluid material coming from the air tank takes the form of two continuous belts by means of a rotary die-cutting machine and then the belts are joined by twin rotating dies. Simultaneously, the measured filling material is injected between the tapes at approximately the same time as the dies form bags in the tapes. Next, these bags of encapsulation material containing the charge are sealed by pressure and heat.

Soft gelatine capsules can be manufactured in different shapes, including round, oblong and tubular shapes, among others. In addition, by using two different colors for the tapes two-tone capsules can be produced. Non-limiting examples of suitable methods for preparing soft gelatine capsules are described in the following patents and publications, each of which is incorporated herein by reference. U.S. Patent No. 3,592,945 to Pesch, U.S. Patent No. 4,609,403 to Wittwer et al, U.S. Patent No. 4,744,988 to Brox, U.S. Patent No. 4,804,542 to Fischer and U.S. Pat. cabbage, U.S. Patent No. 5,146,758 to Herman, U.S. Patent No. 5,254,294 to Wunderlich et al, U.S. Patent No. 6,260,332 to Takayanagi, U.S. Patent No. 6,238,616 to Ulsikawa and co / "and, International Patent Publication No. WO 92/15828 of Herman As used herein, unless the specific context indicates otherwise, the term "capsular shell" (and "gelatin capsule shell") encompasses the capsular half shells (which may be joined together to form an entire capsular shell) and the entire capsular covers (which define a volume of charge). The term also covers soft gelatin capsules and hard gelatin capsules, regardless of the method by which such covers are formed. With the terms "sealed capsular cover", "sealed in a capsular cover", "seal in the capsular cover" and the like is meant an entire capsular cover defining a volume of charge, such a volume of charge may contain a material of filling, that such filler material is included in the entire capsular cover, and that such enclosure provides the filler material with more than a minimal amount of protection from the external atmosphere of the entire capsular cover.

Drug of low solubility in water The capsular covers according to the present invention define a volume of load and such volume of load may be occupied, at least in part, by any filling material. The filler material can comprise any active drug. Preferably, the active drug is a drug of low solubility in water, also referred to herein as a drug of poor water solubility. In the present specification a "drug of low water solubility" or "drug of poor solubility in water" refers to any drug or compound with a solubility in water, measured at 37 ° C, not exceeding about 10 mg / ml and preferably not greater than about 1 mg / ml. In particular, drugs with a solubility in water, measured at 37 ° C, are preferred. greater than about 0.1 mg / ml. Water solubility for many drugs can be easily determined with conventional reference books of pharmaceuticals, for example The Merck Index, 11 ed., 1989 (published by Merck &Co., Inc., Rahway, NJ); United States Pharmacopoeia, 24 ed. (USP 24), 200; The The Extra Pharmacopoeia. 29 ed., 1989 (published by the Pharmaceutical Press, London) and the Phvsicians Desk Reference (PDR), ed. 2001 (published by the Medical Economics Co., Montéale, NJ). For example, individual drugs of low solubility as defined herein include drugs classified as "slightly soluble", "very slightly soluble", "practically insoluble" and "insoluble" in USP 24, pages 2254-2298, and drugs classified as requiring 100 ml of water or more to dissolve 1 g of the drug, as listed in USP 24, pages 2299-2304. By way of example, suitable drugs of low water solubility include, but are not limited to, drugs of the following classes: abortifacients, ACE inhibitors, a and b adrenergic agonists, a and b adrenergic blockers, adrenocortical suppressors, adrenocorticotropic hormones, alcohol dissuasives, aldose reductase inhibitors, aldosterone antagonists, anabolics, analgesics (including narcotic and non-narcotic analgesics), androgens, angiotensin II receptor antagonists, anorectics, antacids, anthelmintics, anti-acne agents, antiallergics, anti-allergy agents, antiabetics, antiandrogens, antianginal agents, antiarrhythmics, antiarteriosclerotic agents, antiarthritic / antirheumatic agents (including selective inhibitors of COX-2), antiasthmatics, antibacterials, antibacterial auxiliaries, anticholinergics, anticoagulants, anticonvulsants, antidepressants, antidiabetic agents, antidiarrheal agents, antidiuretic agents, antidiuretic agents, antidystoletics, anti-eczematics, antiemetics, antiestrogenic, antifibrotic, antiflatulent, antifungal agents, antiglaucoma agents, anti-gonadotropins, anti-gout agents, antihistamines, antihypertensive, antihypoproteinase, antihyperphosphatemic, antihypertensive agents antihyperthyroid, antihypertensive, antihypopyroid, anti-inflammatory, antimalarial, antimaniac, antimetahemoglobinemic agents, antimigraine agents, antimuscarinics, antimicobacter ians, antineoplastic and auxiliary agents, antineutropenic, antiosteroporotic, antipagnetic agents, antiparkinson agents, anti-pheochromocytoma agents, anti-pneumocystis agents, agents against prostatic hypertrophy, antiprotozoal, antipolitic, antipsychotic, antipsychotic, antipyretic, antirickets, anti-seborrheic, antiseptic / disinfectant, antispasmodic, anti-syphilitic, antitrombocitémicos, antithrombotic, antitussives. Anti-ulcers, anti-uroliths, antivenins, antiviral agents, anxiolytics, aromatase inhibitors, astringents, benzodiazepine antagonists, inhibitors of bone resorption, bradycardic agents, bradykinin antagonists, bronchodilators, blockers of the calcium channels, calcium regulators, carbonic anhydrase inhibitors, cardiotonics, CCK antagonists, chelating agents, coleolytolytic agents, cholerectics, cholinergics, cholinesterase inhibitors, cholinesterase reactivators, CNS stimulants, contraceptives, debridement agents , decongestants, depigmenting agents, suppressors of dermatitis herpetiformis, digestive agents, diuretics, dopamine receptor agonists, dopamine receptor antagonists, ectoparasiticides, emetics, enkephalinase inhibitors, enzymes, enzymatic cofactors, estrogens, expectorants, antagonists of fibrinogen receptors, fluorinated supplements, stimulants of gastric and pancreatic secretions, gastric cytoprotectors, proton gastric pump inhibitors, gastric secretion inhibitors, gastroprokinetics, glucocorticoids, α-glucosidase inhibitors, gonad stimulating principles, in growth hormone inhibitors, growth hormone releasing factors, growth stimulants, haematinics, haematopoietics, haemolytics, haemostats, heparin antagonists, hepatic enzyme inducers, hepatoprotective agents, histamine H2 receptor antagonists, inhibitors of HIV protease, HMGCoA reductase inhibitors, immunomodulators, immunosuppressants, insulin sensitizers, ion exchange resins, keratolytics, lactation-stimulating hormones, laxatives / catars, leukotriene antagonists, LH-RH agonists, lipotropic , 5-lipoxygenase inhibitors, lupus erythematosus suppressors, matrix inhibitors, metalloproteinase, mineralocorticoids, miotics, monoamine oxidase inhibitors, mucolytics, muscle relaxants, mydriatics, narcotic antagonists, neuroprotectors, notrópicos, ovarian hormones, oxytocics, pepsin inhibitors, pigmentation agents, plasma volume expanders, activators / inducers the opening of potassium channels, progestogens, prolactin inhibitors, prostaglandins, protease inhibitors, radioactive pharmaceuticals, 5-a reductase inhibitors, respiratory stimulators, reverse transcriptase inhibitors, sedatives / hypnotics, selenics, serotonin noradrenaline reuptake inhibitors, serotonin receptor agonists, serotonin receptor antagonists, serotonin reuptake inhibitors, somatostatin analogues, thrombolytics, thromboxane FK2 receptor antagonists, thyroid hormones, thyrotropic hormones, tocolytics, topoisomerase I and II inhibitors, uricosurics, vasomodulators including vasodilators and vasoconstrictors, vasoprotectors, oxidized xanthine inhibitors and combinations thereof. Illustrative non-limiting examples of suitable drugs of low solubility include acetohexamide, acetylsalicylic acid, alclofenac, allopurinol, atropine, benzathiazide, carprofen, celecoxib, chlordiazepoxide, chlorpromazine, clonidine, codeine, codeine phosphate, codeine sulfate, deracoxib, diacerein, diclofenac , diltiazem, estradiol, etodolaco, etoposide, etoricoxib, fenbufeno, fenclofenac, fenprofen, fentiazac, flurbiprofen, griseofulvin, haloperidol, ibuprofen, indomethacin, indoprofen, ketoprofen, lorazepam, medroxyprogesterone acetate, megestrol, metoxalem, methylprednisone, morphine, morphine sulfate, naproxen, nicergoline, nifedipine, niflumic, oxaprozin, oxazepam, oxifenbutazone, paclitaxel, fenindione, phenobarbital, piroxicam, pirprofen, prednisolone, prednisone, procaine , progesterone, pyrimethamine, rofecoxib, sulfadiazine, sulfamerazine, sulfisoxazole, sulindac, suprofen, temazepam, tiaprofenic acid, tilomisol, tolmetic, valdecoxib, etc. The amount of drug incorporated in the filling material to be introduced into a capsule of the invention can be selected according to known principles of the pharmacy. Specifically, a therapeutically effective amount of the drug is contemplated. The term "therapeutic and / or prophylactically effective amount", as used herein, refers to a quantity of drug sufficient to elicit the desired therapeutic and / or prophylactic response. Preferably, the therapeutic agent is present in an amount of at least about 0.01%, more 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 in dry weight.

Selective COX-2 Inhibitory Drugs In a preferred embodiment, the drug is a selective cyclooxygenase-2 inhibitory drug. A selective inhibitory drug of the Preferred cyclooxygenase-2 useful herein, or in which a salt or prodrug useful herein is converted in vivo, is a compound of formula (I) wherein: A is a substituent selected from unsaturated or partially unsaturated and unsaturated carbocyclic unsaturated or partially unsaturated carbocyclic rings, preferably a heterocyclyl group selected from pyrazolyl, furanolyl, isoxazolyl, pyridinyl, cyclopentenonyl and pyridazinonyl groups; X is O, S or CH2; R1 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, hydroxy, hydroxyalkyl, haloalkoxy, amino, alkylamino , arylamino, nitro, alkoxyalkyl, alkylsulfinyl, halo, alkoxy or alkylthio; R 2 is methyl, amino or aminocarbonylalkyl; R3 is one or more radicals selected from hydrurom halo, alkyl alkenyl, alkynyl, oxo, cyanomyl carboxyl, cyanoalkyl, heterocyclyloxy, alkyloxy, alkylthio, alkylcarbonyl, ciclaoalquilo, aryl, haloalkyl, heterocyclyl, cycloalkenyl, aralkyl, heterocyclylalkyl, acyl, alkylthioalkyl, hydroxyalkyl, alkoxycarbonyl, arylcarbonyl, aralkylcarbonyl, aralkenyl, alkoxyalkyl, arylthioalkyl, aryloxyalkyl, aralkylthioalkyl, aralkoxyalkyl, alkoxyaralkoxyalkyl, alkoxycarbonylalkyl, aminocarbonyl, aminocarbonylalkyl, alkylaminocarbonyl, N-arylaminocarbonyl, N-alkyl-N-arylaminocarbonyl, alkylaminocarbonylalkyl, carboxyalkyl, alkylamino, N-arylamino, N-alakylamino, N-alkyl-N-aralkylamino, N-alkyl-N-arylamino, aminoalkyl, alkylaminoalkyl, N-arylaminoalkyl, N-aralkylaminoalkyl, N-alkyl-N-aralkylaminoalkyl, N-alkyl-N-arylaminoalkyl, aryloxy, aralkoxy, arylthio, aralkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, N-arylaminosulfonyl, arylsulfonyl and N-alkyl- N-arylaminosulfonyl, wherein R3 is optionally substituted in a substituted position containing one or more radicals selected from alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino, alkylamino, arylamino, nitro, alkoxyalkyl, alkylsulfinyl, halo, alkoxy and alkylthio; and R4 is selected from hydride and halo. The compositions of the invention are especially useful for the selective inhibitors of cyclooxygenase 2 having the formula (II): where R5 is a methyl or amino group, R6 is hydrogen or a Ci-4 or alkoxy alkyl group, X 'is N or CR7, where R7 is hydrogen or halogen and Y and Z are independently carbon or nitrogen atoms that define adjacent atoms of a five to six membered ring which is optionally substituted on one I plus positions with oxo, halo, methyl or halomethyl groups, or an isomer, tautomer, pharmaceutically acceptable salt or prodrug thereof. Preferred five or six member rings are rings of cyclopentenone, furanone, methylpyrazole, isoxazole and pyridine substituted in no more than one position. By way of example, the capsules of the invention are suitable for releasing celecoxib, deracoxib, valdecoxib, rofecoxib, etoricoxib, 2- (3,5-difluorophenyl) -3- [4- (methylsulfonyl) phenyl] 2-cyclopenten-1 - nona, 2- (3,4-difluorophenyl) -4- (3-hydroxy-3-methyl-1-butoxy) -5- [4- (methylsulfonyl) phenyl] -3- (2H) -pyricazinone, salts and prodrugs pharmaceutically acceptable thereof. The capsules of the invention are also useful for the compounds of the formula (III) where X "is O, S or lower N-alkyl, R8 is lower haloalkyl, R9 is hydrogen or halogen, R10 is hydrogen, halogen, lower alkyl, lower alkoxy or haloalkoxy, lower aralkylcarbonyl, lower dialkylaminosulphonyl or heterocyclochloromethyl of 5 or 6 members containing nitrogen, and R 1 and R 12 are independently hydrogen, halogen, lower alkyl, lower alkoxy or aryl, and for their pharmaceutically acceptable salts A particularly useful compound of formula (III) is (S) -6 acid , 8-dichloro-2- (trifluoromethyl) -2H-1-benzopyrran-3-carboxylic acid, in particular in the form of its water-soluble salt, for example the sodium salt The invention is illustrated in the present specification with particular reference to celecoxib, and it should be understood that any other selective COX-2 inhibitory drug may, if desired, be replaced in whole or in part with celecoxib in the dosage forms described herein. For example, the dosage forms of the invention are suitable for the formulation of valdecoxib, alone or in combination with celecoxib. When the drug is celecoxib, the dosage form typically comprises celecoxib in a total therapeutic and / or prophylactically effective amount of about 10 mg to about 1000 mg per unit dose. When the drug is any other selective COX-2 inhibitory drug, the amount of the drug per unit dose is therapeutically effective at about 10 mg to about 1000 mg of celecoxib. It should be understood that the therapeutic and / or prophylactically effective amount of a drug for a subject depends, among other things, on the subject's body weight. In the present specification, a "subject" to which the therapeutic agent or composition thereof can be administered includes a human patient of any sex and age and also includes any non-human animal, in particular a pet or companion animal, for example a cat, a dog or a horse. When the subject is a child or a small animal, (for example a dog), for example, it is likely that a relatively low amount of celecoxib in the range of about 10 mg to about 1000 mg will be consistent with therapeutic efficacy. When the subject is a human adult or a large animal (eg a horse), therapeutic efficacy is likely to require dose units containing a relatively greater amount of celecoxib. For a human adult, typically a therapeutically effective amount of celecoxib per unit dose in a dosage form of the present invention is from about 10 mg to about 400 mg. Especially preferred amounts of celecoxib per unit dose are from about 100 mg to about 200 mg, for example from approximately 100 mg or approximately 200 mg. For other selective COX-2 inhibitory drugs, an amount of the drug per unit dose may be in a range that is known to be therapeutically effective for such drugs. Preferably, the amount per unit dose is in a range that provides therapeutic equivalence to celecoxib at the dose ranges indicated just above.

Capsule filled with liquid In a preferred embodiment, a capsule of the invention is filled with a liquid filling material. More preferably, the filler material emulsifies when it comes into contact with simulated gastric fluid. The filler material according to this embodiment comprises at least one solvent which is preferably suitable for dissolving the drug and / or any of the additional ingredients or excipients present therein. q Qolol solvents A preferred liquid solvent is a glycol or a glycol ether. The glycol ethers include those which are suitable for the formula (X): R1-0 - ((CH2) mO) n-R2 in which R and R2 are independently hydrogen or Ci_6 alkyl, C alkenyl groups 6, phenyl or benzyl, but not more than one of R1 and R2 is hydrogen, m is an integer from 2 to about 5 and n is an integer from 1 to about 20. It is preferred that one of R1 and R2 is a C1-4 alkyl group and the other is hydrogen or a C1-4 alkyl group; more preferably at least one of R and R2 is a methyl or ethyl group. It is preferred that m is 2. It is preferred that n is an integer of about 4, more preferably 2. Typically, the glycol ethers used as solvents in the fillers have a molecular weight of from about 75 to about 1000, preferably from about 75 to about 500 and more preferably from about 100 to about 300. It is important that the glycol ethers used in the fillers of this embodiment must be pharmaceutically acceptable and must meet all the other conditions prescribed in the present descriptive memory. Non-limiting examples of glycol ethers can be used in the fillers 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 dicylether, monophenylether ethylene glycol, ethylene glycol monobenzyl ether, ethylene glycol butyl phenyl 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 monoobutyl ether, triethylene glycol dimethylether, triethylene glycol monoethyl ether, triethylene glycol monobutyl ether, tetraethylene glycol dimethyl ether, and mixtures thereof. See for example, Flick (1998): Industrial Solvents Handbook. 5th ed., Noyes Data Corporation, Westwood, NJ. A particularly suitable glycol ether solvent is diethylene glycol monoethyl ether, sometimes referred to in the DGME or ethoxydiglycol technique. It is available with, for example, the Transcutol ™ brand from Gattefossé Corporation. Suitable glycols as solvents for the fillers include propylene glycol, 1,3-butanediol and polyethylene glycols. At present, a preferred solvent is polyethylene glycol (PEG). Any pharmaceutically acceptable PEG can be used. Preferably, the PEG has an average molecular weight of from about 100 to about 10,000 and more preferably from about 100 to about 1,000. Still more preferably the PEG is liquid grade. Non-limiting examples of PEG 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., Page 392. A currently preferred PEG has an average molecular weight of about 375 to about 450, such as PEG-400. Polyethylene glycols such as PEG-400 possess many desirable properties, such as drug solvents with poor water solubility. In the case of celecoxib, for example, the drug can be dissolved or solubilize at a very high concentration in PEG-400, which allows the formulation of a therapeutically effective dose in a very small volume of liquid solvent. This is especially important when the resulting solution is to be encapsulated, as capsules of a practical size to swallow, can be prepared so as to contain a therapeutically effective dose, even of a drug such as celecoxib, which has a relatively high dose requirement. to be effective. It is important that ethanol, water or other excipients identified as co-solvents hereinafter or elsewhere, if desired, can be used as solvents in a filler material of the invention. Typically, one or more solvents will be present in the filler material in a total amount of from about 5% to about 95%, preferably from about 10% to about 90% and more preferably from about 15% to about 85%, by weight of filler material. ii Cosolvents A filler material of this embodiment optionally comprises one or more pharmaceutically acceptable cosolvents. Non-limiting examples of suitable cosolvents include additional glycols and alcohols, for example ethanol and n-butanol; triglycerides of oleic and linoleic acid, for example soybean oil; caprylic / capric triglycerides, for example Miglyol ™ 812 from Huís; mono and diglycerides of caprylic / capric, for example Capmul ™ MCM from Abitec; caprylic / capric polyoxyethylene glycerides such as caprylic / capric polyoxyethylene (8) mono and diglycerides, for example Labrasol ™ from Gattefossé; propylene glycol fatty acid esters, for example propylene glycol laurate; polyoxyethylene (35) castor oil, for example Cremophor ™ EL or BASF; polyoxyethylene glyceryl triolate, for example Tagat ™ TO by Goldschmidt; lower alkyl esters of fatty acids, for example ethyl butyrate, ethyl caprylate and ethyl oleate; and water.

Excipient filler material Sulphite Compound When a pharmaceutical dosage form is to be provided, the filler material introduced into a capsule of the present invention may further comprise a sulfite compound. In a preferred embodiment, in the filling material there is at least about 40%, preferably at least about 50%, still more preferably about at least 55%, even more preferably at least about 60% and still further preferably at least about 70% of all the sulfite compound present in the dose unit of the invention.

Amine Agent When a pharmaceutical dosage form is to be provided, the filler material (which is introduced into a capsule according to the present invention) may further comprise a primary or secondary amine compound. However, in a preferred embodiment, in the capsular shell there are at least about 40%, preferably at least about 50%, still more preferably about at least 55%, even more preferably at least about 60% and still more preferably at least about 70% of all the primary or secondary amine compound present in the dose unit of the invention.

Amine and sulfite agents In light of the present disclosure it should be readily understood that in the dosage form of the present invention, the capsular shell comprises at least one primary or secondary amine and optionally a sulfite compound. The filling material of the dosage form optionally comprises (a) at least one primary or secondary amine or (2) a sulfite compound or (3) at least one primary or secondary amine and a compound is sulfite. In addition, it should be understood that "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.

Other excipient fillers The filler material of the present invention may further optionally comprise at least one pharmaceutically acceptable free radical scavenger antioxidant. An antioxidant scavenger of free radicals must be contrasted with an "antioxidant sequestrant of radicals that are not free", that is, an antioxidant that does not possess free radical sequestering properties. Illustrative non-limiting examples of suitable free radical scavenger antioxidants include α-tocopherol (vitamin E), ascorbic acid (vitamin C) and salts thereof, including sodium ascorbate and ascorbic acid palmitate, butylated hydroxyanisole (BHA) ), bitylated hydroxy toluene (BHT), fumaric acid and its salts, hydrophosphorous acid, malic acid, alkyl gallates, for example propyl gallate, octyl gallate and laurylgalate, sodium sulfite, sodium bisulfite and sodium metabisulfite. The preferred free radical scavenger antioxidants are alkyl gallates, vitamin E, BHA and BHT. More preferably, the at least one free radical scavenging antioxidant is propyl gallate. In the dosage forms of the invention, one or more antioxidant free radical scavenger are optionally present in a total amount effective to substantially reduce the formation of an addition compound, typically in a total amount of about 0.01% to about 5%, preferably from about 0.01% to about 2.5% and more preferably from 0. 01% to about 1%, by weight of the filling material. The filler material according to the invention optionally comprises one or more pharmaceutically acceptable sweeteners. Non-limiting examples of suitable sweeteners include mannitol, propylene glycol, sodium saccharin, acesulfame K, neotame and aspartame. Alternatively or in addition to, a viscous sweetener such as a solution of sorbitol, syrup (sucrose solution) or high fructose corn syrup may be used and, in addition to the sweetening effects, may also be useful for increasing viscosity and delaying the sedimentation The filler material according to the invention optionally comprises one or more pharmaceutically acceptable preservatives apart from the free radical scavenging antioxidants. Non-limiting examples of suitable preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, chlorobutanol, phenol, phenylethyl alcohol, phenylmercuric nitrate, trimerosal, etc. The filler material according to the invention optionally comprises one or more pharmaceutically acceptable wetting agents. Surfactants, hydrophilic polymers and certain clays may be useful as wetting agents to aid in the 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, nonxinol 9, nonoxynol 10, octoxynol 9, poloxamers, mono and diglycerides of caprylic / capric polyoxyethylene (8) (eg Labrasol ™ by Gateffossé), polyoxyethylene castor oil (35), polyoxyethylene (20) keto stearyl ether, hydrogenated polyoxyethylene castor oil (40), polyoxyethylene oleic ether ( 10), polyoxyethylene stearate (40), polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80 (for example, Tween ™ 80 from ICI), propylene glycol laurate (for example Lauroglicol ™ from Gattefossé), sodium lauryl sulfate, sorbitan monolaurate , sorbitan monooleate, sorbitan rnonopalmitate, sorbitan monostearate, tyloxapol and mixtures thereof. In addition, the 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 the pH of a formulation and, therefore, can modulate the solubility of the drug. Flavoring agents can increase patient compliance by making the dosage form more palatable and colorants can provide a product with a more aesthetic and / or characteristic appearance. Non-limiting examples of suitable dyes include red D and C n ° 33, red FD & C n ° 3, red FD & C n ° 40, yellow D & C n ° 10 and yellow C n ° 6.

Drug dissolution and gelatin cross-linking Without being supported by theory, the inventors believe that the cross-linking of gelatin may be the result of a process whereby the amino acid residues of gelatin are covalently bound to form an insoluble material. The process may be be the result of contact of low levels of aldehydes with gelatin. The crosslinking of a gelatin capsule can affect the performance of the product by delaying the release of the formulation (containing the active compound) from the capsule shell. The delay in the release can, in turn, affect the rate of absorption of the compound into the bloodstream and the clinical onset of the action. While "mild" crosslinking does not have a significant impact on the release of the formulation from the dosage form, "intense" crosslinking can have a significant impact. When crosslinking is intense, it can lead to a delay in the release of the formulation from the dosage form in humans, possible problems of bioequivalence and a possible delay in the clinical onset of the action. Capsules according to the present invention exhibit less gelatin crosslinking (and film formation) and, therefore, when loaded with a composition containing the drug and introduced in an in vitro dissolution assay, they are capable of exhibiting advantageous, a lower change in the rate of dissolution during storage under stressful conditions than conventional capsules. Likewise, it is believed that the capsules according to the present invention exhibit a dissolution rate of the drug between capsules more uniform than standard gelatin capsules. In one embodiment of the present invention, after (a) filling two or more capsules of the present invention with a filling material in which the filling material optionally comprises a drug and at least one substance that stimulates crosslinking of the gelatin when put in contact with it (the substance being the drug itself or an excipient substance, and the substance acting independently or in combination with one or more substances to stimulate said cross-linking); (b) sealing the capsules; (c) testing immediately in a sealed first capsule in a first in vitro dissolution test; (d) storage of a second sealed capsule in a closed container maintained at 40 ° C and at a relative humidity of 75% for a period of four weeks and, after said storage (e) testing in the second capsule sealed in a second in vitro dissolution test that is identical to the first in vitro dissolution test; the amount of drug dissolved at 45 minutes in the second dissolution test is ± 15% and preferably ± 10% of the amount of drug dissolved at 45 minutes in the first dissolution test. Since the crosslinking of gelatin can lead to a delay in dissolution, delays in the dissolution profile dependent on storage time can be a good indicator of the crosslinking of the gelatin during such storage. There are numerous trials of suitable in vitro dissolution to determine the dissolution profile. In fact, one skilled in the art is capable of designing other tests or modifications thereof. Two test methods of the dissolution type were developed, which are set forth in the present specification and are referred to as "Tier I" and "Tier II" tests. In the Tier I test, a gelatin capsule dosage form is introduced into a USP II apparatus with a rotating blade with a blade speed of 50 rpm in 900 ml of 0.01 N HCl + 1% Tween 80. Typically, the sample are removed at 15, 30, 45, 60 and 90 minutes and analyzed for drug content by HPLC. The Tier II test uses the addition of the pepsin enzyme to the medium. Pepsin in the human stomach digests reticulated gelatin. The appropriate amount of pepsin added to the medium (750,000 units / l) was determined and published in the Collaborative Development of Two-Tier Dissolution Testing for Gelatin Capsules and Gelatin-Coated Tablets using Enzyme-Containing Media, Stimuli to the Revision Process Phramacopeial Forum, Vol. 25, No. 5, Sep.-Oct. 1998. It is expected that the Tier II drug release test designed in this way will produce a drug release profile reasonably close to the release profile of drugs in humans. For each dosage form, an "initial" drug release profile is determined in a reasonably short period of time after the formation (ie, the dosage form prior to formulation). exposes to conditions that could result in the crosslinking of gelatin, such as temperature or relative humidity). For samples extracted at later time points, another profile is determined. A change of the Tier I profile with respect to the initial one (that is, a delay in the dissolution) can be attributed to the cross-linking of the gelatin. When such a change is reduced in the Tier II trial (containing pepsin), it is estimated that this reduction is further evidence of gelatin cross-linking during storage.

EXAMPLES The following non-limiting examples are provided for illustrative purposes and should not be construed as limitations.

EXAMPLE 1 A formulation with liquid filler, F =, is prepared as shown in Table 1.

TABLE 1 Formulation of liquid filling FO (mq / ml) EXAMPLE 2 Various compositions suitable for the preparation of a capsular wall, C1-C14, are prepared as shown in Tables 2 and 3 according to the following procedure. The gelatin and one of the primary and / or secondary amines are mixed together to form a dry mixture. Then one or more plasticizers (glycerol and / or sorbitol) are 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 paste. The paste is cooled to 60 ° C to form a fluid gelatin mezcal and is introduced into the two spreader boxes of a rotary die cutter of a gelatin capsule making machine, which controls the flow of said mixture in the rotating drums cooled by air, where two opaque white gelatin tapes are poured and then processed to form opaque white soft gelatin capsules, to a speed of 15,000 capsules per hour; the capsules are loaded with 1 ml of the filling formulation F0 of Example 1. Afterwards, the capsules are dried in the drying drum with a mass of air at 21 ° C and a relative humidity of 20%, and then brought to the room temperature.

TABLE 2 Compositions C1 -C7 to prepare a capsular wall (% p) TABLE 3 Compositions C8-C14 for preparing a capsular wall (% p) Several comparative compositions (without amine compound), CC1-CC7, are prepared as just described, with the compositions shown in Table 4.

TABLE 4 Comparative Compositions CC1-CC7 for preparing a capsular wall The filled capsules are stored at 40 ° C and with a relative humidity of 75% for up to 24 weeks. After 24 weeks of storage, each of the capsules is analyzed to determine film formation. In total, capsules prepared from compositions C1-C14 (comprising a primary amine) exhibit less film formation than capsules prepared from the CCI-CC / comparative compositions (without primary amine).

EXAMPLE 3 Three filler formulations, F1-F3, were prepared as shown in Table 5. One ml of each filling formulation was loaded into each of the various standard soft gelatin capsules (without primary or secondary amine) (RP Scherer) .

TABLE 5 Compositions of filling formulations F1-F3 The filled capsules were placed in a sealed container and stored at 40 ° C and a relative humidity of 75% for a period of up to 24 weeks. At various times during storage the capsules were removed from the closed container and the presence or absence of film formation (i.e., cross-linking) was evaluated by visual inspection. Each evaluated capsule was assigned to a numerical indicator according to the film observed according to the following scale: (1) = no film; (2) = thin film, incomplete; (3) = fine film, complete; (4) = strong, complete film that inhibits the compression of the capsule; (5) = thick film, strong and intense. The observations about film formation are shown in Table 6.

TABLE 6 Film formation after storage for up to 24 weeks at 40 ° C and 75% relative humidity As shown in Table 6, the capsules containing the filling formulation F1 (comprising tromethamine in an amount of about 3% by weight of the filling material) did not exhibit film formation during storage for a period of six months . In contrast to this, the capsules containing the F2 filling formulation (without primary or secondary amine compound = or F3 (0.5% tromethamine) showed film formation at 15 and 30 days of storage, respectively.

EXAMPLE 4 A composition of the invention is prepared by mixing in a container (a) pharmaceutical grade gelatin with Bloom strength of 150 and B quality at 15%; (b) cooled 15% glycerol; (c) 5% tromethamine; and (d) 45% deionized water cooled. 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 mixture of gelatin fuid and fed to two disperser boxes of a rotary die soft gelatin capsule making machine, which controls the flow of said mixture on said rotary drums cooled with air , in which two opaque white gelatin tapes are melted and subsequently processed to opaque white soft gelatin capsules, at a rate of approximately 15,000 capsules per hour. The capsules are dried in a drum dryer with a blast of air at 21 ° C and 20% relative humidity and then brought to room temperature.

EXAMPLE 5 Several compositions suitable for the preparation of the wall of a capsule, C15-C21 are prepared as shown in Table 7, according to the procedure described in Examples 1 and 2.TABLE 7 Compositions C15-C21 for preparing a capsule wall (% by weight) EXAMPLE 6 The crosslinking behavior of two soft gelatine formulations was investigated over a period of 6 months. As shown below (Table 7), Formulation 30 (the control batch) contains dimethylaminoethanol ("DMAE") and no sulfite. Formulation 19 (the test batch) was similar to Formulation 30, except that Formulation 19 also comprises sodium metabisulfite in the filling material.

TABLE 7 Filling material of Formulations 30 and 19 μm / q) Both formulations of soft gelatin capsules were placed in sealed hydroxypropylethylene bottles without induction and stored at 25 ° C and 60% RH or at 40 ° C and 75% RH. Using such bottles, the RH of the inside of the bottles easily balances with the RH of the outside of the bottles (60% or 75%). Periodically, the capsules were tested to determine the degree of crosslinking of the soft gelatin samples as estimated by the release profile of the drug.

Formulation 30 The results of drug release Tier 1 of Formulation 30 control at 25 ° C / relative humidity of 60% ("HR") and 401 C / 75% RH are shown in figures 1 and 2 and the results of Drug release Tier II of the same batch and conditions are shown in Figures 3 and 4. Already after one month of storage a marked delay was observed with the time of storage. The release profile of the Tier II drug at 25 ° C / 60% RH and at 40 ° C / 75% RH shows a significant but markedly reduced delay in the release profile.

Formulation 19 The results of drug release Tier 1 of Formulation 19 of the conditions 25 ° C / 60% RH are shown in Figure 5. For 6 months no change was observed in the profile of drug release, which indicates that crosslinking has not occurred. Consequently, the analogous Tier II test was not performed for this sample. Figure 6 shows the results of the Tier I test for formulation 19 at 40 ° C / 75% RH. During most of the stability time points, except for 6 months, no change in the release profile of the drug was observed. To determine if the change in the release profile of the drug at 6 months is the result of cross-linking, in this sample the Tier II test was performed. The results of the Tier II test are shown in Figure 7. The results of the Tier I and Tier II tests are very similar to this 6-month sample, which indicates that the change that occurs in the drug release profile it can not be attributed to crosslinking. These data indicate that there was intense crosslinking in the Formulation 30. The change in the release profile of the Tier II drug (ie, little delay) indicates that the delayed release of Tier I is the result of crosslinking for this formulation and also indicates that it would be possible to significant delay in the release profile of the drug in humans. Formulation 19 containing sodium metaisulfite does not show appreciable cross-linking at 6 months under stringent storage conditions (40 ° C / 75% RH). These data demonstrate that the addition of sodium metabisulfite to this formulation significantly reduces the rate of crosslinking and, in fact, can totally inhibit crosslinking. Without being bound by theory, it is believed that sodium metabisulfite inhibits crosslinking by a process in which sodium metabisulfite reacts with aldehydes to form a bisulfite addition product. Thus, sodium metabisulfite can efficiently capture aldehydes by rendering them unavailable to promote cross-linking in gelatin.

EXAMPLE 7 Four formulations of Celecoxib were prepared in gelatin capsules as shown in Table 8 and tested for film formation at 40 ° C and 75% relative humidity ("RH"). In the absence of sulfite, a total film formation was evident only after 2 weeks of storage at 40 ° C / 75% RH (Formulation 30, crosslinking titration = 3). At a Tris concentration of 5 mg / g in the formulation (Formulation 20), film formation was delayed but was insufficient to prevent complete film formation (crosslinking titration = 3) after 1.5 months of storage at 40 ° C / 75% RH. At a higher concentration of Tris in the formulation (26 mg / g, Formulation 50), the cross-linking of the gelatin is completely prevented after 6 months of storage at 40 ° C / 75% RH. It appears that a low concentration of sodium metabisulphate (SMB) of 4 mg / g in the formulation (Formulation 19) is sufficient to prevent film formation after 2 months of storage at 40 ° C / 75% RH.

TABLE 8 Analysis of soft gelatin cross-linking during storage at 40 ° C / 57% RH Months to Formulation 50 Formulation 30 Formulation 19 Formulation 20 40 ° C / 75% mg / ml mg / ml mg / ml mg / ml HR Celecoxib 200 Celecoxib 278 Celecoxib 270 Celecoxib 270 PEG400 271 PEG400 337 PEG400 335 PEG400 334 Tween80 217 Tween80 195 Tween80 195 Tween80 194 Oleic acid 61 Oleic acid 80 Oleic acid 78 Oleic acid 78 RRP 47 HPMC 74 HPMC 74 HPMC 74 EtOH 113 D AE 34 DMAE 35 DMAE 33 HP C 38 Propyl gallate 2 Propyl gallate 2 Propyl gallate 2 Propyl gallate 1 Water 7 Water 10 Water 26 SMB 4 Tris 5 Tris 26 0 1 1 1 1 0.5 3 1 1 1 1 3 1 2 1.5 3 1 3 2 1 4 1 3 3 1 1 EXAMPLE 8 In order to obtain a better understanding of the mechanism by which Tris (hydroxymethylaminomethane) in the filling material of a gelatin capsule prevents the formation of film, a dosage form was prepared (Formulation X-60, as set forth). in Table 9) and stored under two different conditions as shown in Table 10. At the indicated times, the capsules were removed and the content of Tris was quantified in the filling material and in the capsule. As shown in Table 10, after storage over time, the content of Tris in the capsules increased and the content in the filler material decreased compared to the initial formulation.

TABLE 9 Formulation X-60 soft gelatin capsule TABLE 10 Tris content in capsular covers after storage of Formulation X-60 Conditions of Tris in the material of Tris in the cover storage of filled capsules (mg) of soft gelatine (mg) 25 ° C / 60% RH T = 2 months 18.7 5.3 T = 6 months 17.9 6.0 T = 8 months 16.4 6.5 T = 10 months 17.6 7.0 40 ° C / 75% HR T = 2 months 13.5 10.5 T = 6 months 10.8 11.1 T = 8 months 10.0 10.6 T = 10 months 10.0 13.3 26 mg of Tris in a soft gelatin capsule at T = 0

Claims (1)

1. NOVELTY OF THE INVENTION CLAIMS 1. A composition comprising gelatin and an amine agent comprising at least one pharmaceutically acceptable primary or secondary amine, the composition being suitable for the preparation of a pharmaceutical capsular coating. 2 - The composition according to claim 1, further characterized in that the amine agent is present in an amount effective to inhibit crosslinking of the gelatin and / or film formation in a prepared capsular shell of the composition. 3. The composition according to claim 1, further characterized in that the amine agent comprises a compound selected from the group consisting of tromethamines, ethanolamine, ethylenediamine, diethylamine, ethylene N-methyl-D-glucamine, amino acids, diethanolamine, benetamine, benzathine , piperazine, hydrabamine and imidazoles. 4. - The composition according to claim 1, further characterized in that the amine agent is present in an amount of not more than about 10% of the dry weight composition. 5. The composition according to claim 1, further characterized in that the amine agent is present in an amount of not more than about 5% of the composition by dry weight. 6. - The composition according to claim 1, further characterized in that the amine agent is present in an amount of not more than about 2% of the dry weight composition. 7. The composition according to claim 1, further characterized in that it additionally comprises at least one excipient selected from the group consisting of decomposition inhibitors, opacifying agents, preservatives and plasticizers. 8. The composition according to claim 1, further characterized in that it further comprises a plasticizer selected from the group consisting of polyhydroxyalcohols, esters of polyhydroxyalcohols, dialkyl phthalates, lower alkyl citrates in which the lower alkyl has 1 to 6 carbon atoms , glycols, polyglycols, ricinoleic acid and ricinoleic acid esters. 9. - The composition according to claim 1, further characterized in that it additionally comprises a plasticizer selected from the group consisting of sorbitol, glycerol, propylene glycols and polyethylene glycols. 10. The composition according to claim 1, further characterized in that it additionally comprises a preservative selected from the group consisting of methyl parabens, propyl parabens, butyl parabens, sorbic acid, benzoic acid, editic acids, phenolic acids, sorbates and propionates. 11. - The composition according to claim 1, further characterized in that it additionally comprises titanium dioxide. 12. - The composition according to claim 1, further characterized in that it additionally comprises sulfur dioxide. 13. - The composition according to claim 1, further characterized in that it is in the form of capsular covers. 14. The composition according to claim 13, further characterized in that each of the capsular covers defines a load volume. 15. The composition according to claim 13, further characterized in that the capsular covers are soft gelatin capsular covers. 16. - The composition according to claim 14, further characterized in that the loading volume has a capacity of about 0.1 ml to about 2 ml. 17. The composition according to claim 16, further characterized in that the loading volume has a capacity of no more than about 1 ml. 18. The composition according to claim 14, further characterized in that the capsular covers are suitable for oral delivery of a drug contained in the loading volume. 19. - A pharmaceutical dosage form comprising a sealed filler material in capsular caps, wherein the capsular caps comprise gelatin and an amine agent comprising at least a pharmaceutically acceptable primary or secondary amine, and wherein said amine agent is present in an amount sufficient to inhibit crosslinking of the gelatin and / or film formation in the gelatin capsular shells after storage of the dosage form. 20. The dosage form according to claim 19, further characterized in that the filling material is liquid. 21. - The dosage form according to claim 20, further characterized in that the filling material self-emulsifies after contact with the gastric fluid. 22. The dosage form according to claim 19, further characterized in that the filling material comprises an amine agent comprising at least one primary or secondary pharmaceutically acceptable amine, wherein the amine agent in the filling material is present. in an effective amount, in combination with the amine agent in the capsular shell, to inhibit crosslinking of the gelatin and / or film formation in the capsular shell after storage of the dosage form. 23. - The dosage form according to claim 19, further characterized in that the filler material comprises a pharmaceutically acceptable sulfite compound in an effective amount, in combination with the amine agent in the capsular shell, to inhibit crosslinking of the gelatin and / or film formation in the capsular cover after storage of the dosage form. 24. The dosage form according to claim 19, further characterized in that the filling material comprises a drug. 25. The dosage form according to claim 24, further characterized in that the drug is of low solubility in water. 26. The dosage form according to claim 24, further characterized in that the drug is a selective inhibitor drug of cyclooxygenase-2. 27. - The dosage form according to claim 26, further characterized in that the selective inhibitory drug of cyclooxygenase-2 is a compound of formula (I) wherein A is a substituent selected from unsaturated or partially unsaturated and unsaturated carbocyclic unsaturated or partially unsaturated carbocyclic rings, preferably a heterocyclyl group selected from pyrazolyl, furanolyl, isoxazolyl, pyridinyl, cyclopentenonyl and pyridazinonyl groups; X is O, S or CH2; 1 is at least one substituent selected from heterocyclyl, cycloalkyl, cycloalkenyl and aryl, and is optionally substituted in a substitution position with one or more radicals selected from alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxy, hydroxyalkyl, haloalkoxy, amino, alkylamino, arylamino, nitro, alkoxyalkyl, alkylsulfinyl, halo, alkoxy or alkylthio; R 2 is methyl, amino or aminocarbonylalkyl; R3 is one or more radicals selected from halo hydride, 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, aminocarbonyl, aminocarbonyl, alkylaminocarbonyl, N-arylaminocarbonyl, N-alkyl-N-arylaminocarbonyl, alkylaminocarbonylalkyl, carboxyalkyl, alkylamino, N- Arylamino, N-alakylamino, N-alkyl-N-aralkylamino, N-alkyl-N-arylamino, aminoalkyl, alkylaminoalkyl, N-arylaminoalkyl, N-aralkylaminoalkyl, N-alkyl-N-aralkylaminoalkyl, N-alkyl-N-arylaminoalkyl, aryloxy, aralkoxy, arylthio, aralkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylamide minosulfonyl, N-arylaminosulfonyl, arylsulfonyl and N-alkyl-N-arylaminosulfonyl, wherein R3 is optionally substituted in a substituted position with one or more radicals selected from alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxy, hydroxyalkyl, haloalkoxy, amino, alkylamino , arylamino, nitro, alkoxyalkyl, alkylsulfinyl, halo, alkoxy and alkylthio; and R4 is selected from hydride and halo. 28. The dosage form according to claim 26, further characterized in that the selective inhibitory drug of cyclooxygenase-2 is selected from the group consisting of celecoxib, deracoxib, valdecoxib, rofecoxib, etoricoxib, 2- (3,5-difluorophenyl) - 3- [4- (Methylsulfonyl) phenyl] 2-cyclopenten-1-one, 2- (3,4-difluorophenyl) -4- (3-hydroxy-3-methyl-1-butoxy) -5- [4- ( methylsulfonyl) phenyl] -3- (2H) -pyricazinone, pharmaceutically acceptable salts and prodrugs thereof. 29. The dosage form according to claim 26, further characterized in that the selective inhibitor drug of cyclooxygenase-2 is celecoxib. 30. - The dosage form according to claim 24, further characterized in that the filling material additionally comprises at least one substance that stimulates the crosslinking of gelatin in contact therewith, said substance being the drug itself or an excipient substance, and said substance acting independently or in combination with one or more substances to stimulate said cross-linking. 31. - The dosage form according to claim 30, further characterized in that it comprises a first and a second of said capsular caps, said first and second cap caps being substantially identical; in which after (a) testing in a first capsular shell in a first in vitro dissolution assay; (b) storage of a second capsular cover in a closed container maintained at 40 ° C and a relative humidity of 85% during a period of four weeks; and, after said storage, (c) performing tests on the second capsular cover sealed in a second in vitro dissolution test that is substantially identical to the first in vitro dissolution test; the amount of drug dissolved at 45 minutes in the second dissolution test is ± 15% of the amount of drug dissolved at 45 minutes in the first dissolution test; and wherein the first in vitro dissolution test is carried out in a reasonably short time after preparation of the composition.