Title of Invention


Abstract A process for preparing a pharmaceutical composition in fast-dispersing dosage form having an active ingredient and fish gelatin carrier comprising the step of forming a network of the active ingredient and fish gelatin carrier by subliming a conventional solvent from an admixture in the solid state in which the admixture comprises the active ingredient, the carrier and a solvent for the carrier.
Full Text Technical Field
This invention relates to pharmaceutical compositions. In particular the invention relates to freeze-dried fast-dispersing dosage forms containing fish gelatin
Background of the Invention
Fast-dispersing dosage forms which are designed to release the active ingredient in the oral cavity are well known and can be used to deliver a wide range of drugs Many such fast-dispersing dosage forms utilize gelatin as a carner Gelatin B P , which is normally utilized in such formulations, is defined as a protein obtained by partial hydrolysis of animal collagenous tissues such as skin, tendons ligaments and bones, with boiling water However, such mammalian derived gelatin has an unpleasant taste and thus necessitates the use of sweeteners and flavors in such fast-dispersing dosage forms to mask the taste of the gelatin in addition to any sweeteners and flavors which may be required to mask the taste of the active ingredient Moreover, when conventional mammalian derived gelatin is used in tne production of such fast-dispersing dosage forms, it is necessary to heat the gelatin solution to 60°C in order to effect solution This heating step increases processing times and incurs heating costs thereby increasing the overall costs of the process
US Patent No 5,120 549 to Gole et al discloses a fast-dispersing matnk system which is prepared by first solidifying a matrix-forming system disoersed in a first solvent and subseauenty contacting the solidified matnx with a second solvent ihat is substantially miscible with the first solvent at a temperature lower chan the solidification point of the first solvent, the macn\ forming elements and active ingredient being substantially insoluble in the second solvent, whereby the first solvent is substantially removed resulting in a fast-dispersing matrix
US Patent No 5,079,018 to Ecanow discloses a fast-dispersing dosage form which comprises a porous skeletal structure of a water soluble, hydracable ge! or foam forming material that has been hydrated with water, ngidified in the hydrated state with a ngidifying agent and dehydrated with a liquid organic solvent at a temperature of about 0°C or below to leave spaces in the place of the hydration liquid
Published International Application No WO 93/12769 (PCT/JP93/01631) describes fast-dispersing dosage forms of very low density formed by gelling, with agar, aqueous systems containing the matrix-forming elements and active ingredient, and then removing water by forced air or vacuum drying
US Patent No 5,298 261 to Pebley et al discloses fast-dispersing" dosage forms which comprise a partially collapsed matrix network that has been vacuum aned above the collapse temperature of the matrix. However, the matm is preferably at lease partially dried below the equilibrium freezing point of the matrix
Published International Application No WO 91/04757 (PCT/XJS90/05206) discloses fasc-dispersing dosage forms which contain an effervescent disintegration
agent designed co effervesce on contao with sanva to provide rapid disintegration of the dosage form and dispersion of the active ingredient in the oral cavity
US Patent No 5,595 761 to Allen Jr et al discloses a paniculate suopon matrix for use in making a raoidly dissolving tablet, comprsing a first polypeptide component having a net charge when in solution, e g non-hydrolyzed gelatin, a second polypeptide component having a net charge of the same sign as (he net charge of the firsv polypeptide component when in solution e g hydrolyzed gelatin, and a bulking agent, and wherein the first polypeptide component and the second polypeollde component together comprise about 2% to 20% by weight of the paniculate suppon matrix and wherein the bulking agent comprises about 60% to 96% by weight of (he paniculate suppon matrix, and wherein the second polypeptide component has a solubility in aaueous solution greater than that of the first polypeptide component and wherein the mass to mass ratio of the first polypeptide component to the second polypeptide component is from about 2 1 to about I 14, and wherein when the support matrix is introduced into an aqueous environment the suppon matrix disintegrates within less than about 20 seconds
EP 0 690 74-7 BI to Nguyen et al describes panicles comprising an excipient forming a matrix and at least one active ingredient uniformly distributed in the mass of the matrix which are Drepared by a process comprising the steps of preparing a homogenous pasty mixture with a viscosity below \ Pa s measured at room temperature (15-208C), at least one active ingredient, a physiologically acceptable hydrophilic excipient and water, extruding the resulting homogenous mixture and
cutting the excruciate to give moist parucles, freezing the resulting panicles as they fall under gravity through a stream of inert gas at a temperature below 0°C and drying the panicles by freeze drying
Australian Patent No 666 666 discloses a rapidly dismtegracable multiparticulate cablet having a mixture of excipiences in which the active substance is present in the form of coaced microcrystals or optionally coated microgranules Such tablets are thought to disintegrate in the mouth typypically less than 60 seconds
U S Patent No 5,382,437 to Ecanow discloses a porous carner material having sufficient rigidity for carrying and administering an active agent which is capable of rapid dissolution by saliva The porous earner material of Ecanow ts formed by freezing a liquified ammonia solution comprising liquid ammonia, liquid ammonia soluble gel or foam matenal, and a ngidifying agent for the gel or foam material selected from the group consisting of a monosaccharide, a polysaccharide and combinations thereof, and deammomaung the frozen materia! thus formed, by causing material transfer of ammonia from the frozen srate to the gas state thereby leaving spaces in the carrier material in place of the frozen ammonia
Published International Application No WO 93/13753 (PCT/US92/07497) desenbes tablets of increased physical strength which are prepared by combining and compressing a meltable binder excipiencs and a pharmaceutically active agent into a tablec, melting the binder into the tablet and then solidifying the binder In one embodiment a disintegrating agent is utilized lo increase the disintegration rate of the tablet after oral intake In another embodiment, a volanzable component is used to
form porous cablets Some emobodiments disintegrate in the mouth in less chan 10 seconds
US Patent No 3 385,026 to Heinemannet al and U S Patent No 4, 164,943 to Knitscn et al also disclose fasi-dispersmg porous tablets and a method for increasing their physical strength by first comoressmg the tablet and then volatilizing a readily volanhzable solid adjuvant incorporated in the tablet to attain the aesired porosity
Published International Application No WO 94/14422 describes a process for drying frozen discrete units tn which the solvent is removed under conditions whereby the solvent is evaporated from the solid through the liquid phase io a gas, rather chan subliming from a solid to a gas as in lyophilization This is achieved by vacuum drying at a temperature below che equilibrium freezing point of the composition at which pome the solvent (such as water) changes phase
While che prior an is replete wuh methods and techniques for the preparation of rapidly dispersing dosage forms, it has failed to consider che benefits associated with the use of fish gelatin, especially non-gelling, non-hydrolyzed fish gelatin, in such dosage forms The pharmaceutical indusxry would be able to avoid the use of mammalian derived gelatin due to taste considerations Thus, there exists the need for improved fasi-dispcrsing dosage forms which are designed to quickly release the active ingredient in the oral cavit chat avoid the use of mammalian derived gelatin
Summary of the Invention
It has now been found that many of the problems associated with the use of mammalian-denved gelatin can be overcome if fish gelatin, especially non-gelling fish gelatin, is utilized for preparing fasc-dispersmg dosage forms Surprisingly, the non-gelling form of fish gelatin from sources such as cold water fish can be advantageously used in rapidly disintegrating dosage forms Moreover, a number of further advantages have been identified in terms of processing paramefers and the qualities of the resultant producl
The present invention discloses a pharmaceutical composition comprising a carner and an active ingredient (e g , drug, compound, and the like) wherein the earner is fish gelatin and the composition is in the form of a fast-dispersing dosage form which releases the active ingredient rapidly on contact with a fluid (c g , saliva, bodily fluids, water, and the like) Preferably, the composition is designed for oral administration and releases the active ingredient rapidly in the oral cavity In another embodiment, the composition can be applied topically for instance, to wee skin, or dispersed or dissolved in a liquid pnor to topical or oral administration
The invention also discloses a process for preparing fast-dispersing dosage forms by freeze-drying or lyophilizing a combination of the active ingredient and fish gelatin (e g , non-gelling fish gelatin)
The invention further includes a method of using fish gelatin (e g , non-gelling fish gelatin) in pharmaceutical compositions in fast dispersing dosage form, and m particular, freeze dned fast-dispersing dosage forms
[n a preferred embodiment the comoosition of the invention is a solid fast dispersing dosage form containing a network, of che active ingredient ana a j/acer-soluble or water-aisoersible earner compnsing fish gelatin (e g non-gelling fish gelatin), the network having been obtained by subliming solvent from a composition in the solid state containing the active ingredient and a solution or dispersion of the earner in a solvent
The fish gelatin used in accordance with cite invention is preferably obtained from cold water fish sources and is the non-gelJing type of fish gelatin More preferably, the non-hydrolyzed form of non-gelling fish gelatin is used In an alternative embodiment, spray-dned non-hydrolyzed non-gelling fish gelatin can be used
Detailed Description of the Invention
The phxase "fast-dispersing dosage form" refers to compositions which disintegrate or disperse within 1 to 60 seconds, preferably I to 30 seconds, more preferably 1 to 10 seconds and particularly 2 to 8 seconds, after being placed in contacc with a. fluid," The fluid is preferably that found in the oral cavity, i e , saliva, as with oral administration In a general context the phrase encompasses all the previously mentioned dosage forms described herein as well as any other equivalent dosage form
In a preferred embodiment, the compositions of che invention are solid fast-dispersing dosage forms compnsing a solid network of the active ingredient and a
water-soluble or water -disperstole earner concaining fish gelatin Accordingly, the came is inert towards the active ingredient The network, is obtained bv subliming solvent from a composition m the solid state the composition comprising che active ingredient and a solution oftne earner in the solvent Tne dosage forms according to che invention can be prepared according to tne process disclosed in Gregory et al, UK Patent No 1,548,022 using fish gelatin as the earner
Accordingly, an initial composition (or admixture) comprising the active ingredient and a solution of the fish gelatin earner in a solvent is prepared followed by sublimation The sublimation is preferably earned out by freeze drying che composition The composition can be contained in a mold during the freeze-arymg process to produce a solid form in any desired shape The mold can be cooled using liquid nitrogen or solid carbon dioxide m a preliminary step pnor to the deposition of the composition therein. After freezing the mold and composition, they are next subjected to reduced pressure and, if desired, controlled application of heat to aid in sublimation of solvent The reduced pressure applied in the process can be below about 4 mm Hg, preferably below about 0 3 mm Hg The freeze dned compositions can then be removed from the mold if desired or stored therein until later use
When che process is used with active ingredients and fish gelatin as the earner, a solid fast-dispersing dosage form is produced having the advantages associated with the use of fish gelatin described herein Generally, fish gelatin is categonzed as being from cold water and warm water fish sources and as being of the gelling or non-gelling vanety The non-gelling vanety of Fish gelaun, in companson to gelling fish
gelatin and boMne gelatin, contains lower proline and hydroxyprolme ammo acid content which arc known to be associated with cross-linking properties and gelling ability Non-gelling fish gelatin can remain at solution concentrations of UD to about 40% as well as in cemperacures as low as 20° C The fish gelatin used in accordance with the invention is preferably obtained from cold water fish sources and is the non-gelling type of fish gelatin More preferably, che non-hydroIyzed form of non-gelling fish gelatin is used In an alternative embodiment, spray-dned non-hvdrolyzed non-gelhng fish gelatin can be used Fish geiacins suitable for use in che invention can be obtained from Croda Colloids Ltd (Chestre, England), for example
(Table Removed)
Despite the comparatively lower oroline and hvdrcuyproline concent and other differences in non-gelling fisn ge"aun as compared to gelling fish gelatin and bovine gelatin, non-gelling fish gelatin can be successfully used in a matrix for preparing fast-dispersing dosage forms in accordance with the invention
The composition according co the invention can also contain, in addition to the active ingredient and fish gelatin earner other matrix forming agents and secondary components Matrix forming agents suitable foruse in the present invention include materials derived from animal or vegetable proteins, such as other gelatins, dectirins and soy, wheat and psyllium seed proteins, gums such as acacia, guar, agar and xanthan, polysaccharides, alginates, carboxymethylcelluloses, carrageenans, dextrans, pectins, synthetic polymers such as polyvinylpyrrolidone, and polypeptide/protem or polysaccharide complexes such as gelatin-acacia complexes
Other materials whicn may also be incorporated into the composition of the presenc invention include sugars such as mannitol, dextrose, lactose, galactose, and trehalose, cyclic sugars such as cyclodextnn, inorganic salts such as sodium phosphate, sodium chloride and aluminum silicates, and ammo acias having from 2 to 12 carbon atoms such as glycine, L-alanine, L-aspartic acid, L-glutamic acid L-hydroxyprohne, L-isolaucine, L-leucme and L-phenylalamnc
One or more matrix forming agents may be incorporated into the solution or suspension prior to solidification (freezing) The matrix forming agent may be present in addition to a surfactant or lo the exclusion of a surfactant In addition to forming the matrix, the matrix forming agent may aid in maintaining the disoersion of
any active ingredient within the solution of suspension This is especially heloful in the case of active agents that are not sufficient^ soluble in water and must therefore, be suspended rather than dissolved
Secondary components such as preservatives, antioxidants surfactants, viscosity enhancers, coloring agents, flavoring agents, pH modifiers, sweeteners or taste-masking agents may also be incorporated into the composition Suitable coloring agents include red black and yellow iron"oxides and FD L C dyes such as FD&C Blue No 2 and FD &.C Red No 40 available from Ellis & Everard Suitable flavoring agents include mint raspberry, licorice, orange, lemon, grapefruit, caramel, vanilla, cherry and grape flavors and combinations of these Suitable pH modifiers include the edible acids and bases, such as citric acid, tartaric acid, phosphoric acid, hydrochloric acid, maleic acid and sodium hydroxide Suitable sweeteners include aspartame, acesulfame K and thaumatin Suitable taste-masking agents in include sodium bicarbonate, ion exchange resins, cyclodextnn inclusion compounds, adsorbates or microencapsulated actives
A variety of drugs can be can be used as the active ingredient in the composition of the p"resent invention, including but not limited to analgesics and antiinflammatory agents, antacids, anthelmintics anti-arrhythmic agents, anti-bactenal agents, anti-coagulants, anti-depressants, anti-diabetics, anti-diarrheals, anti-epileptics, anci-fungal agents, anti-gout agents, anti-hypenensive agents, antimalarials, anti-migraine agents, anci-muscannic agents, anti-neoplastic agents and immunosuppressants anti-protazoal agents, anti-rheumatics, anti-thyroid agents
antivirals, anxiolytics sedatives hypnotics and neuroleptics, beta-blockers, cardiac inotropic agents, corticosteroids cough suppressants, cytotoxics, decongestants, diuretics, enzymes, anti-parkinsonian agents, gastro-intestinal agents, histamine receptor antagonists, lipid regulating agents, local anesthetics, neuromuscular agents, nitrates and anti-anginal agents, nutritional agents, opioid analgesics, oral vaccines, proteins, peptides and recombinant drugs, sex hormones and contraceptives, spermicides, and stimulants Specific examples of these drugs are found below
Analgesics and anti-inflammatory agents aloxiprin, auranofin, azapropazone, benorylate, diflunisal, etodolac, fenbufen, fenoprofen calcum, flurbiprofen, ibuprofen, indomethacin, ketoprofen, meclofanamic acid, mefenamic acid, nabumetone, naproxen, oxaprozin, oxyphenbutazone, phenylbutazone, piroxicam, sulmdac
Antacids aluminum nydroxide, magnesium carbonate, magnesium crisilicate, hydrotalcite, dimethicone
Anthelmintics albendazole, bephenium hydroxynaphthoate, cambendazole, dichlorophen, ivermectin, mebendazole, oxamniquine, oxfendazole, oxantel embonare, praziquantel, pyrantel embonate, thiabendazole
Anti-arrhvthmtc agents amiodarone HC1 disopyramide, flecainide acetate, qunidine sulphate
Anti-bactenal agents benethamme penicillin, cmoxacin, ciprofloxacin HC1, clarithromycin, clofazimine, cloxacillin, demeclocyclme, doxycychne, erythromycin, ethionamide, imipenem, nalidixic acid, nitrofuranto in, rifampicin, spiramycin,
sulphabenzamide, sulphadome sulphamerazme, sulphacecamide, sulphadiazine, sulphafurazole, sulphamechov azole, sulohapyndine, tetracycline tnmechoprim
Anti-coagulants dicournarol dipyridamole, incoumalone, phenindione
Anti-depressants amo caspine, ciclazmdol, maprocilme HCl mianserin HCl, nortriptyline HCl, trazodone HCl, inmipramionme maleate
Ami-diabetics acetohe\£mide, chlorpropamide, glibenclamide, sliclaziae, glipizide, tolazamide, tolbutamide
Antt-diarrheals codeine phosphate, co-phenocrope, loperamide hydrochloride, suphasolazine, mesalaztne, olsalazine, corticosteroids, prednisolone
Anti-epileptics beclamice, carbamazepine, clonazepam, echotoin, mechoin, mechsuxirmde, methylphenobarbuone, oxcarbazepme, paramethadione, phcnacemide, phenobarbitone, phenyxoin, phensuximide, primidone, sulthiame, valproic acid
Anti-fungal agents amphotericin, butoconazole nitrate, cloenmazole, econazole nitrate, fluconazole, flucytosine, gnseofuivin, itraconazole, ketoconazole, miconazole, nacamycm, nystatin sulconazole nitrate, terbmafine HCl, terconazole, cioconazole, undeccnoic acid
Anti-gout agents allopunnol, probenecid, sulphmpyrazone Anti-hypenensive agents amlopidme, bemdipine, darodipine, dilitazem HCl, diazoxide, felodipme, guanabenz acetate, indoramin, isradipine, minoxidil, nicardipine HCl, nifedipine, nimodipine, phenoxybenzamme HCl, prazosin HCl, reserpine, terazosin HCl
Anti-malanals amodiaquine chloroquinc, chloroproguanil HCI, halofantnne HCI, mefloquine HCI proguanil HCI, pynmchamme, quinine sulphate
Anti-migrane agents dihvdroergocamme mesylate, ergotamine tartrate mechysergide maleace, pizotifen maleate, sumatriptan succinate
Anti-muscannic agents atropine benzhecol HCI, bipenden, ethopropazine HCI, hyoscine butyl bromide, hyoscyamine, meoenzolaie bromide orphenadnne, oxyphencylcimine HCI, trapicamide
Anci-negolastic agents and Immunosuppressants aminoglutethimide, amsaenne, azathioprene, busulphan, chlorambucil, cyclosporin, aacarbazine, escramuscine, etoposide, lomustme, melphalan, mercaptopunne, methotrexate, mitomycin, mitocane, intozamrone, procarbazine HC1, tamoxifen citrate, testolactone
Anti-protazoal agents benznidazole, choqumol, decoqumate, duodohydraxyquinohne, diloxanide furoats, dirutolmide, furzolidone, metronidazole, nimorazole, nitrofurazone, omidazole, tinidazole
Anti-rheumatics ibuprofen, aceclofenac, acemecacin, azapropazone, diclofenac sodium, diflunisal, etodolac, ketoprofen, mdomethacm, mefenamic acid, naproxen, ptroxicam, aspirin, benorylate, auranofin, penictllamine
Anti-thyroid agents carbimazole, propylthiouracil Antivirals acyclovir, amantadine hydrochloride, famciclovir, zidovadine, didanosine, zalcuabtne, foscamet sodium
Anxiolytic sedatives hypnotics and neuroleptics alprazolam, amylobarbitone, barbitone bentazepam, bromazepam, brompendol, brotizolam.
butobarbitone carbromal, cnlordiazcpoxide, chlormethiazole chlorpromazine clobazam clonazepam clozapine, diazepam, dropendol, ethinamate, flunamsone, flunicrazepam fiuoDromazine fiupenthixol decanoace, fluphenazme decanoate, flurazepam, halopendol, lorazeoam, lormetazepam, medazeparn, meprobamate mechaqualone, midazolam nitrazepam, oxazepam, pentobarbitone, perphenazine pimozide, prochlorperazine, sulpnde, cemazepam, thioridazine cnazolam zop"done
ß-Blockers, acebutolol, alprenolol, atenolol, labetajol, metoprolol, nadolol, oxprenolol, pindolol, propanolol
Cardiac inotropic agents amnnone, digitoxin, digoxin enoximone, lanatoside C, medigoxin
Corticosreroids beclomethasone, betamethasone, budesomde, cortisone acetate, desoxymediasone, dexamethasone, fludrocortisone acetate, flunisohde, flucortolone, fluticasone propionate, hydrocortisone, rnethylprednisolone, prednisolone, prednisone, tnamcmolone
Cough suppressants coaeme phosphate, pholcocune, diamorphine, methadone
Cytotoxics ifosfamide, chlorambucil, melphalan, busulphan, cytotoxic antibodies doxorubicin, epirubicin, plicamycm, bleomycin, methotrexate, cvtarabme, fludarabine, gencnabme, fluorouracil, mercaptopunne, chioguarune, vincristine, vinblastine, vindesme, etoposide
Decongestants pseudoephednne hydrochlonde
Drurecics acecazolamide amilonde bendrofluazide, bumetanide, chlorothiazide chlorthalidone ethacp/nic acid frusemide, metolazone, spironolactone, triamterene
Enzvmes pancreaun, pepsin, lipase
Anti-oarkmsoman agents bromocriptine mesylate, lysunde maleace, selegiline, para-fluoroselegiune, lazabemide, rasagilme, 2-BUMP (N-(2-butyl)-N-mechylpropargylamine], M-2-PP [M-methyl-N-(2-pentyl)-propargylamine], MDL 72145 [beta-(fluoromethylene)-3,4-dimethoxy-benzeneethanamine], rnofegiline, apomorphine, N-propylnoraporphine, cabergohne, metergohne, naxagolide, pergohde, pinbedil ropinirole, tergunde, qumagohde
Gastro-intestinal agencs btsacodyl, cimeudme, cisapride, diphenoxylate HO, dompendone, famotidine, loperamide, mesalazme, nizatidine, omeprazole, ondansetron HC1, ranitidine HCl, sutohasalazine
Histamine Receptor Antagonists acnvastine, astemizole, cinnarizine, cyclizine, cyproheptadine HCl aimeahydnnatc, fJunanzme HCl, loracadine, meclozine HCl, oxatomidc, terfenadine, tnprohdme
Lipid regulating agents bezafibrate, clofibrace, fenofibrate, gemfibrozil, probucol
Local anaesthetics amethocainc, amylocaine, benzocaine, bucncame, bupivacame, butacaine, butamlicame, butoxycaine, butyl aminobenzoate, carticaine, chloroprocaine, cinchocaine, cltbucaine, clormecaine, coca, cocaine, cyclomcthycame, dimethisoquin, diperodon, dyclocaine ethyl chloride, ethyl p-
pipendinoacetvlaminobenzoate eudocaine, hexylcaine, isobuiamben kstocaine, Itgnocaine mepivacaine rneon/kaine myrtecame, octacame, oxethazame, oxybuprocaine, parethoxycaine, pramoxtne, pnlocame, orocame, prooranccaine propoxycame, proxymetacame, rooivacaine, calycame, incaine, tnmecaine, vadocame
Neuro-muscular agents pynaosngmine
Nitrates and ocher anci-angmal agents argyl ni trate, glyceryl trinitrate, isosorbide dmurate, isosorbide mononitrate, pentaerythntol tetramtrate
Nutritional agents betacarocene, vitamins, such as vitamin A, vitamin BZ, vitamin D, vitamin E, vitamin K, minerals
Opioid analgesics codeine, dextropropyoxyphene, diarnorphme, dihydrocodeine, meptazmol, methadone, morphine, nalbuphine, pentazocine Oral vaccines to prevent or reduce che symptoms of diseases such as Influenza, Tuberculosis, Meningitis, Hepatitis, Whooping Cough, Polio, Tetanus, Diphtheria, Malaria, Cholera, Herpes, Typhoid, HIV, AIDS, Measles, Lyme disease. Traveller"s Diarrhea, Hepatitis A, B and C, Otitis Media, Dengue Fever, Rabies, Parainfluenza, Rubeila, Yellow Fever, Dysentery, Legionnaires Disease, Toxoplasmosis, Q-Fever, Haemorrhegic Fever, Argentina Haemorrhegic Fever, Canes, Chagas Disease, Urinary Tract Infection caused by E coll. Pneumococcal Disease, Mumps, Chikungunya, Hayfever, Asthma, Rheumatoid Arthritis, Carcinomas, Coccidiosis, Newcastle Disease, Enzootic pneumonia, Felme leukemia, Atrophic rhinitis. Erysipelas, Foot and Mouth disease and Swine pneumonia, or to
prevent or reduce the symptoms of diseases caused by Vibno species Salmonella species Bordetella species Haemoph"lus species, Toxoplasmosis gondii Cytomegalovirus, Chiamyoia species Streptococcal species, Norwalk. Virus Eschenscnia coli Helicobacter pylon, Rotavirus Neisseria gonorrhae Neissena meningidms, adenovirus, Epstein Ban Virus, Japanese Encephalitis Virus, Pneumocvsns canni Herpes simples, Clostridia species, Respiratory S^ncyna! Virus, Klebsiella species Shigella species, Pseudomonas aeruginosa, Parvovirus, Campylobacter species, Rickettsia species, Varicella zoster, Yersinia species, Ross River Virus, J C Virus, Rhodococcus equi, Moraxella cacarrhahs, Borreha burgdorferi and Pasteurella haemolytica
Proteins peptides and recombinant drugs, recombinant hormones and ISO-hormones, recombinant cytokines, recombinant plasminogens, TNF receptor fusion protein, monoclonal antibodies, nucleic acids, antisense oligonucleotides, oligonucleotides, glycoproteins and adhesion molecules
Sex hormones and Contraceptives clomiphene citrate, danazol, desogesxrel, ethinyloestradiol, ethynodiol, ethynodiol diacecate, levonorgestrel, medroxyprogesterone acetate, mestranol, rnechyltestosterone, norethisterone, norethisterone enanthate, norgestrel, estradiol, conjugated estrogens, progesterone, stanozolol, stilboestrol, testosterone, tibolone
Spermicides nonoxynol 9
Stimulants amphetamine, dexamphetamine, dexfenfluramine, fenfluramine, mazmdol, pemoline
The precise quancitve of active ingredient will vary accorame to the particular drug selected and the patten" s needs However, tne active ingredient can be generally present in an amount from aoout 0 2% to about 95%, typically from about 1% to about 20% by weighc of the composition of the dried dosage form The invention is further illustrated by the following Examples
Preparation of a Placebo Fast-Dispersing Dosage Form using Fish Gelatin Spray-dried fish gelatin (4 gj and mannitol (3 g) were added to a glass beaker Punfied water (93 g) was then added and solution effected by stirring using a magnetic follower No heating was required A Gilson pipette was then used to deliver 500 mg of this solution into each one of a series ofpre formed blister pockets having a pocket diameter of about 16 mm The blister laminate comprised PVC coated wuh PVdC The dosed units were then frozen at a temperature of—110° C in a freeze tunnel with a residence time of 3 2 minutes and the frozen units were then held in an upright freezer for a time greater than 1 5 hours at a temperature of-25° C (±5° C) The units were then fresze-dnec overnight with an initial shelf temperature of-10° C nsing to +20" C at a pressure of 0 5 mbar The units were checked for moisture pnor to unloading by the drying trace and by the pressurized moisture check The resultant units had the following composition
(Table Removed)

* signifies removal during cne lyopruhzacion process "" EP = European Pharmacopoeia USP = United States Pharmacoooeta
Preparation of a Placebo Fast-Dispersing Dosage Form using Alkaline Bovine Hide Gelatin
Alkaline bovine hide gelatin (4 g) was added to punfiea water (93 g) in a glass
beaker and evenly heated to 60° C while constantly stirring with a magnetic follower
Care was taken to ensure that all the gelatin had dissolved The mix was then cooled
to a temperature of 25° C by means of a water bath before the addition of mannitol (3
g) Whan the mannitol had dissolved stirring was continued for I hour at ambient
conditions This solution was then dosed into blister pockets, frozen, stored and
free2e-dned as described in Example 1 above The resultant units had the following

(Table Removed)

"signifies removal during the lyopnilization process

The following additional comparative examples were prepared using the process described in Comparative Example A
Preparation of a Placebo Fas.t-Disaersing Dosage Form using Pig Skin Gelatin
A fast-dispersing dosage form using pig skin gelatin was prepared in a manner
similar to that found in Comparative Example A, and the resultanc units had cne
following compositions
(Table Removed)

* signifies removal during (he Ivoohilaanon process
Preparation of a Placebo Fast-Dispersing Dosage Form using Limed Hide Gelatin
A fast-dispersing dosage form using limed hide gelatin was prepared in a
manner similar to chat found in Comparative Example A, and the resultant units had
the following composition

(Table Removed)

* signifies removal during die lyoDhihzauon process
Comparative Tensile Strenth and Dispersion Testing
The units produceo in Example 1 ana the Comparative Examples A tarougn C were subjected to tensile strength and disintegration tests according to methods conforming to (he USP monograph requirements An additional dispersion test was also earned out to identify any subtle differences which may not be apparent from the disintegration test.
The dispersion test was performed by,adding 500 ml volume of purified water into a glass beaker The water was then heated to a temperature of 37° C The units were carefully drooped onco the surface of the water and the time taken to fully disperse noted The water was then changed for subsequent unit testing
The units produced in Example I exhibited a disintegration time of 0 85 seconds and gave a mean tensile strength value of 0 267 N mm " In contrast, the units produced in Comparative Example A exhibited a disintegration time of 4 28 seconds and had a mean tensile strength value of 0 408 N mm 2 The disp"ersion test confirmed these results The units produced in Comparative Examples B and C exhibited a mean tensile strength of 0 407 U mm 2 and 0 433 N mm 2 respectively In addition, it was noted that the units produced tn Example 1 had no unpleasant smell or taste and a better mouth-feel than the units produced
the Comparative Examples
In particular, the units of Comparative Examples B and C were slow 10 disperse and had a gummy mouth-feel
It is apparent from cne above chat fast-disoersmg dosage forms produced using fish gelatin have a numoer of advantages over those produced using mammalian-denved gelatin For instance, such dosage forms containing fish gelatin have a faster disintegration time, a better caste and a becter moudvfeel than dosage forms containing mammalian derived gelatin Moreover, there is no need for sweeteners and flavors to be added to mask the taste or smell of the gelatin since fish gelatin has an acceptable taste and smell Thus, although some sweeteners and flavors may still be required co mask the taste of an unpalatable active ingredient, the overall quantity of sweeteners and flavors can be greatly reduced with attendant cost benefits In addition, since fish gelacin is soluble in cold water the heating step, which is required when mammalian denved gelatin is used, can be omitted thereby productng cost savings in heating costs and shorter mixing times The overall process is therefore more controllable when fish gelacin is used in olace of mammalian denved gelatin The following examples further exemplify formulations which can be prepared using the process described in Example I.
Fast-Dispersing Dosage Form using. Fish Gelatin with Dextromethorphan as the Active Ingredient

(Table Removed)

" signifies removal during the lyaohilizatjon process , " USNF " United Scares National Formulary
A mean Tensile strength value of 0 206 N mm2 was obtained for these dosage forms, with a disintegration time of 0 78 seconds
Fast-Dispersins Dosage Form using Fish Gelatin

(Table Removed)
" signifies removal during the lyopmlizacion process
These units had a mean Tensile strength value of 0 269 N mm2 with a disintegration time of under 2 seconds
Testing of "Gelling" Fish Gelatin
A formulation containing "gelling" fish gelatin was prepared ana evaluated for disintegration time and mouin feel Gelatin, mannitol and ounfied water were weighed into plastic vessels The gelatin and mannuol were added 10 the vortex of continually stirred purified water, and the mixture was heated to a temperature of 60°C in order to effect solution of t.he gelatin Once dissolved, the solution was then cooled to a temperature of about 23 4° C prior to dosing All quo cs of 500 mg were dosed into pre-formed blister pockets and frozen, stored and freeze-dned
A total batch of 100 grams was prepared containing the following formulation
(Table Removed)
The dosage forms were analyzed for disintegration time and mouth feel Disintegration time of the samples was measured according to USP methods The samples had disintegration times of greater than 5 seconds The mouth feel of the samples was found to be slow to disperse, "gummy " in nature, and overall unsatisfactory.
Industrial Applicability
The pharmaceutical industry is constantly searching for improved dosage forms chat are economical to produce and avoic problems associated with mammalian gelatin Tne cosage forms according to the presenc indention addresses tnese needs and does so with superior results
The invention has been aescnbed with reference co various specific and preferred embodiments and techniques However, it should be understood that many variations and modifications can be made while remaining within the spine and scope of the invention.


1. A process for preparing a pharmaceutical composition in fast-dispersing dosage form having an active ingredient of the kind such as herein described and fish gelatin carrier comprising the step of forming a network of the active ingredient and fish gelatin carrier by subliming a conventional solvent from an admixture in the solid state in which the admixture comprises the active ingredient, the carrier and a solvent for the carrier.
2. A process for preparing a pharmaceutical composition as claimed in claim 1, wherein the composition disintegrates within 1 to 60 seconds of being placed in contact with fluid.
3. A process for preparing a pharmaceutical composition as claimed in claim 1 wherein the fish gelatin is non-gelling fish gelatin.
4. A process for preparing a pharmaceutical composition as claimed in claim 3 wherein the fish gelatin is non-hydrolyzed.
5. A process for preparing a pharmaceutical composition as claimed in claim 4 wherein the fish gelatin is spray-dried.




inpct-2001-1026-del-complete specification (as files).pdf

inpct-2001-1026-del-complete specification (granted).pdf



inpct-2001-1026-del-description (complete).pdf












Patent Number 222203
Indian Patent Application Number IN/PCT/2001/01026/DEL
PG Journal Number 33/2008
Publication Date 15-Aug-2008
Grant Date 28-Jul-2008
Date of Filing 06-Nov-2001
# Inventor's Name Inventor's Address
PCT International Classification Number A61K 9/20
PCT International Application Number PCT/US00/09278
PCT International Filing date 2000-04-07
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 9908014.5 1999-04-08 U.K.