MXPA05001167A - Gelatin capsule exhibiting reduced cross-linking. - 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

GELATINE CAPSULE THAT EXHIBITS REDUCED RETICULATION FIELD OF THE INVENTION The present invention relates to gelatin capsules exhibiting a reduced gelatin crosslinking. Said capsules are useful, inter alia, in the pharmaceutical, nutraceutical and food industries.

BACKGROUND OF THE INVENTION Gelatin, a mixture of water soluble proteins derived from collagen by hydrolysis, is widely used in the pharmaceutical and food industries, among others. A main application of gelatin is in the preparation of both hard and soft gelatin capsules. Said capsules are desirable, inter alia, for their versatility (they may contain drug formulations in solid, semi-solid or liquid form) and for their rapid dissolution characteristics. Unfortunately, it is known that dosage forms of gelatin-containing drugs in an outer layer (eg, liquid or powder as a gelatin capsule filling) exhibit a decrease in the rate of dissolution with the passage of time. This decrease in the dissolution ratio can lead to inconvenient and unacceptable alterations in an in vitro dissolution profile and in bioavailability, particularly for drugs of low solubility in water or drugs whose absorption is limited by the proportion of dissolution. It is believed that such changes in the dissolution profile arise from the cross-linking of the gelatin that occurs in the coatings of the gelatin capsules. Singh et al., Alteration in Dissolution Characteristics of Gelatin-Containinq Formulations. Pharmaceutical Technology, April 2002, incorporated herein by reference in its entirety but not admitted as prior art, discloses reports suggesting that various agents, including hydroxylamine hydrochloride, glycerin and glycine, upon incorporation into gelatin capsule filling contents, they can limit the cross-linking of gelatin. Unfortunately, existing methods that address the problem of gelatin crosslinking in capsule coatings are very unsatisfactory, particularly in situations where a longer shelf life and real-life deposit stability are desired. of shipping and handling. If gelatin capsules capable of providing a predictable and stable dissolution rate of a drug contained within said capsule could be prepared, even after the storage of said capsules under extreme conditions, a significant advance in the oral administration of drugs would arise, particularly drugs of little solubility in water or drugs whose absorption is limited by the proportion of dissolution.

BRIEF DESCRIPTION OF THE INVENTION A composition suitable for preparing a pharmaceutical capsule coating is now provided in the present invention, the composition comprising gelatin and a pharmaceutically acceptable sulfite compound. Conveniently, the sulfite compound is present in an amount effective to inhibit crosslinking of the gelatin and / or film formation in a capsule coating prepared from the composition. A capsule coating of the present composition is also provided. Further provided is a pharmaceutical dosage form comprising capsule coatings of the present composition, wherein the capsule coatings define a volume of filling that is at least partially occupied by a filling material. Suitably, the sulfite in the capsule coating of the pharmaceutical dosage form is present in an amount effective to inhibit gelatin cross-linking and / or film formation in the capsule coating. Conveniently, the dosage form of the present invention contains a drug in the filling material, more preferably a drug of poor water solubility.

In one embodiment, the drug is a selective cyclooxygenase 2 inhibitor drug. The composition and dosage form of the present invention are specifically useful for liquid filling materials and soft gelatin capsules. The term "film" refers herein to a relatively water insoluble membrane formed in a gelatin capsule coating, wherein the membrane tends to be thin, rigid and rubbery. It is now to be understood that a mechanism underlying film formation is the cross-linking of gelatin. The crosslinking of the gelatin and the film formation result in reduced dissolution rates. Accordingly, the quantification of the dissolution ratio of a first capsule within a reasonably short period of time after the preparation of the capsule and a second capsule after storage under extreme conditions (eg, four weeks to 40 days). ° C and 85% relative humidity in a closed container), as described herein, provides a means for determining film formation and / or gelatin cross-linking. The expression "within a reasonably short period of time after the formation of the capsule" means within, of such a period that it is unlikely that cross-linking and / or substantial film formation has yet occurred, for example within a week. , depending on the storage condition during that period.

The term "film resistant" herein means that said gelatin capsule so described has a reduced tendency to form, or exhibit delayed, delayed or reduced formation of a film after storage under extreme conditions. Similarly, Inhibition of cross-linking "(or inhibition of film formation") herein means a delayed, delayed or reduced formation of gelatin crosslinks (or film formation) compared to a quantity of a similar capsule which it lacks only an agent such as the one provided herein. It has been found that the pharmaceutical dosage forms according to the present invention exhibit an unexpected and surprisingly substantial reduction in gelatin cross-linking of the capsule coating and in film formation. As a consequence, said dosage forms are capable of consistently satisfying the desired in vitro dissolution criteria, even after storage under extreme conditions. The present invention represents a significant advance depending on the conventional dosage forms and the coatings of conventional gelatin capsules.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a graph showing a level I dissolution ratio of Formulation 30 after storage at 25 ° C, as described in Example 5. Figure 2 is a graph showing a Dissolution Ratio of Level I of Formulation 30 after storage at 40 ° C, as described in Example 5. Figure 3 is a graph showing a level II dissolution ratio of Formulation 30 after storage at 25 ° C, such as described in Example 5. Figure 4 is a graph showing a Level II dissolution ratio of Formulation 30 after storage at 40 ° C, as described in Example 5. Figure 5 is a graph showing a dissolution ratio of Level I of Formulation 19 after storage at 25 ° C, as described in Example 5. Figure 6 is a graph showing a dissolution ratio of Level I of Formulation 19 after storage at 40 ° C, as described in Example 5. Figure 7 is a graph showing a level II dissolution ratio of Formulation 19 after storage at 40 ° C, as described in Example 5 DETAILED DESCRIPTION OF THE INVENTION Composition suitable for the preparation of a capsule coating In one embodiment, the present invention provides a composition suitable for the preparation of a capsule coating. Said composition, according to the present invention, comprises gelatin and at least one sulfite compound present in an amount effective to inhibit gelatin cross-linking and / or film formation upon storage. A "composition suitable for the preparation of a capsule coating" according to the present invention comprises gelatin, at least one sulfite compound, and optionally one or more excipients. Before using said composition in the preparation of gelatin capsules, a liquid, for example water, is typically added to the composition to form an aqueous mixture. In one embodiment, said composition suitable for the preparation of the wall of a capsule comprises gelatin, at least one sulfite compound and water. Preferably, the water will be present in an amount such that the weight ratio of water to gelatin will be 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 of about 1% to about 99%, more preferably about 10% to about 80%, and even more preferably about 15% to about 90% of the composition based on to dry weight. It is to be understood that "based on dry weight" means the total weight, except the weight of the water.

Sulfites of the composition Any pharmaceutically acceptable sulfite compound can be used in a composition of this embodiment. Illustrative pharmaceutically acceptable sulfite compounds include sodium metabisulfite, sodium bisulfite and sodium thiosulfate (sodium hyposulfite). Preferably, one or more sulfite compounds are 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 based on dry weight.

Optional amines of the composition Optionally, a composition of the invention may comprise an amine agent comprising at least one pharmaceutically acceptable primary or secondary amine. The examples do not Limitations of suitable primary amines include tromethamine (Tris), ethanolamine, 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, benetamine (ie, N-phenethyl) benzeneethanamine), benzathine (ie, N, N-dibenzylethylenediamine), piperazine, hydrabamine (i.e., N, N-bis (dehydroabietil) ethylenediamine) and imidazole. If desired, the amine compound is present in a composition of the invention in an amount of not more than about 10%, preferably not more than about 5%, and more preferably not more than about 2.5% of the composition based on the dry weight .

Optional Excipients of the Composition A composition of the invention, in addition to gelatin and a sulfite compound, preferably also comprises one or more pharmaceutically acceptable excipients. For example, if the composition of the invention is to be used to prepare soft gelatin capsules, the composition will preferably comprise at least one plasticizer in a total amount of from about 2% to about 60%, preferably about 5% to about 45%, and more preferably about 10% to about 40% of the composition based on the dry weight. When a plasticizer is present, the weight ratio of the plasticizer (non-aqueous portion) to gelatin will be about 0.3 to about 1.8 and preferably from about 0.4 to about 0.75. Non-limiting examples of suitable plasticizers include polyhydric alcohols such as sorbitol, glycerol and mannitol; dialkyl phthalates; lower alkyl citrates in which the lower alkyl possesses 1-6 carbon atoms; glycols and polyglycols, including polyethylene glycols with a molecular weight range of from about 200 to about 40,000, methoxyl-propylene glycol and 1,2-propylene glycol; esters of polyhydric alcohols such as glycerol mono, di and triacetate; ricinoleic acid and its esters; and mixtures of the aforementioned. A composition of the invention may further comprise one or more preservatives, opacifying agents (e.g., titanium dioxide), decomposition inhibitors (e.g., sulfur dioxide), dyes, flavorings, etc. Illustrative non-limiting examples of suitable preservatives include methyl paraben, propyl paraben, butyl paraben, sorbic acid, benzoic acid, editic acid, phenolic acid, potassium sorbate and sodium propionate. A composition suitable for the preparation of the wall of a capsule can take the form of a solid, a dry powder, a semi-solid, a liquid solution or a liquid suspension. Importantly, 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 process, if any, that is used. to make the capsules, and for the type particular of capsule to be prepared (hard or soft). A person with ordinary skill in the art will readily select a suitable physical form for a composition of the invention, taking these and other factors into account.

PROCEDURE FOR PREPARING THE CAPSULES OF THE INVENTION 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, those methods described in the following patents and / or publications. , each of which is incorporated herein by reference. U.S. Patent No. 3,656,997 for Cordes. U.S. Patent No. 4,231, 21 1 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. 4,756,902 to 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 for Sanso.

International patent publication No. WO 84/00919 for Mackie International patent publication IsT WO 85/04100 for Kalidindi. A person of ordinary skill in the art will readily adapt the methods described in the aforementioned documents in view of the present disclosure, for the purpose of preparing capsules comprising a sulfite compound according to the present invention. A preferred method for preparing hard gelatine capsules of the invention comprises the steps of (a) providing a composition suitable for the preparation of a capsule coating (comprising gelatin and a sulfite compound) in the form of dry powder, (b) preparing a liquid solution or suspension / solution comprising water and the composition, (c) heating the liquid, (d) immersing stainless steel molds to make capsules in the heated liquid, (e) removing the submerged molds from the liquid to form molds coated, and (f) subjecting the coated molds to a drying process to produce one half of a dry capsule coating. After drying, the coating halves are removed from the molds, cut to the desired length. The capsule coating halves can then be filled with any desired filler material, joined in a cooperative fashion to form a capsule coating, and then capped. Optionally, the lid can be welded by points, melted or bond with melted gelatin to provide a fracture resistant product. According to this method, the sulfite compound is preferably present in the composition suitable for the preparation of a capsule coating and / or, if desired, may also be added during stages (b), (c) and / or (d).

Soft Capsules The soft gelatin capsules of the invention can be prepared according to any suitable method, including, but not limited to, the rolling process, the vacuum process or the rotary nozzle procedure, See, for example, ( 1) Ansel et al (1995) in Pharmaceutical Dosaqe Forms and Druq Delivery Systems, 6th ed., Williams & Wilkins, Baltimore. MD, pp. 176-182; and (2) Remington: The Science and Practice of Pharmacy, 19th Ed., Mack Publishing Co. Easton, PA, pp. 1646-1647, whose pages mentioned are incorporated herein by reference. The rotary nozzle method is a currently preferred process for making the soft gelatin capsules according to the present invention. According to the rotary nozzle method, a composition of the invention comprising gelatin and a sulfite compound, is dissolved or suspended in water to form a fluid material and then placed in an upper tank. The rotating nozzle machine forms two continuous bands of fluid material from the tank upper and the bands are then joined by two twin rotating nozzles. Simultaneously, dosed filling material is injected between the bands, at about the same time as the bands form cavities. These cavities of encapsulation material containing the filler are then sealed by pressure and heat. The soft gelatine capsules can be manufactured in different shapes including oval, oblong and tube, among others. Additionally, by using two different band colors, two-tone capsules can be produced. Non-limiting examples of suitable methods for preparing soft gelatin 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 ef al. 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 Ishikawa ef al, and International Patent Publication No. WO 92/15828 for Herman As used herein, unless the specific context indicates otherwise, the term "capsule coating" (and "gelatin capsule coating") encompasses capsule coating halves (which may cooperate to form a coating of whole capsule) and whole capsule coatings (which define a filling volume). Said expression also covers coatings of soft gelatin capsule and hard gelatin capsule, independently of the process by which the capsules are manufactured. The terms "sealed capsule coating", "sealing in a capsule coating", "sealing the capsule coating" and the like are meant to denote an entire capsule coating defining a volume of filling, which said volume of filling can contain a filler material, said filler material is closed in the entire capsule shell and that said closure produces the filler material with more than the minimum amount of protection against the atmosphere that is outside the entire shell of the capsule.

Drug of low solubility in water Capsule coatings according to the present invention define a volume of filler and said volume of filler can be occupied at least partially by any filler material. The filler material can comprise any active drug. Preferably, the active drug is a drug of poor solubility in water, in the present also called drug poorly soluble in water. A "low water solubility drug" or "poorly water soluble drug" refers herein to any drug or compound having a solubility in water, measured at 37 ° C, not higher than about 10 mg / ml, and preferably not more than about 1 mg / ml. Particularly preferred drugs have a solubility in water, measured at 37%, not higher than about 0.1 mg / ml. The water solubility for many drugs can be easily determined from standard reference pharmaceutical books, for example, The Merck Index, 1st ed., 1989 (published by Merck &Co., Inc., Rahway, NJ); United States Pharmacopoeia, 24th ed. (USP 24), 2000; The Extra Pharmacopoeia, 29th ed., 1989 (published by Pharmaceutical Press, London); and Physicians Desk Reference (PDR), 2001 ed. (published by Medical Economics Co., Montvale, NJ). For example, individual drugs of low solubility, as defined herein, include those drugs categorized as "mildly soluble", "very mildly soluble", "practically insoluble" and "insoluble" in USP 24, pp. 2254 -2298, and those drugs categorized with a requirement of 100 ml or more of water to dissolve 1 g of the drug, as mentioned in USP 24, pp. 2299-2304. For illustrative purposes, suitable drugs of low solubility include , not limited to, drugs of the following classes: abortifacient, ACE inhibitors, agonists a and ß-adrenergic, ß-adrenergic blockers, adrenocortical suppressors, adrenocorticotropic hormones, alcohol deterrents, aldose reductase inhibitors, aldosterone antagonists, anabolics, analgesics (including narcotic and non-narcotic analgesics), androgens, angiotensin II receptor antagonists, anorexics, antacids, anthelmintics, anti-acne agents, antiallergic agents, antiabetes agents, anti-diabetics, antiandrogens, antianginal agents, antiarrhythmics, antiarteriosyndromic agents, antiarthritic / antirheumatic agents (including selective COX-2 inhibitors), antiasthmatics, antibacterials, complementary antibacterial aids, anticholinergics, anticoagulants, anticonvulsants, antidepressants , antidiabetics, antidiarrheal agents, antidiuretics, antidotes for poison, antidiscinetics, antieczematics, antiemetics, antiestrogens, antifibrotic, antifattuous, anti-fungal, antiglaucoma agents, antigonadotropins, agent antigota, antihistamines, antihypertensive, antihyperlipoproteinemic, antihyperphosphatemic, antihypertensive, antihyperthyroid, antihypertensive, antihypothyroid, anti-inflammatory, antimalarial, antimanic agents, antimetahemoglobinemia agents, antimigraine agents, antimuscarinics, antimycobacteria, adjuvants and antineoplastic agents, antineutropenia, antiosteoporotic, antipagetic agents, antiparkinson agents, anti-pheochromocytoma agents, anti-pneumocystis agents, antihypertrophic prosthetic agents, antiprotozoar, antipruritic, antipsoriatic, antipsychotic, antipyretic, antirickettsial, antiseborrheic, antiseptic / disinfectant, antispasmodic, anti-syphilitic, antithrombotic, antithrombotic, antitussive, antiulcerative, anthurolytic agents, antiviral agents, anxiolytics, aromatase inhibitors, astringents, benzodiazepine antagonists, bone resorption inhibitors, bradycardic agents, bradykinin antagonists, bronchodilators, calcium channel blockers, calcium regulators, carbonic anhydrase inhibitors, cardiotonic, CCK antagonists, chelating agents, colelitolytic agents, choleretics, cholinergics, cholinesterase inhibitors, cholinesterase reactivators, CNS stimulants, contraceptives, debridement agents, decongestants, depigmenting agents, dermatitis herpetifonnis suppressors, digestive auxiliaries , diuretics, dopamine receptor agonists, ectoparasiticides, emetics, enkephalinase inhibitors, enzymes, enzymatic cofactors, estrogens, expectorants, fibrinogen receptor antagonists, fluoride supplements, gastric and pancreatic secretion stimulants, gastric cytoprotective substances, gastric proton pump inhibitors , gastric secretion inhibitors, gastroprokinetics, glucocorticoids, a-glucosidase inhibitors, gonad-stimulant principles, somatotropin inhibitors, somatotropin releasing factors, growth stimulants, hematinics, hematopoietics, hemolytics, haemostats, heparin antagonists, enzyme inducers hepatic, hepatoprotective, histamine H2 receptor antagonists, HIV protease inhibitors, HMG CoA reductase inhibitors, immunomodulators, immunosuppressants, insulin sensitizers, ion exchange resins, keratolytics, lactation-stimulating hormones, laxatives / cathartics, leukotriene antagonists, LH-RH agonists, lipotropic agents, 5-lipoxygenase inhibitors, lupus erythematosus suppressors, matrix metalloproteinase inhibitors, mineralocorticoids, miotics, monoamine oxidase inhibitors, mucolytics, relaxants muscle, mydriatics, narcotic antagonists, neuroprotectors, nootropics, ovarian hormones, oxytocics, pepsin inhibitors, pigmentation agents, plasma volume expanders, activated potassium channel cleaners, progestogens, prolactin inhibitors, prostaglandins, protease inhibitors, agents radiopharmaceuticals, 5a-reductase inhibitors, respiratory stimulants, transcriptase inhibitors, sedatives / hypnotics, tranquilizers, serotonin noradrenaline reuptake inhibitors, serotonin receptor agonists, serotonin receptor antagonists, serotonin uptake inhibitors, analogs from somatostatin, thrombolytics, thromboxane A2 receptor antagonists, thyroid hormones, thyrotropic hormones, tocolytics, topolsomerase I and II inhibitors, uricosurics, vasomodulators, including vasodilators and vasoconstrictors, vasoprotectors, xanthine oxidase inhibitors and their combinations. Illustrative, non-limiting examples of suitable drugs of poor water solubility include acetohexamide, acetylsalicylic acid, alciofenac, allopurinol, atropine, benzthiazide, carprofen, celecoxib, ciordiazepoxide, ciorpromazine, cionidine, codeine, codeine phosphate, codeine sulfate, deracoxib, diacerein , diclofenac, diltiazem, estradiol, etodolac, etoposide, etoricoxib, fenbufeno, fenclofenac, fenprofen, fentiazac, flurbiprofen, griseofulvin, haloperidol, ibuprofen, ndometacin, indoprofen, ketoprofen, lorazepam, medroxyprogesterone acetate, megestrol, methoxsalen, methylprednisone, morphine, molfine sulfate, naproxen, nicergoline, nifedipine , niflumic, oxaprozin, oxazepam, oxifeributazone, paclitaxel, fenindione, phenobarbital, piroxicam, pirprofen, prednisolone, prednisone, procaine, progesterone, pyrimethamine, rofecoxib, sulfadiazine, sulfamerazine, sulfisoxazole, sulindac, suprofen, temazepam, thiaprofenic acid, tilomisol, tolmetic, valdecoxib, etc. The amount of drug incorporated into the filling material to be poured into a capsule of the invention can be selected according to known pharmacy principles. A therapeutically effective amount of a 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 produce the required or desired therapeutic and / or prophylactic response. Preferably, 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 even more preferably at least about 5% by weight of the filling.

Selective COX-2 Inhibitory Drugs In a preferred embodiment, the drug is a selective cyclooxygenase-2 inhibitory drug. A preferred cyclooxygenase-2 selective inhibitor drug, useful herein, or to which a salt or prodrug useful herein it becomes alive, it is a compound of the formula (I) wherein: A is a substitute 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 CH2; n is 0 or 1; R1 is at least one substituent selected from heterocyclyl, cycloalkyl, cycloalkenyl and aryl, and is optionally substituted in 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; R3 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, aralquenllo, alkoxyalkyl, to ltioalquilo, aryloxyalkyl, aralkylthioalkyl, aralkoxyalkyl, alkoxyaralkoxyalkyl, alkoxycarbonylalkyl, aminocarbonyl, aminocarbonyl, alkylaminocarbonyl, N-arylaminocarbonyl, N-alkyl-N-arylaminocarbonyl, alkylaminocarbonylalkyl, carboxyalkyl, alkylamino , N-arylamino, N-aralkylamino, 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, alky ilaminosulfonyl, N-arylaminosulfonyl, arylsulfonyl and N-alkyl-N-arylaminosulfonyl, wherein R3 is optionally substituted in 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; and R4 is selected from hydrido and halo.

The compositions of the invention are especially useful for selective cyclooxygenase 2 inhibitor drugs, which have the formula (II): wherein R5 is a methyl or amino group, R6 is hydrogen or an alkoxy or C1.4 alkyl group, X 'is N or CR7, wherein R7 is hydrogen or halogen, and Y and Z are independently carbon or nitrogen atoms which define adjacent atoms of a five to six member ring optionally substituted at one or more positions with oxo, halo, methyl or halomethyl groups, or an isomer, tautomer, one of its pharmaceutically acceptable salts or prodrugs. Said preferred five to six member rings are rings of cyclopentenone, furanone, methylpyrazole, isoxazole and pihdine substituted in no more than one position. Illustratively, the capsules of the invention are suitable for administering 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) phenylJ-3-1 (2H) -pyridazinone, its salts and prodrugs pharmaceutically acceptable The capsules of the invention are also useful for compounds having the formula (III): wherein X "is O, S or N-lower alkyl, R8 is lower haloalkyl, R9 is hydrogen or halogen, R0 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 heterocyclsulfonyl, and R and R12 are independently hydrogen, halogen, lower alkyl, lower alkoxy or aryl, and for their pharmaceutically acceptable salts A particularly useful compound of the formula (III ) is (S) -6,8-dichloro-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid, particularly in the form of one of its water-soluble salts, for example the sodium salt. 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 u When the drug is a selective COX-2 inhibitor drug other than celecoxib, the amount of the drug per unit dose is therapeutically equivalent to about 10 mg to about 1000 mg of celecoxib. It is to be understood that a therapeutically and / or prophylactically effective amount of a drug for a subject depends, inter alia, of the subject's body weight. A "subject" herein who can be administered a therapeutic agent or its composition includes a human patient of either sex and of any age, and also includes any non-human animal, particularly a pet or companion animal, illustratively a cat , dog or horse. When the subject is a child or a small animal (eg, a dog), for example, a relatively small amount of celecoxib in the preferred range of about 10 mg to about 1000 mg will likely be consistent with the therapeutic efficacy. When the subject is an adult human being or a large animal (eg, a horse), the therapeutic efficacy will likely require dose units containing a relatively greater amount of celecoxib. For an adult human, a therapeutically effective amount of celecoxib per unit dose in a dosage form of the present invention is typically about 10 mg to about 400 mg. Especially preferred amounts of celecoxib per unit dose are about 100 mg to about 200 mg, for example about 100 mg or about 200 mg.

For other selective COX-2 inhibitor drugs, an amount of the drug per unit dose may be in a range known to be therapeutically effective for said drugs. Preferably, the amount per unit dose is in a range that provides therapeutic equivalence to celecoxib at the above-indicated dose ranges.

Capsule with liquid filler In a preferred embodiment, a capsule of the invention is filled with a liquid filler material. More preferably, the filling material is self-emulsifying after contact with simulated gastric fluid. The filling material according to the present embodiment comprises at least one solvent which is preferably suitable for dissolving the drug and / or any additional ingredient or excipient therein present. i. Cholol Solvents A preferred solvent is a glycol or glycol ether. Suitable glycol ethers include those which form the formula (X): R1-0 - ((CH2) mO) n -R2 (X) wherein R1 and R2 are independently hydrogen or alkyl C1-6, Ci_6 alkenyl, phenyl or benzyl groups, but not more than one of R1 and R2 is hydrogen; del 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 an alkyl group C and the other is hydrogen or an alkyl group more preferably, at least one of R and R2 is a methyl or ethyl group. It is preferred that of sea 2. It is preferred that n is an integer from 1 to about 4, more preferably 2. The glycol ethers used as solvents in fill material typically have a molecular weight of from about 75 to about 1000, preferably about 75. to about 500 and more preferably about 100 to about 300. Importantly, the glycol ethers used in the filling material of this embodiment must be pharmaceutically acceptable and must meet all other conditions stated herein. Non-limiting examples of glycol ethers that can be employed in the filling 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 ether ethylene glycol, 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, dimethyl ether of tetraethylene glycol and their mixtures. See, for example, Flick (1998): Industrial Solvent Handbook, 5th ed., Noyes Data Corporation, Westwood, NJ. A particularly suitable glycol ether solvent is diethylene glycol monoethyl ether, sometimes referred to as DGME or ethoxydiglycol in the art. It is marketed, for example, with the Transcutol ™ brand from Gattefossé Corporation. Glycols suitable as solvents in filler material include propylene glycol, 1,3-butanediol and polyethylene glycols. A currently 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 about 100 to about 1,000. Even more preferably, the PEG is of liquid grade. Non-limiting examples of PEG that can be used in solvent liquids of the present invention include PEG-200, PEG-350, PEG-400, PEG-540 and PEG-600. See, for example Flick (1998), op. cit., p. 392. A currently preferred PEG possesses an average molecular weight of about 375 to about 450, as exemplified by PEG-400. PEGs such as PEG-400 have many desirable properties as solvents for poorly water soluble drugs. In the case of celecoxib, for example, the drug can be dissolved or solubilized in a very high concentration in PEG-400, allowing the formulation of a dose Therapeutically effective in a very small volume of solvent liquid. This is especially important when the resulting solution is to be encapsulated, since capsules of a suitable size for swallowing containing a therapeutically effective dose can be prepared, even of a drug such as celecoxib, which has a relatively high dose requirement to be effective. Importantly, ethanol, water and other excipients, such as solvents, identified herein or elsewhere as co-solvents in a filler material of the invention may be used, if desired. Typically, one or more solvents will be present in a filler material, in a total amount of from about 5% to about 95%, preferably about 10% to about 90% and more preferably about 15% to about 85% by weight of the material of filling. ii. Co-solvents A filler material of the present 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; triglycerides of oleic and linoleic acid, for example soybean oil; caprylic / capric triglycerides, for example Miglyol ™ 812 from Huís; caprylic / capric diglycerides and diglycerides, for example Capmul ™ CM from Abitec; caprilic / capric polyoxyethylene glycerides, such as mono and diglycerides caprylic / capric polyoxyethylene (8), for example Labrasol ™ by Gattefossé; fatty acid esters of propylene glycol, for example propylene glycol laurate; polyoxyethylene castor oil (35), for example Cremophor ™ EL from BASF; polyoxyethylene glyceryltrioleate, for example Tagat ™ TO from Goldschmidt; lower alkyl esters of fatty acids, for example ethyl butyrate, ethyl caprylate and ethyl oleate; and water.

Filling material Amine Agent When a pharmaceutical dosage form is to be provided, the filling material disposed in a capsule of the present invention may further comprise an amine agent comprising at least one primary or secondary amine compound. However, any pharmaceutically acceptable primary or secondary amine may be used, as described above (for optional amine agents of the composition of the present invention). Preferably, when a filler material comprises primary or secondary amine compounds, said amine compounds are not therapeutically or nutritionally active. In a preferred embodiment, about 50%, preferably at least about 55%, more preferably at least about 60% and even more preferably about 65% of any primary amine compound or secondary present in a dosage form of the invention is present in the filling material.

Sulphite Compound The filler material disposed in a capsule of the present invention may further comprise a sulfite compound, as described above. In a preferred embodiment, at least about 40%, preferably at least about 50%, even more preferably at least about 55%, even more preferably at least about 60%, and even more preferably about 70% of all the Sulphite compound present in a dosage unit of the invention is present in the capsule coating.

Amine and sulfite agents It is to be readily understood from the description herein that in the dosage form of the present invention, the capsule coating comprises at least one primary or secondary amine and optionally a sulfite compound. The filling 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. In addition, it is to be understood that "at least one primary or secondary amine" it contemplates the presence of one or more primary amines, one or more secondary amines and combinations of primary and secondary amines.

Other excipient filler material The filler material of the present invention optionally comprises at least one pharmaceutically acceptable free radical scavenger antioxidant. An antioxidant free radical scavenger will contrast with an "antioxidant scavenger without free radical", that is, an antioxidant that does not have free radical scavenging properties. Illustrative non-limiting examples of free radical scavenging antioxidants include a-tocopherol (vitamin E), ascorbic acid (vitamin C) and its salts, including sodium ascorbate and ascorbic acid, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), fumaric acid and its salts, hypophosphorus acid, malic acid, alkylgalates, for example propylgalate, octylgalate and laurylgalate, sodium sulfite, sodium bisulfite and sodium metabisulfite. The preferred free radical scavenging antioxidants are alkylgalates, vitamin E, BHA and BHT. More preferably, the at least one free radical scavenging antioxidant is propylgalate. One or more free radical antioxidants are optionally present in the dosage forms of the invention in a total amount effective to substantially reduce the formation of an addition compound, typically in a total amount of from about 0.01% to about 5%, preferably about 0.01% a about 2.5%, and more preferably about 0.01% to about 1%, by weight of the filler 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 additionally, a viscous sweetener such as sorbitol solution, syrup (sucrose solution) or high fructose corn syrup may be used and, in addition to its sweetening effects, may also be useful for increasing viscosity and retarding the sedimentation. The filler material of the invention optionally comprises one or more pharmaceutically acceptable preservatives which are not 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. The filler material of 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, cetylpyridinium chloride, dioctyl sodium sulfosuccinate, nonoxynol 9, nonoxynol 10, octoxynol 9, poloxamers, caprylic / capric polyoxyethylene (8) monomers and diglycerides (eg, Labrasol ™ from Gattefosse), polyoxyethylene castor oil (35), polyoxyethylene ketoestearyl ether (20), polyoxyethylene hydrogenated castor oil (40), polyoxyethylene oleyl ether (10), polyoxyethylene stearate (40), polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80 (e.g. ., 80 of ICI), propylene glycol laurate (eg, Lauroglycol ™ from Gattefosse), sodium lauryl sulfate, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, tyloxapol and mixtures thereof. Additionally, the dosage forms of the invention optionally comprise one or more pharmaceutically acceptable buffering agents, flavoring agents, colorants, stabilizers and / or thickeners. The buffers can be used to control the pH of a formulation and can thereby modulate the solubility of the drug. Flavoring agents can improve patient compliance, making the dosage form more palatable, and dyes can provide a product with a more aesthetic and / or distinctive appearance. Non-limiting examples of suitable dyes include D &C Red No. 33, FD &C Red NI 3, FD &C Red N040, D &C Yellow No. 10, and C Yellow No. 6.

Drug dissolution and gelatin crosslinking Without wishing to be influenced by theory, the inventors believe that gelatin crosslinking may arise from a process whereby the amino acid residues of gelatin are covalently bound to form an insoluble material. The process can be the result of reduced levels of aldehydes that come in contact with the gelatin. The crosslinking of a gelatin capsule can impact the performance of the product, 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 in the bloodstream and the clinical onset of the action. While 'mild' crosslinking does not necessarily have a significant impact on the release of the formulation from the dosage form, 'severe' crosslinking can have a significant impact. When the crosslinking is severe, it can lead to a delay in the release of the formulation from the dosage form in humans, problems of potential bioequivalence and a potential delay in the clinical onset of action. It is believed that the capsules according to the present invention exhibit reduced gelatin / and film formation) crosslinking and, therefore, upon being filled with a drug-containing composition and disposed in an in vitro dissolution test, they are capable of exhibiting advantageously less change in the dissolution ratio during storage under extreme conditions than conventional capsules. It is also believed that the capsules according to the present invention exhibit a more uniform dissolution ratio of the drug between capsules than the standard gelatin capsules. Without wishing to be influenced by the theory, the inventors believe that gelatin cross-linking can arise from a process whereby the amino acid residues of the gelatin are covalently bound to form an insoluble material. The process can be the result of reduced levels of aldehydes that come in contact with the gelatin. The crosslinking of a gelatin capsule can impact the performance of the product, delaying the release of the formulation (containing the active compound) from the coating of the capsule. The delay in the release can, in turn, affect the rate of absorption of the compound in the bloodstream and the clinical onset of the action. While 'mild' crosslinking does not necessarily have a significant impact on the release of the formulation from the dosage form, 'severe' crosslinking can have a significant impact. When the crosslinking is severe, it can lead to a delay in the release of the formulation from the dosage form in humans, problems of potential bioequivalence and a potential delay in the clinical onset of action. It is believed that the capsules according to the present invention exhibit reduced gelatin crosslinking (and film formation) and, consequently, upon being filled with a drug-containing composition and disposed in an in vitro dissolution test, they are able to exhibit advantageously less change in the dissolution ratio during storage under extreme conditions than conventional capsules. It is also believed that capsules according to the present invention exhibit a more uniform dissolution rate of the drug between capsules than standard gelatin capsules.

EXAMPLES The following non-limiting examples are provided with illustrative only and should not be construed as restrictions.

EXAMPLE 1 A liquid filling formulation, FO, is prepared as shown in Table I. TABLE 1 Formulation of liquid filling FO (mg / g) Component FO Celecoxib 278 PEG400 335 T een 80 197 Oleic acid 80 Hydroxypropylmethylcellulose ("HP C") 74 Propylgalate L 2 Dimethylaminoethanol ("DMAE") 34 Total 1000 EXAMPLE 2 Several suitable compositions are prepared for the preparation of the wall of a capsule, C1-C14, as shown in Tables 2 and 3, according to the following procedure. Gelatin and one of the sulfite compounds are mixed together to form a dry mixture. One or more plasticizers (glycerol and / or sorbitol) and water are then added to the mixture to form a liquid mixture. The liquid mixture is melted at 80 ° C for four hours to form a melt. The melt is cooled to 60% to form a fluid gelatine mixture and fed to two distributor boxes of a soft gelatin capsule manufacturing machine with rotating nozzle, which controls the flow of said mixture in two revolving rotating cylinders, where two white, opaque gelatin strips are melted and further processed into white opaque soft gelatin capsules, soft gelatin capsule, at a rate of approximately 15,000 capsules per hour; the capsules are filled with 1 ml of the filling Formulation F0 of Example 1. The capsules are then dried in a drum dryer with an air stream at 21 ° C and 20% relative humidity, and then brought to room temperature .

TABLE 2 Compositions C1-C7 for preparing the wall of a capsule (% by weight) TABLE 3 Compositions C8 - C14 for preparing the wall of a capsule (% by weight) Several comparative compositions (no sulfite compound), CC1 -CC7, as described above, are prepared with composition, which are set forth in Table 4.

TABLE 4 Comparative Compositions CC1 - CC7 for preparing the wall of a capsule (% by weight) The filled capsules are stored at 40 ° C and 75% relative humidity for up to 24 weeks. After 24 weeks of storage, each of the capsules is analyzed for film formation. In general, the capsules are prepared from the C1-C14 compositions (comprising a sulfite compound) which exhibit less film formation than the capsules prepared from the comparative compositions CC-1-CC7 (without sulfite compound) .

EXAMPLE 3 Two filler formulations, F1-F2, were prepared as shown in Table 5. One ml of each filling formulation was poured into each of the various standard soft gelatin capsules (without sulfite compound present in the wall) (RP Scherer).

TABLE 5 Composition of filling formulations F1 - F2 The filled capsules were placed in a sealed container and stored at 40 ° C and 75% relative humidity for a maximum period of 24 weeks. At different times during storage, the capsules were removed from the closed container and evaluated by visual inspection, to check for the presence or absence of film formation (i.e., cross-linking). Each evaluated capsule was assigned a numerical indicator based on any film observed according to the following scale: (1) = no film; (2) = thin film, incomplete; (3) = thin film, complete; (4) = strong, complete film that inhibits the compression of the capsule; and (5) thick, strong and rigid film. The film formation observations are shown in Table 6.

TABLE 6 Film formation after storage for a maximum of 8 weeks at 40 ° C and 75% relative humidity As shown in Table 6, the capsules containing the filler formulation F1 (comprising sodium metabisulfite in an amount of about 3% by weight of the filler) did not exhibit film formation during storage for a period of six months. months In contrast, the capsules containing the F2 fill formulation (without sulfite compound) exhibited film formation for 15 and 30 days of storage, respectively.

EXAMPLE 4 A composition of the invention is prepared by mixing in a container (a) 35% Boom Strength grade B, pharmaceutical grade gelatin; (b) 15% cooled glycerol; (c) 5% sodium thiosulfate; and (d) 45% deionized water cooled. The mixture is melted at 80 ° C for a maximum of four hours to form a melt. The melt is cooled to 60 ° C to form a fluid gelatine mixture and fed to two boxes distributors of a rotary nozzle soft gelatin capsule manufacturing machine, which controls the flow of said mixture to two rotating, air-cooled cylinders, where two white, opaque gelatin strips are melted and further processed to soft, opaque gelatin capsules , white, at a rate of approximately 15,000 capsules per hour. The capsules are then dried in a drum dryer with an air stream at 21 ° C and 20% relative humidity, and then brought to room temperature.

EXAMPLE 5 The cross-linking behavior of two soft gelatin formulations was investigated over a period of 6 months. As shown below (Table 7), Formulation 30 (the control batch) contains dimethylaminoethanol ("D AE") and does not contain sulfite. Formulation 19 (the test batch) was similar to Formulation 30, except that Formulation 19 additionally comprises sodium metabisulfite in the filler material.

TABLE 7 Filling material of Formulations 30 and 19 (mq / q) Both soft gelatin capsule formulations were placed in hydroxypropylethylene bottles sealed without induction and stored at 25% and 60% RH or at 40 ° C and 75% RH. Using said bottles, the RH inside the bottles is easily balanced with the RH outside the bottles (60% or 75%). Periodically, the capsules were tested for the degree of cross-linking of the soft gelatin samples, as estimated by the release profile of the drug.

Formulation 30 The results of the release of the Level 1 drug for control of Formulation 30 at 25 ° C / 160% relative humidity ("RH") and 40 ° C / 175% RH are shown in Figures 1 and 2 , and the results of the Level II drug release for the same batch and conditions are shown in Figures 3 and 4. In just one month of storage, there was a marked delay in the Level I drug release profile in both temperature conditions. This delay increased with storage time. The release profile of Level II drug at 25 ° C / 160% RH and at 40 ° C / 175% RH shows a significant but markedly reduced delay in the release profile.

Formulation 19 The results of the drug release of Level I of Formulation 19 for the condition of 25 ° C / 60% RH are shown in Figure 5. No change in the profile of drug release during the 6 months is observed. months, indicating that no cross-linking has occurred. Therefore, the analogous Level II test was not performed for this sample. Figure 6 shows the results of Level I for Formulation 19 at 40 ° C / 1 75% RH. No change in the release profile of the drug is observed during most of the stability time points with the exception of the 6 month time point. To determine if the change in the profile of drug release at 6 months is a consequence of cross-linking, the Level II test was performed on this sample. The results of Level II are shown in Figure 7. Level results I and Level II are very similar for this 6-month sample, indicating that the change in the release profile of the drug is not attributable to cross-linking. These data indicate that a rigorous cross-linking was observed in Formulation 30. The change in the Level II release profile (ie, reduced delay) indicates that the delayed release of Level I is the result of cross-linking for this formulation and also indicates that a significant delay in the release profile of the drug in humans would be likely. Formulation 19, which contains sodium metabisulfite, does not exhibit measurable cross-linking in 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 can actually completely inhibit crosslinking. Without wishing to be influenced by theory, it is believed that sodium metabisulfite inhibits crosslinking by a process in which sodium metabisulfite reacts with aldehydes that form a bisulfite addition product. Therefore, sodium metabisulfite can effectively purify aldehydes, making them available to promote cross-linking in gelatin.

EXAMPLE 6 Four formulations of soft gelatin Celecoxib were prepared, as shown in Table 8 and film formation was tested at 40 ° C and 75% relative humidity ("RH"). In the absence of sulfite, complete film formation was obvious after only 2 weeks of storage at 40 ° C / 75% RH (Formulation 30, cross-linking rating = 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 (crosslink rating = 3) after 1.5 months of storage at 40 ° C / 75% RH At a higher Tris concentration in the formulation (26 mg / g, Formulation 50), the crosslinking of the gelatin is completely prevented after 6 months of storage at 40 ° C / 75% RH. A concentration of reduced sodium metabisulfite (S B) of 4 mg / g in the formulation (Formulation 19) appeared sufficient to prevent film formation after 2 months of storage at 40 ° C / 75% RH.

TABLE 8 Analysis of soft gelatin crosslinking at 40 ° C / 75% RH EXAMPLE 7 In order to obtain an understanding of the mechanism by which Tris (hydroxymethylaminomethane) in the filling material of a gelatin capsule prevents film formation, a dosage form was prepared (of Formulation X-60 set forth in the 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 with time, the content of Tris in the capsules increased and the content of Tris in the filling material decreased as compared to the initial formulation.

TABLE 9 Formulation X-60 soft gelatin capsule TABLE 10 Content of Tris in capsule coatings after storage of Formulation X-60 Conditions of Tris in filling Tris in storage coating of the (mg) (mg) soft gelatine capsule 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 1 1 .1 T = 8 months 10.0 10.6 T = 10 months 10.0 13.3 26 mg of Tris in a soft gelatin capsule in T-0

Claims (31)

1. NOVELTY OF THE INVENTION CLAIMS 1. - A composition comprising gelatin and a pharmaceutically acceptable sulfite compound, the composition being suitable for the preparation of a pharmaceutical capsule coating. 2. - The composition according to claim 1, further characterized in that the sulfite compound is present in an amount effective to inhibit the crosslinking of the gelatin and / or the formation of film in a capsule coating prepared from the composition . 3. - The composition according to claim 1, further characterized in that the sulfite compound is selected from the group consisting of sodium metabisulfite, sodium thiosulfate and sodium bisulfite. 4. The composition according to claim 1, further characterized in that the sulfite compound is present in an amount of not more than about 10% of the composition based on dry weight. 5. The composition according to claim 1, further characterized in that the sulfite compound is present in an amount not greater than about 5% of the composition based on the dry weight. 6. - The composition according to claim 1, further characterized in that the sulfite compound is present in an amount not greater than about 2% of the composition based on the dry weight. 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 additionally comprises a plasticizer selected from the group consisting of polyhydric alcohols, polyhydric alcohol esters, dialkyl phthalates, lower alkyl citrates in which the lower alkyl has 1-6 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, glycerols, 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 methylparabens, propylparabens, butylparabens, sorbic acid, benzoic acid, editic acids, phenolic acids, sorbates and propionates. 1. 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 has the form of capsule coatings. 14. The composition according to claim 13, further characterized in that one of said capsule coatings defines a volume of filling. 15. The composition according to claim 13, further characterized in that the capsule coatings are soft gelatin capsule coatings. 16. - The composition according to claim 14 further characterized in that the filling 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 filling volume has a capacity not exceeding approximately 1 ml. 18. The composition according to claim 14, further characterized in that the capsule coatings are suitable for oral administration of a drug contained in the filling volume. 19. - A pharmaceutical dosage form comprising a sealed filling material in capsule coatings, wherein the Capsule coatings comprise a sulfite compound, and wherein said sulfite compound is present in an amount sufficient to inhibit gelatin cross-linking and / or film formation in capsule coatings upon 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 is self-emulsifying 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 material of The filler is present in an effective amount in combination with the amine agent in the capsule coating, to inhibit the crosslinking of the gelatin and / or film formation in the capsule coating 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 present in an effective amount in combination with the amine agent in the coating the capsule to inhibit crosslinking and / or film formation in the capsule coating 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 cyclooxygenase 2 inhibitor drug. 27. The dosage form according to claim 26, further characterized by the selective inhibitory drug. of the cyclooxygenase 2 is a compound of the formula (I) wherein: A is a substituent selected from partially unsaturated or unsaturated heterocyclyl and partially unsaturated or unsaturated carbocyclic rings, preferably a heterocyclyl group selected from groups pyrazolyl, furanonyl, isoxazolium, pyridinyl, cyclopentenonyl and pyridazinonyl; X is O, S or CH2; n is 0 or 1; 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, hydroxyl, hydroxyalkyl, haloalkoxy, amino, alkylamino, arylamino, nitro, alkoxyalkyl, alkylsulfinyl, halo, alkoxy and alkylthio; R 2 is methyl, amino or aminocarbonylalkyl; R3 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, aminocarbonyl, aminocarbonyl, alkylaminocarbonyl, N-arylaminocarbonyl, N-alkyl-N-arylaminocarbonyl, alkylaminocarbonylalkyl, carboxilaquilo, alkylamino, N-arylamino, N-aralkylamino, 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, al Quilaminosulfonyl, N-arylaminosulfonyl, Arylsulfonyl and N-alkyl-N-arylaminosulfonyl, wherein R 3 is optionally substituted in a substitutable position with one or more radicals selected from alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl, hydroxylalkyl, haloalkoxy, amino, alkylamino, arylamino, nitro, alkoxyalkyl, alkylsulfinyl, halo, alkoxy and alkylthio; and R4 is selected from hydrido and halo. 28. - The dosage form according to claim 26, further characterized in that the selective drug cyclooxygenase-2 inhibitor is selected from the group consisting of celecoxib, deracoxib, valdecoxib, rofecoxib, etoricoxib, 2- (3,5-difluorophenyl) ) -3- [4- (Methylsulfonyl) phenyl] -2-cyclopenten-l-one, 2- (3,4-difluorophenyl) -4- (3-hydroxy-3-methyl-1-butoxy) -5- [ 4- (methylsulfonyl) phenyl] -3- (2H) -pyridazinone and its pharmaceutically acceptable salts and prodrugs. 29. - The dosage form according to claim 26, further characterized in that the selective drug cyclooxygenase 2 inhibitor is celecoxib. 30. - The dosage form according to claim 24, further characterized in that the filler material additionally comprises at least one substance that promotes the crosslinking of gelatin when in contact with it, said substance being the drug or an excipient substance , and said substance acting independently or in combination with one or more other substances to promote said crosslinking. 31 - The dosage form according to claim 30, further characterized in that it comprises a first and a second of said capsule coatings, said first and second capsules being second coatings of substantially identical capsules; wherein after (a) testing a first capsule coating in a first dissolution test in vitro; (b) storing a second capsule coating in a closed container maintained at 40 ° C and 85% relative humidity for a period of four weeks and, after said storage; (c) testing the second sealed capsule coating in a second in vitro dissolution test substantially identical to the first in vitro dissolution test; the amount of drug dissolved in 45 minutes in the second dissolution test is within ± 15 percent of the amount of drug dissolved in 45 minutes in the first dissolution test, and in which the first in vitro dissolution test takes performed within a reasonably short period of time after preparation of the composition. 32 - The dosage form according to claim 19, further characterized in that it further comprises (a) at least one excipient selected from the group consisting of decomposition inhibitors, opacifying agents and preservatives; and (b) a plasticizer selected from the group consisting of sorbitol, glycerols, propylene glycols and polyethylene glycols; wherein the sulfite compound is selected from the group consisting of sodium metabisulfite, sodium thiosulfate and sodium bisulfite; and wherein the sulfite compound is present in an amount of not more than about 10% of the composition based on dry weight. 33 -. 33 - The dosage form according to claim 32, further characterized in that the filling material further comprises celecoxib in an amount of about 10 to about 400 mg.