Title of Invention


Abstract A composition for oral administration containing a pharmaceutically active ingredient in fast-dispersing dosage form comprising: a fish gelatin carrier and a pharmaceutically active ingredient as herein described, wherein the active ingredient is present in an amount ranging from about 0.2% to about 95% by weight of the composition in dried dosage form wherein the composition disintegrates within 1 to 60 seconds in saliva in the oral cavity, thereby releasing the pharmaceutically active ingredient.
Technical Field
This invention relates to fasc-dispersing pharmaceutical compositions. In particular, the invention relates :o freezs-dried fast-dispersing dosage forms containing fish gelatin.
Backpround of the Invention
Fast-dispersing dosage forms which are designed co release the active ingredient in ihe oral cavity are well known and can be used co deliver a wide range of drugs. Many such fast-dispersing dosage forms utilize gelacin as a carrier. Gelatin B, P., which is normally utilized in such formulations, is defined as a pro win obtained by partial hydrolysis of animal collagenous tissues such as skin, tendons, ligaments and bones, with boiling water. However, such mammalian derived gelacin has an unpleasant caste and thus necessitates the use of sweeteners and flavors in such fast-dispersing dosage forms 10 mask the casce 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 gelacin is used in the production of such fast-dispersing dosage forms, ic is necessary to heac the gelatin solution co 60°C in order to effect solution. This heating step increases processing times and incurs heating costs thereby increasing the overall coses of die process,

U.S. Patent No. 5,120.549 to Gole ei al. discloses a fast-dispersing matrix system which is prepared by first solidifying a matrix-forming system dispersed in a first solvenl and subsequently contacting the solidified matrix with a second solvent that is substantially miscible v.-ich the first solvent at a temperature lower than che solidification, point of the first solvent, the matrix forming elements and active ingredient being substantially insoluble in the second solvent, whereby the first solvent is substantially removed resulting in a fas?-dispersing matrix.
U.S. Patent No. 5,079,018 to Ecanow discloses a fast-dispersing dosage form which comprises a porous skeletal structure of a water soluble, hydratable gel or foam forming material that has been hydrated with water, rigidified in the hydrated state with a rigidifying 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 hydratjon 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.
U.S. Patent No. 5,298,261 to Pebley et al. discloses fast-dispersing' dosage forms which comprise a partially collapsed macrix network that has been vacuum dried above the collapse temperature of che matrix. However, che matrix is preferably at least partially dried below the equilibrium freezing point of the matrix.
Published International Application No. WO 91/04757 (PCT/US90/05206)
discloses fasc-dispersing dosage forms ^hich contain an effervescent disintegration

agent designed to effervesce on contact .with saiiva to provide rapid disintegration of the dosage form and dispersion of the active ingredient in the oral cavfcy. •
U.S. Patent N'o. 5,595,761 to Allen Jr. et al. discloses a paniculate support matrix for use in making a rapidly dissolving tablet, comprising 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 the net charge of the firsc polypeptide component when in solution e.g. hydrolyzed gelatin; and a bulking agent, and wherein the first polypeptide component and the second polypeptide component together comprise about 2% to 20% by weight of the paniculate support matrix and wherein the bulking agent comprises about 60% to 96% by weight of the paniculate support matrix; and wherein the second polypepcide component has a solubility in aqueous solution greater than chat 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 1:14; and wherein when the support macrix is introduced into an aqueous environment the support matrix disintegrates wichin less than about 20 seconds.
EP 0 690 747 BI to Nguyen et al. describes particles comprising an excipient forming a macrix and at least one active ingredient uniformly distributed in the mass of the matrix which are prepared by a process comprising the steps of preparing a homogenous pasty mixture wjch a viscosity below 1 Pa.s measured at room temperature (15-209C), at least one active ingredient, a physiologically acceptable hydrophilic excipient and water; extruding the resulting homogenous mixture and

cutting the excrudate to give moist panicles; freezing die resulting particles as they fall under gravity through a stream of inen gas at a temperature below 0°C: and drying the panicles by freeze drying,
Australian Patent No, 666.666 discloses a rapidly disintegracable muldparticulace cablet having a mixture of excipiencs in which the active substance is present in the form of coated microcrystais or optionally coated microgranules. Such cablets are thought to disintegrate in the mouth injypically less than 60 seconds.
U.S. Patent No, 5,382,437 to Ecanow discloses a porous carrier material
having sufficient rigidity for carrying and administering an active agent which is capable of rapid dissolution by saliva. The porous carrier material of Ecanow is formed by freezing a liquified ammonia solution comprising liquid ammonia, liquid ammonia soluble gel or foam material, and a rigidifying agent for the gel or foam material selected from the group consisting of a monosaccharide, a polysaccharide and combinations thereof, and deammoniating the frozen material thus formed, by causing material transfer of ammonia from the frozen state to the gas state thereby leaving spaces in the carrier macerial in place of the frozen ammonia.
Published International Application No. WO 93/13753 (PCT/US 9 2/07497) describes cablets of increased physical strength which are prepared by combining and compressing a meltable binder, excipients and a pharmaceutically active agenc into a tablet, making the binder into the cablet and then solidifying the binder. In one embodiment, a disintegrating agenc is utilized 10 increase the distncegracion rate of the . tablet after oral intake. In another embodiment, a volarizable component is used to

form porous tablets. Some embodiments disintegrate in the mouth in less chan 10 seconds.
U.S. Patent No. 3,385,026 co Heinemannec al. and U.S. Patent No. £.134,943 to Knicsch et al. also disclose fast-dispersing porous tablets and a method for increasing cheir physical strength by first compressing the tablet and then volatilizing a readily volatilizable solid adjuvant incorporated in Che tablet to attain che desired porosity.
Published Internationa! Application No. WO 94/14422 describes a process for drying frozen discrete units in which the solvent is removed under conditions whereby the solvent is evaporated from the solid through, the liquid phase lo a gas, rather than 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 point the solvent (such as water) changes phase.
While the prior art is replete with methods and techniques for the preparation of rapidly dispersing dosage forms, it has failed to consider the benefits associated with the use offish gelatin, especially non-gelling, non-hydrolyzed fish gelatin, in such dosage forms.- The pharmaceutical industry would be able to avoid the use of mammalian derivad gelatin due to caste considerations. Thus, there exists the need for improved fast-dispersing dosage forms which are designed to quickly release the active ingredient in che oral cavity chat avoid the use of mammalian derived gelatin.

Summary of the Invention .
[t has now been found that many of the problems associated with the use of mammalian-derived gelatin can be overcome if fish gelatin, especially non-gelling fish gelatin, is utilized for preparing fast-dispersing dosage forms, Surprisingly, the non-gelling form offish 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 parameters and che qualities of the resultant product.
The present invention discloses a pharmaceutical composition comprising a carrier and an active ingredienc (e.g., drug, compound, and the like) wherein the carrier 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 (e.g., saliva, bodily fluids, water, and the like). Preferably, the composition is designed for oral administration and releases the active ingredient rapidly in che oral cavjry. In another embodiment, the composition can be applied topically, for instance, to wet skin, or dispersed or dissolved in a liquid prior 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 in particular, freeze dried fast-dispersing dosage forms.

En a preferred embodiment, (he composition of (he invention is a solid fast-dispersing dosage form containing a network of che active ingredient and a water-soluble or wacer-dispersible carrier comprising 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 carrier in a solvent.
The fish gelatin used in accordance with tire invention is preferably obtained from cold water fish sources and is the non-gelling type offish gelatin. More preferably, the non-hydrolyzed form of non-gelling fish gelatin is used. In an alternative embodiment, spray-dried non-hydrolyzed non-gcllir.g fish gelatin can be used.
Detailed Description of.che Invention
The phrase "fast-dispersing dosage form" refers to compositions which disintegrate or disperse within 1 to 60 seconds, preferably I to 30 seconds, more preferably 1 co 10 seconds and parn'cularly 2 to 8 seconds, afcer being placed in contact 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 ofHhe invention are solid fast-dispersing dosage forms comprising a solid network of the active ingredient and a

water-soluble or water-dispersible carrier containing fish gelatin. Accordingly, (he carrier is inert cowards the active ingredient, The network is obtained by subliming solvent from a composition in the solid state, the composition comprising the active ingredient and a solution of the carrier in the solvent. The dosage forms according to the invention can be prepared according to the process disclosed in Gregory ec al., U.K. Patent No. 1,548,022 using fish gelatin as the carrier.
Accordingly, an initial composition (or astmixcure) comprising the active ingredient and a solution of the fish gelatin carrier in a solvent is prepared followed by sublimation. The sublimation is preferably carried out by freeze drying the composition. The composition can be contained in a mold during the freeze-drying process to produce a solid form in any desired shape. The mold can be cooled using liquid nitrogen or solid carbon dioxide in a preliminary step prior 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 dried compositions can then be removed from the mold if desired or stored therein until later use.
When the process is used with active ingredients and fish gelatin as the carrier, a solid fast-dispersing dosage form is produced having the advantages associated with the use of fish gelatin described herein. Generally, fish gelatin is categorized as being from cold water and warm water fish sources and as being of the gelling or non-gelling variety. The non-gelling variety of fish gelatin, in comparison co gelling fish

gelacin and bovine gelacin, concains lower praline and hydroxyproline amino acid concenc. which are known to be associated ^ich cross-linking properties and gelling ability. Non-gelling fish gelacin can remain at solution concentrations of up to about 40% 25 well as in cemperacures as low as 20° C. The fish gelacin used in accordance wich the invention is preferably obtained from cold wacer fish sources and is the non-gelling cype offish gelacin. More preferably, the non-hydrolyzed form of non-gelling fish gelacin is used. In an alternative embodiment', spray-dried non-hydrolyzed non-gelling fish gelatin can be used. Fish gelacins^suicable for use in the invention can be obtained from Croda Colloids Led. (Chesire, England), for example.

Amino Acid Geiliag Fish Gelatin Bovine Gelatin Noo-GelUng Fish Gelatin
Aspanic Acid 46,0 46.0 52.0
Threonine 26,0 16.9 25.0
Serine 37.0 36.5 69.0
Glucamic Acid 66.0 70.7 75.0
Pro line 119,0 ,129.0 102.0
Glycine 343.0 333.0 | 345,0
AJanine 121.0 112.0 107.0
Valine 17.0 20.1 19.0
Mechionine 9.5 5.5 13.0
Isoleucine 8.0 12.0 | 11.0
Leucine 23.0 23.1 | 23.0
Tyrosine 3.0 1.5 | 3.5
Phenylalanine 12,0 12.3 | L3.0
Histidine 9.5 4.5 | 7.5
Lystae 25.0 27.8 | 25.0
Argmme 54.0 | 46.2 51.0
Hydroxyproline 76.0 97.6 53.0
Hydroxylysine 7.5 5.5 | 6.0

Despite che comparatively lower proline and hydroxyproline concent and other differences in non-gelling fish gelatin 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 composicion according to the invention can also contain, in addition to the active ingredient and fish gelatin carrier, 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, dexmns and soy, v/heat and psyllium seed proteins; gums such as acacia, guar, agar. and xanthan; polysaccharides; alginates; carboxymethylcelluloses; carrageenans; dextrans; '. pectins; synthetic polymers such as polyvinylpyrrolidone; and polypepcide/protein or polysaccharide complexes such as gelatin-acacia complexes.
Other materials which-'raay also ba incorporated into the composition of the present invention include sugars such as mannitoi, dextrose, lactose, galactose, and trehalose; cyclic sugars such as cyclodextrin; inorganic salts such as sodium phosphate, sodium chloride and aluminum silicates; and amino acids having from 2 to 12 carbon atoms such as glycine, L-alanine, L-aspanic acid, L-glucarnic acid. L-hydroxyproline, L-isoleucine, L-Ieucineand L-phenylalanine.
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 dispersion of

any active ingredient within the solution of suspension. This is especially helpful in the case of active agents that are not sufficiently soluble in water and must, therefore, be suspended rather than dissolved,
Secondary components such as_preservatives, amioxidariis. surfactants, viscosity enhancers, coloring agenls, 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 & C dyes such as FD&C Blue No. 2 and FD&C Red No. 40 available from Ellis & Everard. Suitable flavoring agents include mine, 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, cyclodextrin 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 buc not limited to analgesics and ami-infJammatory agents, antacids, anthelmintjcs. anti-arrhythmic agents, ami-bacterial agents, anti-coagulants, anti-depressants, anti-diabetics, anti-diarrheals, anti-epileptics, anci-funga) agents, anti-gout agents, anti-hypertensive agents, ami-malarials, anti-migraine agents, anti-muscarinic agents, anti-neoplastic agents and immunosuppressants. anti-procazoai agents, anti-rheumatics, anti-thyroid agcncs,

antivirals, anxiolyrics. sedatives, hypnotics and neuroiaptics, b«ca-b lockers, cardiac inorropic agents, corticosteroids. cough suppressants, cywcoxics, decongestants, diuretics, enzymes, anti-parkinsonian agents, gastro-intestinal agents, histamine receptor antagonises, lipid-regulating agents, local anesthetics, neuromuscular agents, nicrares and anti-anginal agents, nucriciona! agents, opioid analgesics, oral vaccines, proteins, peptides and recombmant drugs, sex hormones and contraceptives, spermicides, and stimulants. Specific examples ©f these drugs are found below;
Analgesics and_and-inflammatorv agents: aloxiprin, auranofm, azapropazone, benorylate, diflunisal, etodolac, fenbufen, fenoprofen calcim, flurbiprofen, ibuprofen, indomethacin, ketoprofen, maclofenamic acid, mefenamic acid, nabumetone, naproxen, oxaprozin, oxyphenbucazone, phenylbucazone, piroxicara, sulindac.
Anc-ac-i'ds: aluminum hydroxide, magnesium carbonaw, magnesium crisilicace, hydrotalcice, dimethicone.
fisi the Im In ties: albendazole, bephenium hydroxynaphthoate, cambendazole, dichlorophen, ivenneciin, mebendazole, oxamniquine, oxfe'ndazole, oxantel embonare, praziquantel, pyrantel emboaace, thiabendazoJe.
Anti-arrhvthmic agents: amiodarone HCI, disopyramide, fleciinide acetate, quinidine sulphate.
Anti-bacceri_al agents: benechamine penicillin, cinoxacin, ciprofloxacin HCI, clarithromycin, clofazimine, cloxacilljn, demeclocycfine, doxycycline, erythromycin, echionamjde, irnipenem, nalidixic acid, nicrofurancoin, rifampicin, spiramycin,

sulphabenzamide, sulphadoxine. sulphamerazine. sulphacetamide, sulphadiazine, sulphafurazole, sulphamecho.vazole, sulphapyridine, tetracycline. trimethoprirn. Anti-coagulants: dicoumarol. dipyridamok, nicoumalone, phenindione. Ami -depressants: amoxapine, ciclazindol, maprotiline HCI. mianserm HCI, nortriptyline HCI, trazodone HCI, [rirnipramine maleace,
Anti-diabetics: acetohe.vamide, chlorpropamide. glibenclamide,'gliclazide,
glipizide, tolazamidd, tolbucamide. *
Anti-diarrheajs: codeine phosphate, cp-phenorrope, loperamide hydrochloride, suphasolazine, mesalaztne, olsalazine, co ra'co steroids, prednisolone. Anti-epileoiics: beclamide, carbamazepine, clonazepam, ethotoin, methoin, mechsuximide, mcthylphenobarbitone, oxcarbazepine, paramethadione, phenacemide, phenobarbitone, phenyroin, phensuximide, primidone, sulthiame, valproic acid.
Antj-fungalaggnts: amphotericin, bucoconazole nitrate, clotriraazole, econazole nitrate, fluconazole, flucytosine, griseofinvin, icraconazole, ketoconazole, miconazole, natamycin, nystatin, suJconazolc nitrate, terbinafins HCI, terconazole, cioconazole, undeccnoic acid.
Anti-gout agents: allopurinol, probenecid, sulphinpyrazone. '. Anti-hvpenensive agents: amlopidine, benidipine, darodipine, diliuzern HCI, diazoxide, felodipin
Anci-malarials: amodiaquine. chloroquinc, chloroproguanil HCI,- halofancrine HCI, mefloquine HCI. prosuanil HCI, pyrimcchamine, quinine sulphate.
Anti-migrane agenca; dihydroergocamine mesylate, ergocamina carrrate, mechysergide maleace, pizonfan maleace, surr.acripcan succinacii.
Ami-muscarinic agents; atropine, benzhexol HCI, biperiden, echopropazine HCI, hyoscine bucyl bromid;, hyoscyamine, mepenzolate bromide, orphcnadrine, oxyphencylcimine HCI, tropicamide.
Anci-neo_pla5cic agenrs and Immunosunaressancs: aminoglutechimide. amsacrine, azachioprene, busulphan, chlorambucil, cyclosporin, dacarbazine, es cram us cine, etoposide, lomusdne, melphalan, mcrcaptopurine, raethotrexate, micomycin, mitocane, micozancrone, procarbazine HCI, camoxifen citraw, tescolactone.
Anti-procazoaf az_encs: benznidazole, clioquinol, decoquinace, diiodohydroxyquinoline, diloxanide furoacs, dinitoimide, furzolidone, mecronidazole, nimorazole, nirrofurazone, ornidazole, tinidazole.
Anci-rheurnacics: ibuprofen, aceclofenac, acemecacih, azapropazone, diclofenac sodium, diflunisal, ecodolac, kecoprofen, mdomechacm, mefenamic acid, naproxen. piroxicam. aspirin, benorylaie, auranofin, penicilJamine. Ajici-chvrgid agents: carbimazole, propylchiouracil. Ancivirals: acyclovir, amantadine hydrochJoride, famciclovir, zidovadine, didanosine, zalcicabine, foscamec sodium.
Anxiolvtic. sedacives._hvpnoiics and neuroleacics: alprazolam, amylobarbicone, barbicone, bencazepam, bromazepam, bromperidol, brotizolam,

bucobarbicone. carbromal, chlordiazcpoxide, chlormeJhiazole, chjorpromazine, clobazam. clociaz-spam. clozapine, diazepam, dropeddol, ethinamace, flunanisone, flunicrazepam. fiuopromazina. fiupenchixol decanoace, fluphenazine decanoate, flurazspam, haloperidol, lorazapam, lormeuzepam, medaz«pam, meprobamate, methaqualone, rnidazolam. rmrazepam, oxazepam, pentobarbicone, perphenazine pimozide, prochlorperazina, sulpride, temazcpam, thioridazine. criazotam, zopiclona.
S-Blockers: acebutolol, alprenolol, acenolol, labecalot, metoprolol, nadolol. oxprenolol, pindolol, propanolol.
Cardiac inoirooic agents: amrinone, digicoxia, digoxin, enoximone, lanacoside C, medigoxin.
Conicosreroids: beclomechasone, becamcthasone, budesonide, cortisone acecate, desoxymethasone, dexamechasone, fludrocortisone acetate, fluTiisoIide, flucortolone, flucicasone propionate, hydrocortisone, methylprednisolone, prednisoione; prednisone, triamcinolone.
Cough suooressancs: codeine phosphate, pholcodine, diamorphine, methadone.
Cvtocoxics: ifosfamide, chlorambucil, melphalan, busulphan.'cytocoxic ann'bodies, doxorubicin, epirubicin, plicamycin, bleomycin, mechocrexate, cytarabine, fludarabine, gencitabinc, fluorouracil, mercaplopurine, thioguanine, vincristine, vinblasiine, vindesine> ecoposide.
Decongesian^: pseudoephedrine hydrochloride,

Diuretics: acecazolamide. amiloride. bendrofluazide, bumetanide, chlorochiazide. chlonhalidone, echacrynic acid, frusemide, metolazone, spironolactone, triamterene,
Enzymes: pancreatin, pepsin, lipase,
Arui-oarkinsonian agents: bromocripline mesylate, lysuride maleace, sekgiline, para-fluoroselegiiine, lazabemide, rasagiline, 2-BUMP [N-(2-bwy|)-N-mechyipropargylamine], M-2-PP [M-mechyl-N-^-jpencyO-propargylamine], MDL-72145 [beca-(fIuoromethylene)-3,4-dimeChoxy-benzeneethanamine]1 mofegiline, apomorphine, N-propylnoraporphine, cabergoline, metergoline, naxagolide, pergolide, piribedil. ropinirole, terguride, quinagolide.
Gasn-o-iniesiinal agents: bisacodyl, cimecidine, cisapridi, diphenoxylate HC1,. domperidone, famotidine. loperamide, mesalazine, nizatidine, omeprazole, oadansstron HC1, ranitiduie HCl, sulphasalazine.
Histamine Recencor Antagonises: acrivastine, asccmizole, cinnarizine; cyclizine, cyproheptadine HCl, a'imenhydrinate, flunarizinffHCl, Ibracadine, maclozineHCl, oxatomide, c«rfenadine, triprolidine.
Lioid regulating agents: bezafibrace, clofibrace, fenofibrate, gfernfibrozll, probucol.
Local anaesthetics: amethocainc, amylocaine, beruocaine, bucricaine, bupivacaine, butacaine, butanilicaine, butoxycaine, butyl aminobenzoate, canicaine, chloroprocaine, cinchocaine, clibucaine, clormccaine, coca, cocaine, cyclomcthycaine, dimethisoquin, diperodon, dyclocaine. ethyl chloride, ethyl p-

piperidinoacecylaminobenzoace, ecidocaine, hexylcaine, isobutamben. kecocaine, lignocaine, mepi'vacaine, meprylcaine, mynecaine, occacaine, oxethazaine, oxybuprocaine, paretho.xycaine, pramoxina, prilocatne, procaine, propranccaine, propoxycaine, proxymecacaine, ropivacaine, colycaine, tricaine, trimecaine, vadocaine,
N'euro-muscular agents: pyridoscigmine.
Nitrates and other anti-anginal agents: anjy! nitrace, gjyceryl crinicrace, isosorbide dtnitrace, isosorbide mononitrare, pentaerytiimol tetranicrate.
Nutricionaf agents: becacarocane, vitamins, such as vicamin A, vitamin BZ, vitamin D. vicamin E, vicamin K, minerals,
Qoioid analgesics: codeine, dexcropropyoxyphene, diamocphine, dihydrocodeine, mepcazinol, mechadone, morphine, nalbuphine, pentazocine. Oral vaccines: to prevent or reduce che sympcoms of diseases such as Influenza, Tuberculosis, Meningitis, Hepatids, Whooping Cough, Polio, Tetanus, Diphtheria, Malaria, Cholera, Herpes, Typhoid, HIV, AIDS, Measles, Lyme disease, Traveller's Diarrhea, Hepatitis A, B and C, Oucis Media, Dengue Fever, Rabies, Parainflucnza, Rubdla, Yellow Fever, Dysentery, Legionnaires Disease, -Toxoplasmosis, Q-Fever, Haemorrhegic Fever, Argentina Haemorrhegic Fever, Caries, Chagas Disease, Urinary Tract Infection caused by E. coli, Pncumococcal Disease, Mumps. Chikungunya, Hayfever, Asthma, Rheumatoid Arthritis, Carcinomas, Coccidiosis, Newcastle Disease, Enzootic pneumonia, Feline leukemia, Atrophic rhinitis. Erysipelas, Foot and Mouth disease and Sv/ine pneumonia, or to

prevent or reduce che symptoms ofdisaases caused by Vibrio species. Salmonella species. Bordetella species, Haemophilus species, Toxoplasrnosis gondii, Cyromegalovirus, Chiamydta species, Streptococcal species, Norv/alk Virus, Escherischia coli. Helicobacter pylori, Rotavirus. N'eisseriagonorrhae, Neisseria meningidicis, Adenovirus, Epstein Barr Virus, Japanese Encephalitis Virus, Pneumocysds carini. Herpes simplex, Closcridia species, Respiratory Syncycial Virus, Klebsiella species. Shigella species, Pseudornonas aeruginosa, Parvovirus, Campylobacter species, Rickettsia species,-Varicella zoster, Yersmia species, Ross
River Virus, J,C. Virus, Rhodococcus equi, Moraxella cacarrhalis, Borrelia burgdorferi and Pasteurella haemolytica.
Proteins, peptides and recombinant drugs: recombinam hormones and iso-hormooes, rccombinant cyrokines, recombinant plasminogens, TNF receptor fusion procfiin, monoclonal antibodies, nucleic acids, antisense oligonucleotides, oligonucleotides, glycoproceins and adhesion molecules.
Sex hormones and Contraceptives: clomiphene citrate, danazol, desogestrel, echinyloestradiol, echynodiol, echynodiol diacecate, levonorgestrel, medroxyprogesteroRe acetate, mestranol, methylcestosterone, norethisterone, norechisterone enanchate, norgestrel, estradiol, conjugated estrogens, progesterone, atanozolol, stilboescrol, testosterone, tibolone. Spermicides: nonoxynol 9.
Stimulants: amphetamine, dexamphetamine, dexfenfluramine, fenfluramine, mazindol, pemoline.

The precise quantity of active ingredient will vary according 10 ihe particular drug selected and the patient's needs. However, the active ingredient can be generally present in an amount from about 0.2% to about 95%, typically from about 1% to about 20%. by weight of the composition of the dried dosage form. The invention is further illustrated by the following Examples.
EXAMPLE 1 Preparation, of a Placebo. Fast-Dispersing Dosage Form using,Fish Gelatin
Spray-dried fish gelatin (4 g) and maanilol (3 g) were added to a glass beaker.
- . /
Purified water (93 g) was then added and solution effected by srirring 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 wich P VdC. The dosed units were then frozen at a temperature of-110° C in a freeze tunnel wich a residence time of 3.2 minutes and the frozen units'were then held in an upright frsezer for a time greater than 1.5 hours at a temperature of-25° C (±5° C). The units were then freeze-dried overnight with an initial shelf temperature of-10° C rising to +20° C at a pressure of 0.5 mbar. The units were checked "for moisture prior to unloading by the drying trace and by the pressurized moisture check. The resultant units had the following composition:

(Table Remove)
Preparation of a Placgbo Fast-Dispersing Dosage Form using • Alkaline Bovine Hide Gelatin
Alkaline bovine hide gelatin (4 g) was added to purified water (93 g) in a glass beaker and evenly heaced co 60" C while constantly stirring with a magnetic follower. Care was taken to ensure chat all the gelatin had dissolved. The mix was then cooled to 2. remperacure of 25° C by means of a water bach before the addition of mannitol (3 g). Whan the manrtitol had dissolved, stirring was continued for 1 hour at ambient conditions. This solution was then dosed into blister pockets, frozen, stored and freeze-dried as described in Example I above. The resultant unics had the following composition:

(Table Remove)
ihe following additional comparative examples were prepared using the process described in Comparative Example A.
COMPARATIVE EXAMPLE B Preparation ofa Placebo Fast-Dispersing Dosage Form using Pig Skin Gelatin
A fast-dispersing dosage form using pig skin gelatin was prepared in a manner similar co chat found in Comparative Example A,, and the resulranc units had the
following compositions:

(Table Remove)
Preoaracion of a Placebo Fasc-Disogrsing 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 Remove)
Comoarauya Tensile Strenach and Dispersion Testing
The units produced in Example 1 and che Comparative Examples A through C
were subjected to tensile strength and disintegration ces:s according co methods
conforming co the USP monograph requirements. /Vn additional dispersion test was
also cam'ed ouc Co 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 dropped onto the surface of the water and the time taken to fully disperse noted. The warer was then changed for subsequent unit testing.
The units produced in Example \ exhibited a disintegration time of 0.85 seconds and gave a mean tensile strength value of 0.267 N mm"2. 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'1. The disp'ersion test confirmed these results, The units produced in Comparative Examples B and C exhibited a mean tensile strength of 0.407 N mm"2 and 0.433 N mm"2 respectively. In addition, it was noted that the units produced in Example 1 had no unpleasant smelJ or taste and a better mouth-feel than the units produced in 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 the above that fasi-dispersing dosage forms produced using fish gelatin have a number of advantages over chose produced using mamrnaljan-derived gelatin. For instance, such dosage forms containing fish gelacin have a faster disintegration time, a better caste and a better mouth-feel than dosage forms containing mammalian derived gelacin. Moreover, there is no need for sweeteners and flavors to be added to mask the taste or sjmell 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 ingrediam, 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, che heating step, which is required when mammalian derived gelatin is used, can be omirced thereby producing cost savings in heating costs and shorter mixing times. The overall process is therefore more controllable when fish gelatin is used in place of mammalian derived gelatin, The following examples funher exemplify formulations which can be prepared using the process described in Example 1.
Fasc-Dispenine Dosage Form using Fish Gelacin with Dextromechofphan as (he Acr.ive_In_gTgdiem

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A mean Tensile strength value of 0.206 N mm2 was obcained for chese dosage forms, svith a disintegration time of 0.78 seconds.
EXAMPLE 4 Fasi-Dispersing_pQsage Form using Fish Gelatin

(Table Remove)
These units had a mean Tensile strength value of 0.269 N mm2, wich a disintegration time of under 2 seconds.
EXAMPLE 5 Testing of "Gelling" Fish Gejatin
A formulation containing "gelling" fish sslacin was prepared and evaluated for disintegration time and mouth feel. Gelatin, mannicol and purified water were weighed into plastic vessels, The gelatin and mannitol were added co che vortex of continually stirred purified water, and the mixture was heated to a temperature of 60°C in order to effect solution of che gelatin. Once dissolved, the solution was then cooled to a temperature of about 23,4" C prior co dosing. Aliquocs of 500 mg were dosed into pre-forrned blister pockets and frozen, stored and frceze-dried.
A total batch of 100 grams was prepared containing the following formulation:
Ingredient | Amount (% by weight)

(Table Remove)
The dosage forms were analyzed for disintegration time and mouth feel. Disincegration time of che samples was measured according to USP methods, The samples had disintegration times of greater than 5 seconds. The mouth fe'el of the samples was found co be slow to disperse, "gummy" in nature, and overall unsatisfactory.

Industrial Appiicabjlirv
The pharmaceutical industry is constantly searching for improved dosage forms chac are economical co produce and avoid problems associated «/ith mammalian gelacin, The dosage forms according co the presenc invention addresses these needs and does so with superior results.
The invention has bean described with reference co various specific and
preferred embodimencs and techniques. However./ ic should be understood chac many variacions and modifications can be made while remaining within the spiric and scope of the invention.

1. A composition for oral administration containing a pharmaceutically
active ingredient in fast-dispersing dosage form comprising:
a fish gelatin carrier and
a pharmaceutically active ingredient as herein described, wherein the active
ingredient is present in an amount ranging from about 0.2% to about 95% by
weight of the composition in dried dosage form
wherein the composition disintegrates within 1 to 60 seconds in saliva in the
oral cavity, thereby releasing the pharmaceutically active ingredient.
2. A composition as claimed in claim 1, wherein the composition is
designed for oral administration and releases the active ingredient rapidly in
the oral cavity.
3. A composition as claimed in claim 1 wherein the composition is in solid
form and is preparable by subliming solvent from an admixture in the solid
state in which the admixture comprises the active ingredient, the carrier and a
4. A composition as claimed in claim 1 wherein the active ingredient is
present in an amount ranging from about 1% to about 20% by weight of the
composition in dried dosage form.
5. A composition as claimed in claim 1 wherein the fish gelatin is non-
gelling fish gelatin.
6. A composition as claimed in claim 5 wherein the fish gelatin is non-

7. A composition as claimed in claim 6 wherein the fish gelatin is spray-
8. A composition as claimed in claim 1, wherein it optionally comprises an
additional ingredient selected from the group consisting of matrix forming
agents, sugars, cyclic sugars, amino acids, preservatives, surfactants, viscosity
enhancers, coloring agents, flavoring agents, pH modifiers, sweeteners, taste-
masking agents, and combinations thereof.
9. 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 solvent from an admixture in the solid state at pressure of about 4
mm Hg, preferably about 0.3 mm Hg., in which the admixture comprises the
active ingredient, the carrier and a solvent for the carrier.
10. A pharmaceutical composition in a fast-dispersing dosage form as claimed in claim 1, wherein an active ingredient and fish gelatin carrier which releases the active ingredient rapidly on contact with fluid, said dosage form having a network of active ingredient and fish gelatin preparable by the process of subliming solvent from a admixture in the solid state in which the admixture comprises the active ingredient, the carrier and a solvent.











2513-delnp-2005-description (complete).pdf













Patent Number 219872
Indian Patent Application Number 2513/DELNP/2005
PG Journal Number 28/2008
Publication Date 11-Jul-2008
Grant Date 13-May-2008
Date of Filing 10-Jun-2005
Applicant Address
# Inventor's Name Inventor's Address
PCT International Classification Number A61K 9/20
PCT International Application Number PCT/US2000/009278
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.