A fast dissolving pharmaceutical composition

Fast-dissolving pharmaceutical formulation

A Fast Dissolving Pharmaceutical Composition

Full description

Background of the invention

The present invention relates to rapidly dissolving pharmaceutical compositions, and methods for preparing and using them in the treatment and prophylaxis of diseases in mammals, specifically, humans. Rapidly dissolving pharmaceutical dosage forms that are customized to release the active ingredient into the oral cavity are well known and can be used for the delivery of many drugs:

(Critical Reviews in Therapeutic Drug Carrier Systems, 21(6):433-475 (2004); Seager H. (1998), J. Phar. Pharmacol 50:375-382; Bandari et al. (January 2008), Asian Journal of Pharmaceutics 2-11)

In rapidly dissolving dosage form, the drug can be physically entrapped in a tissue network composed of mannitol, fish gelatin (European Patent No. 1,501,534; European Patent No. 1,165,053), modified starch (U.S. Patent No. 6,509,040), and pullulan in combination with amino acid (European Patent No. 1803446), or maltodextrin in combination with sorbitol (US Patent No. 2004/0228919).

The solution, suspension, or dispersion of the drug and carrier may be filled into the recesses of a granule package, frozen and then freeze-dried. However, most dosage forms produced in this way are brittle and easily crumble, have limited physical resistance and cannot withstand any pressure. In addition, the dosage units produced are difficult to fill and unpack.

General description of the invention

The present invention provides rapidly dissolving pharmaceutical compositions typically administered orally in unit dosage form, typically freeze-dried products administered orally (also called disintegrating tablets). The rapidly dissolving dosage forms of the invention have a relatively high tensile strength (i.e., the force required to break the tablet in a three-point bending test) on the one hand and a rapid disintegration/dissolution time on the other hand. The relatively high tensile strength, among other things, allows the formulation to be removed from its container, typically a granule package, without disintegration. The unit dosage form of the invention can typically be handled in a manner similar to a conventional CD, with disintegration occurring only upon contact with an aqueous liquid or saliva in the mouth. In one embodiment, the present invention provides a pharmaceutical composition comprising an open matrix network carrying a pharmaceutically active ingredient, wherein the open matrix network includes levan.

In another embodiment, the present invention provides a pharmaceutical composition comprising a matrix bearing a pharmaceutically active ingredient, the mesh rapidly disintegrates upon contact with an aqueous solution or with saliva, and said mesh includes levan.

The pharmaceutical composition of the invention is unique in that it has a high tensile strength, on the one hand, and a high dissolution rate in an aqueous medium or in saliva, on the other hand.

The relatively high tensile strength allows the formulation to be handled in a manner similar to a regular compressed tablet including, in particular, removing it from the packaging in which it is held, eg a granule package without the risk of damaging the dosage form between the fingers. Despite the aforementioned tensile strength, the composition of the invention breaks down quickly upon contact with an aqueous medium or with saliva. Disintegration can occur in an aqueous medium or in the oral cavity upon consumption (where it disintegrates on contact with saliva), typically in less than 30 seconds, more typically in less than 10 seconds and in durations of less than 9, 8, 7, 6. , 5, 4, 3, 2 or even 1 second.

Accordingly, the invention also provides a pharmaceutical composition comprising a pharmaceutically active ingredient, having a tensile strength to allow the consumer to handle the composition (typically in unit dosage form) in a manner similar to a CD, typically having a tensile strength ranging from 0.05 to 1, 6 N/mm2 and a rapid dissolution rate such that at least 80% of the formulation disintegrates in an aqueous medium or in saliva in less than 30 seconds, in less than 10 seconds and even in periods of less than 9, 8, 7, 6, 5, 4, 3, 2 or 1 second.

The pharmaceutical composition of the invention may be obtained by sublimation of a solvent (such as water), for example in a freeze-drying process, from a fluid preparation comprising the active ingredient and the mesh-forming agent(s) in solution. According to one embodiment, unit dosage amounts of the liquid preparation are introduced into depressions and a sublimation process is performed to obtain (after sublimation) a pharmaceutical composition in unit dosage form. The depressions can be an open granule packing filler after the sublimation step, thus the solid dose unit image is formed from the composition that is in the cavity, and a sealing film or foil is placed on the depressions to form a sealing granule packing filling. Sealed blister pack.

The invention also provides a process for encapsulating a pharmaceutical composition comprising sublimating the solvent from a liquid preparation comprising a pharmaceutically active ingredient and levan into the solvent.

The invention also provides a process for preparing a pharmaceutical composition comprising the steps of (a) preparing a solution comprising levan and an active ingredient in a solvent, (b) freezing said solution, and (c) sublimating the solvent from the frozen solution, wherein the pharmaceutical composition obtained is A rapidly disintegrating dosage form that disintegrates within less than 30 seconds upon contact with an aqueous solution or with saliva.

Detailed description

The present invention provides a rapidly dissolving pharmaceutical composition, typically friable in the mouth, typically prepared and supplied as a dosage unit, typically as a freeze-dried product for oral administration, comprising an active ingredient and one or more excipients. At least one of the excipients, usually the web-forming agent, is the polysaccharide levan.

Some of the terms used above are presented below and are used in the description of the patent and the elements of protection:

The terms “active ingredient” or “pharmaceutical active ingredient” will be used interchangeably throughout this document. The terms “pharmaceutical composition” and “composition” which are used interchangeably refer to the pharmaceutical composition of the invention.

The term “unit dosage form” or “dose form” is used herein to refer to said formulation that is formulated using an amount of the active pharmaceutical ingredient (API) in dosage form for administration in a single dose to the target individual. The unit dose profile can be configured, based on the nature of the active ingredient, the instructions, the stage of the disease, and several factors specific to one, two, three or multiple administrations per day.

The term “load” includes any form of interaction between the active ingredient and the tissue mesh that allows a quantity of the active ingredient to be maintained and/or contained and released into the aqueous medium or saliva upon breakdown of the tissue mesh.

The term “tissue mesh” refers to the solid medium carrying the active ingredient. The tissue network includes one or more excipients. Excipients that form the web may be referred to in this document, many times, as “web-forming agents” and each of the agents mentioned is referred to as “web-forming agent.”

The term “open matrix network” includes a fabric network of a water-soluble or water-dispersible carrier (network-forming agent(s)) that has separations through which it is dispersed. The mesh rapidly breaks down through contact with aqueous solution or saliva.

In one embodiment, levan is the only mesh-forming agent in the composition. In another embodiment, one or more of the secondary tissue network forming factors remains present in the composition.

Non-specific examples include:

sugars, sugar alcohols, monosaccharides, disaccharides, trisaccharides, polysaccharides, proteins, amino acids, gums and the like, which are useful as secondary network forming agents, but not limited to:

mannitol, trehalose, raffinose, inositol, pullulan, sucrose, lactose, dextrose, erythritol, xylitol, lactitol, maltitol, isomalt, alanine, arginine, threonine, glycine, cysteine, serine, histidine, valine, proline, lysine, asparagine, glutamine, ribose, glucose, galactose, fructose, maltose, maltotriose, guargum, xanthan gum, tragacanth gum, veegum

etc.

In general, the balance of the formula can be represented by the texture grid. Therefore, the levan mesh ratio approaches 100%. The amount of useful secondary tissue mesh according to the present invention can range from about zero to about 90%.

In one embodiment of the invention, levan is the main matrix forming agent in the composition. In another embodiment, the composition further includes mannitol, raffinose, trehalose, or combinations thereof as a secondary mesh-forming agent.

In one embodiment, levan is a textile network forming agent, comprising 10-99.99% of the total weight of the composition. In another embodiment levan comprises 30-75% of the total weight of the composition. In another embodiment, levan comprises 40-70% of the total aggregate composition. In yet another embodiment, levan comprises 50-65% of the total weight of the composition.

In yet another embodiments, mantol, trehalose, raffinose, or combinations thereof are used as the secondary web forming agent, comprising 0-89.99% of the total weight of the aggregate composition. In one embodiment, said secondary textile network forming agents comprise 15-50% of the total weight of the composition. In another embodiment, said secondary textile network forming agents comprise 25-50% of the total weight of the composition.

Thus, the composition of the invention may be one that includes levan as the main matrix forming agent and mannitol, trehalose, or raffinose (or combinations thereof) as the secondary matrix forming agent, of which inulin constitutes 10-99.99%. (The total percentage of the ingredient is w/w, i.e. the weight of all the ingredients that make up the combined composition), the secondary mesh forming factor is 0-89.99%, typically 25-50%. The active ingredient content can typically be (but is not limited to) 90% of the total formulation, and typically ranges from approximately 0.01-70%, based on the nature of the active ingredient. In one embodiment, the active ingredient comprises 0.01-1% of the total weight of the composition. In another embodiment, the active ingredient comprises 0.5-2% of the total composition. In yet another embodiment, the active ingredient comprises 5-30% of the total composition. In other embodiments, the active ingredient comprises 20-40% of the total weight of the composition. In yet another embodiment, the active ingredient comprises 60-90% of the total weight of the composition. In one embodiment, the composition of the invention does not include fish gelatin. In another embodiment, the composition of the invention does not include modified starch. In another embodiment, the composition of the invention does not include pullulan in combination with an amino acid. In another embodiment, the composition of the invention does not include maltodextrin in combination with sorbitol. The terms “disintegration time” and “disintegration time” are used interchangeably in this document and it should be understood that they refer to the average time required for the composition of the invention to dissolve or disintegrate in an aqueous solution or in saliva in the oral cavity.

The term “oral dissolving time” as used herein refers to the average time required for the composition of the invention to dissolve in the oral cavity.

The term “dissolution/disintegration” as used herein refers to the disintegration of at least 80% of the composition of the invention, usually 90% and preferably 100% of the composition in aqueous media or saliva (in the oral cavity) within 30 seconds and Typical during 10 seconds and periods falling at 9, 8, 7, 6, 5, 4, 3, 2, 1 second.

Examples of an aqueous medium as used herein are water, buffer solution (i.e. potassium dihydrogen phosphate, dipotassium hydrogen phosphate, sodium hydrogen phosphate) or artificial saliva as described in:

Morjaria et. al (May 2004), Dissolution Technologies 12 15.

The term saliva as used here refers to the oral cavity of a mammalian organism, specifically a human being. The term “tensile strength” as used here refers to the force required to break a disc, which is measured by a three-point bending test, in which the disc is subjected to a bending stress:

(Mohd et al.(2002), Drug Development and Industrial Pharmacy 28(7):809-813)

In one embodiment, a pharmaceutical composition of the invention has a tensile strength ranging from 0.05 to 1.6 N/mm2. In another embodiment, a pharmaceutical composition of the invention has a tensile strength ranging from 0.15 to 1.4 N/mm2. In yet another embodiment, a pharmaceutical composition of the invention has a tensile strength of 0.3 to 0.85 N/mm2.

The pharmaceutical composition of the invention is envisioned to have a rapid disintegration/dissolution rate such that at least 80% of the composition is dissolved in the aqueous medium or saliva within 30 seconds, typically within 10 seconds. In one embodiment, the pharmaceutical composition of the invention has a rapid disintegration/dissolution rate such that at least 90% of the composition is dissolved in the aqueous medium or saliva within 30 seconds, typically within 10 seconds.

In one embodiment, a pharmaceutical composition of the invention has a tensile strength of about 0.05-1.6 N/mm2 and a disintegration/dissolution rate such that at least 80% of the composition is dissolved in an aqueous medium or saliva within 30 seconds, typically within 10 seconds.

In another embodiment, the invention provides a pharmaceutical composition comprising a pharmaceutically active ingredient, having a tensile strength of about 0.15 to 1.4 N/mm2 and a disintegration/dissolution rate such that at least 80% of the composition is dissolved in an aqueous medium or saliva within 30 seconds, Typically within 10 seconds.

In another embodiment, the invention provides a pharmaceutical composition comprising a pharmaceutically active ingredient, having a tensile strength of about 0.3 to 0.85 N/mm2 and a disintegration/dissolution rate such that at least 80% of the composition is dissolved in an aqueous medium or saliva within 30 seconds, typically within 10 seconds.

In one embodiment, a pharmaceutical composition of the invention has a tensile strength of about 0.05 to 1.6 N/mm2 and a disintegration/dissolution rate such that at least 90% of the composition is dissolved in an aqueous medium or saliva within 30 seconds, typically within 10 seconds.

In another embodiment, the invention provides a pharmaceutical composition comprising a pharmaceutically active ingredient, having a tensile strength of about 0.15 to 1.4 N/mm2 and a disintegration/dissolution rate such that at least 90% of the composition is dissolved in an aqueous medium or saliva within 30 seconds, typically within 10 seconds.

In another embodiment, the invention provides a pharmaceutical composition comprising a pharmaceutically active ingredient, having a tensile strength of about 0.3 to 0.85 N/mm2 and a disintegration/dissolution rate such that at least 90% of the composition is dissolved in an aqueous medium or saliva within 30 seconds, typically within 10 seconds.

The open matrix network helps the liquid enter the dose form through the intervals and allows penetration through its inner part. The penetration of the aqueous medium (such as saliva, water, etc.) leads to the exposure of the carrier substance of the internal and external dosage form to the action of the aqueous medium, whereby the carrier substance is quickly disintegrated/dissolved.

The open matrix network composition is porous in nature and enhances the disintegration of the dosage form compared to solid pharmaceutical dosage forms such as tablets (pellet or compressed), pills, capsules, suppositories and pessaries. Rapid dissolution results in rapid release of the active ingredient carried by the textile network. In the present invention, the carrier material for the open textile mesh is levan or a derivative thereof.

Levan (also called leaven, levulosan, polyfructosan, polyfructose and polylevulan) is a polymer of fructose C6H12O6. Levan is a polysaccharide with β-(2->6) bonds between the fructose rings, where the numbers show which carbon atoms are in the linked fructose ring and β describes the stereochemistry relationship. Levans have also been described as fructans in which the predominant glycosidic bond between the D-FRUCTOFURANOSIDE MONOMERIC units is β-(2->6). In general, levan is produced by microorganisms and does not appear as high molecular weight compounds in plants. Some low molecular weight levan compounds with a molecular weight of less than 100,000 daltons can appear in herbs.

"levan" as used herein includes levan derived from any source including, but not limited to:

A. indicus, A. versicolor, Acetobacter suboxydans, Achromobacter spp., Actinomycenes sp., Actinomyces viscosus, Aerobacter aerogenes, Aerobacter levanicum, Aspergillus sydowi, Azotobacter chroococcum, Bacillus polymyxa, Bacillus licheniformis, Bacillus macerans, Bacillus megatherium, Bacillus mesentericus, Bacillus subtilis, vulgatus, Corynbacterium laevaniformans, Erwinia herbicola, Gluconobacter oxydans, Leuconostoc mesenteroides, Odontomyces viscosus, Phytobacterium vitrosum, Phytomonas pruni, Psuedomonas Fluorescens, Pseudomonas Syringae, Pseudomonas prunicola, Rothis dentocariosa, Serratia kiliensis, Steptococcus bovis, Steptococcus mutans, Steptococcus salivarius, Xanthomonas campestris, Xanthomonas pruni, Zymomonas mobilis

And so on. In a specific embodiment, levan is obtained from Zymomonas and Bacillus species. In a more specific embodiment, levan is obtained from Zymomonas mobilis.

A pharmaceutically active ingredient can include any pharmaceutical ingredient such as drug, compound, peptide, nucleotide, etc.

Examples of non-restrictive drugs that can be carried by the open matrix network of the present invention include analgesics, alpha blockers, anti-allergy, and anti-asthma (allergic rhinitis, chronic uticaria). , anti-inflammatory, antacids, anthelmintics, antiarrhythmic agents, anti-arthritis, and antibacterials. anti-bacterial, anti-anxiety, anti-coagulants, anti-depressants, anti-diabetics, anti-diarrheals, anti-diuretics, anti-epileptics, anti-fungals -fungal, anti-gout, anti-hypertensive, anti-incontinence, anti-insomnia, anti-malarials, anti-migraine, Anti-muscarinic, anti-neoplastic, immunosuppressants, anti-protozoal, anti-rheumatics, allergic rhinitis, anti-spasmatic, anti-thyroid, and anti-inflammatory drugs. antivirals, anxiolytics, sedatives, hypnotics, neuroleptics, beta-blockers, and anti-benign agents. hyperplasia (BHP), cardiac inotropics, corticosteroids, cough suppressants, cytotoxics, decongestants, diabetic gastric stasis, diuretics, enzymes, and anti-Parkinson's agents -parkinsonian, gastro-intestinal, histamine receptor antagonists, infertility, endometriosis, and replacement therapy hormone replacement therapy, lipid regulating agents, local anesthetics, neuromuscular agents, nitrates, anti-anginal agents, menstrual disorders, motion sickness, and anti-pain , anti-nausea, movement disorders, nutritional agents, opioid analgesics, oral vaccines, proteins, peptides, reversal drugs, agents to prevent chemotherapy-induced post-operative nausea, proton pump vomiting inhibitors, schizophrenia, contraceptives, pain and seizure disorder, sexual dysfunction (female male), spermicides, Unloading stimulants, veterinary medicines, etc. Specific non-restrictive examples of these drugs are alpha blockers: Tamsulosine

Analgesics and anti-inflammatory agents:

Aspirin, aloxiprin, auranofin, azapropazone, benorylate, diflunisal, etodolac, fenbufen, fenoprofen calcium, flurbiprofen, ibuprofen, indomethacin, ketoprofen, meclofenamic acid, mefenamic acid, nabumetone, naproxen, oxaprozin, oxyphenbutazone, phenylbutazone, piroxicam, sulindac, para cetamol.

And antacids:

hydroxide, magnesium carbonate, magnesium trisilicate, hydrotalcite, dimethicone.

And deworming agents:

albendazole, bephenium hydroxynaphthoate, cambendazole, dichlorophen, ivermectin, mebendazole, oxamniquine, oxfendazole, oxantel embonate, praziquantel, pyrantel embonate, thiabendazole.

And anti-allergy:

des loratidine, loratidine, Montelukast, Montelukast sodium, Cetirizin, Fexofenadin, Ebastine.

Antiarrhythmic agents:

Amiodarone HCl, disopyramide, flecainide acetate, quinidine sulphate.

And antibacterial agents:

benethamine penicillin, cinoxacin, ciprofloxacin HCl, clarithromycin, clofazimine, cloxacillin, demeclocycline, doxycycline, erythromycin, ethionamide, imipenem, nalidixic acid, nitrofurantoin, rifampicin, spiramycin, sulphabenzamide, sulphadoxine, sulphameraz ine, sulphacetamide, sulphadiazine, sulphafurazole, sulphamethoxazole, sulphapyridine, tetracycline , trimethoprim.

And anti-coagulants:

dicoumarol, dipyridamole, nicoumalone, phenindione.

And anti-depressants: such as

amoxapine, ciclazindol, maprotiline HCl, mianserin HCl, nortriptyline HCl, trazodone HCl, trimipramine maleate.

And anti-diabetics:

acetohexamide, chlorpropamide, glibenclamide, gliclazide, glipizide, tolazamide, tolbutamide.

And anti-diarrheals:

Atropine sulphate, codeine phosphate, co-phenotrope, difenoxin, loperamide hydrochloride, suphasolazine, mesalazine, olsalazine, corticosteroids, prednisolone.

And anti-diuretics: such as desmopressin, desmopressin acetate.

And anti-epileptics: such as

beclamide, carbamazepine, clonazepam, ethotoin, methoin, methsuximide, methylphenobarbitone, oxcarbazepine, paramethadione, phenacemide, phenobarbitone, phenytoin, phensuximide, primidone, sulthiame, valproic acid

And antifungal agents:

amphotericin, butoconazole nitrate, clotrimazole, econazole nitrate, fluconazole, flucytosine, griseofulvin, itraconazole, ketoconazole, miconazole, natamycin, nystatin, sulconazole nitrate, terbinafine HCl, terconazole, tioconazole, undecenoic acid

And anti-gout agents: allopurinol, probenecid, sulphinpyrazone.

Anti-hypertensive agents:

amlopidine, benidipine, darodipine, dilitazem HCl, diazoxide, felodipine, guanabenz acetate, indoramin, isradipine, minoxidil, nicardipine HCl, nifedipine, nimodipine, phenoxybenzamine HCl, prazosin HCl, reserpine, terazosin HCl..

Anti-insomnia: Zolpidem

Anti-malarials:

amodiaquine, chloroquine, chloroproguanil HCl, halofantrine HCl, mefloquine HCl, proguanil HCl, pyrimethamine, quinine sulphate.

Anti-migraine agents:

rizatriptan, dihydroergotamine mesylate, ergotamine tartrate, methysergide maleate, pizotifen maleate, sumatriptan succinate, caffeine.

Antimuscarinic agents:

oxybutinin, tolterodin, atropine, benzhexol HCl, biperiden, ethopropazine HCl, hyoscine butyl bromide, hyoscyamine, mepenzolate bromide, orphenadrine, oxyphencylcimine HCl, tropicamide.

Modern antitumor agents and immunosuppressive agents:

Aminoglutethimide, amsacrine, azathioprene, busulphan, chlorambucil, cyclosporin, dacarbazine, estramustine, etoposide, lomustine, melphalan, mercaptopurine, methotrexate, mitomycin, mitotane, mitozantrone, procarbazine HCl, tamoxifen citrate, testolactone.

And antiprotozoa:

Benznidazole, clioquinol, decoquinate, diiodohydroxyquinoline, diloxanide furcate, dinitolmide, furzolidone, metronidazole, nimorazole, nitrofurazone, ornidazole, tinidazole.

And antirheumatic drugs:

ibuprofen, aceclofenac, acemetacin, azapropazone, diclofenac sodium, diflunisal, etodolac, ketoprofen, indomethacin, mefenamic acid, naproxen, piroxicam, aspirin, benorylate, auranofin, penicillamine.

And anti-rhinitis: Cetirizin, fexofenadin, ebastine, loratidin, montelukast.

And antithyroid agents: carbimazole, propylthiouracil.

Antiviral:

acyclovir, amantadine hydrochloride, famciclovir, zidovadine, didanosine, zalcitabine, foscarnet sodium

Anxiolytics, sedatives, hypnotics, neuroleptics:

Alprazolam, amylobarbitone, barbitone, bentazepam, bromazepam, bromperidol, brotizolam, butobarbitone, carbromal, chlordiazepoxide, chlorpheniramine, chlormethiazole, chlorpromazine, clobazam, clonazepan, clotiazepam, clozapine, diazepam, droperidol, ethinamate, flunanisone, flunitrazepam , fluopromazine, flupenthixol decanoate, fluphenazine decanoate, flurazepam, haloperidol, lorazepam, lormetazepam, medazepam, meprobamate, methaqualone, midazolam, nitrazepam, oxazepam, pentobarbitone, Perphenazine, phenylephrine, pimozide, prochlorperazine, pseudoephedrineHCL, sulpride, temazepam, thioridazine, triazolam, zopiclone.

Obstacles to β:

acebutolol, alprenolol, atenolol, labetalol, metoprolol, nadolol, oxprenolol, pindolol, propanolol

Factors affecting myocardial contraction:

amrinone, digitoxin, digoxin, enoximone, lanatoside C, medigoxin

And Corticosteroids:

beclomethasone, betamethasone, budesonide, cortisone acetate, desoxymethasone, dexamethasone, fludrocortisone acetate, flunisolide, flucortolone, fluticasone propionate, hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone.

Cough soothing agents:

Codeine phosphate, dexomethorphan, guaifenesin, pholcodine, diamorphine, methadone.

Cytotoxic agents:

ifosfamide, chlorambucil, melphalan, busulphan, cytotoxic antibodies, doxorubicin, epirubicin, plicamycin, bleomycin, methotrexate, cytarabine, fludarabine, gencitabine, fluorouracil, mercaptopurine, thioguanine, vincristine, vinblastine, vindesine, etoposide.

Decongestants: pseudoephedrine hydrochloride.

Diuretic agents:

Acetazolamide, amiloride, bendrofluazide, bumetanide, chlorothiazide, chlorthalidone, ethacrynic acid, frusemide, metolazone, spironolactone, triamterene.

Enzymes: pancreatin, pepsin, lipase

Epilepsy: Gabapentin.

Anti-Parkinson's agents:

bromocriptine mesylate, lysuride maleate, selegiline, para-fluoroselegiline, lazabemide, rasagiline, 2-BUMP [N-(2-butyl)-N-methylpropargylamine], M-2-PP [N-methyl-N-(2-pentyl) -propargylamine], MDL-72145 [beta-(fluoromethylene)-3,4-dimethoxy-benzeneethanamine], mofegiline, apomorphine, N-propylnoraporphine, cabergoline, metergoline, naxagolide, pergolide, piribedil, ropinirole, terguride, quinagolide.

Gastrointestinal factors:

bisacodyl, cimetidine, cisapride, diphenoxylate HCl, domperidone, metoclopramide, famotidine, loperamide, mesalazine, nizatidine, esomeprazole, metopimazine, pantoprazole, ondansetron HCl, granisetron, tropisetron, dolasetron, ranitidine HCl, sulphasalazine. lanzoprazole,

And antihistamine receptor antagonist agents:

acrivastine, astemizole, cinnarizine, cyclizine, cyproheptadine HCl, dimenhydrinate, flunarizine HCl, loratadine, meclozine HCl, oxatomide, terfenadine, triprolidine.

Hormone replacement therapy: dydrogesterone.

Antihypertensive drug: Enalapril.

Galactagogues: Oxytocin, and cofactors of Oxytocin.

Lipid control agents/bezafibrate, clofibrate, fenofibrate, gemfibrozil, probucol.

Local anesthetics:

amethocaine, amylocaine, benzocaine, bucricaine, bupivacaine, butacaine, butanilicaine, butoxycaine, butyl aminobenzoate, carticaine, chloroprocaine, cinchocaine, clibucaine, clormecaine, coca, cocaine, cyclomethycaine, dimethisoquin, diperodon, dyclocaine, ethyl chloride, ethyl p -piperidinoacetylaminobenzoate, etidocaine , hexylcaine, isobutamben, ketocaine, lignocaine, mepivacaine, meprylcaine, myrtecaine, octacaine, oxethazaine, oxybuprocaine, parethoxycaine, pramoxine, prilocaine, procaine, propranocaine, propoxycaine, proxymetacaine, ropivacaine, tolycaine, tricaine, trimecaine, vadocaine.

Motion sickness: diphenhydramine.

Neuromuscular agents: pyridostigmine.

Nitrates and other antianginal agents:

amyl nitrate, glyceryl trinitrate, isosorbide dinitrate, isosorbide mononitrate, pentaerythritol tetranitrate.

Nutritional factors: beta-carotene, vitamins, such as vitamin A, vitamin B2, vitamin D, vitamin E, vitamin K, minerals.

Opiate drugs:

Codeine, dextropropyoxyphene, diamorphine, dihydrocodeine, meptazinol, methadone, morphine, nalbuphine, pentazocine.

Oral vaccines: To prevent or reduce the 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, ischemic, long-term and lupus-like hepatitis, Otitis media, Dengue fever, Rabies, Parainfluenza, Rubella, Yellow Fever, Dysentery, Legionnaires Disease, Toxoplasmosis, Q-Fever, Haemorrhage Fever, Argentina Haemorrhage Fever, Caries Chagas Disease, Urinary Tract Infection caused by E. coli, Pneumococcal Disease, Mumps, Chikungunya, Hayfever, Asthma, Rheumatoid Arthritis, Carcinomas, Coccidiosis, Newcastle Disease, Zoonotic pneumonia, Feline leukemia, Inflammation Atrophic rhinitis, erysipelas, foot-and-mouth disease and porcine pneumonia, or preventing or reducing symptoms caused by Vibrio species, Salmonella species, Bordetella species, Haemophilus species, Toxoplasmosis gondii, Cytomegalovirus, Chlamydia species, Streptococcal species, Norrolk virus, Escherichia coli, Helicobacter pylori, Rotavirus, Neisseria gonorrhoeae, Neisseria meningitidis, Adenovirus, Epstein Ban- Virus, Inflammation virus Japanese Encephalitis Virus, Pneumocystis carini, Herpes simplex, Clostridia species, respiratory syncytial virus Respiratory Syncytial Virus, Klebsiella species, Shigella species, Pseudomonas aeruginosa, Parvovirus, Campylobacter species, Rickettsia species, Varicella zoster virus, Yersinia species, Ross River Virus, JC virus , Rhodococcus equi, Moraxella catarrhalis, Borrelia burgdorferi and Pasteurella hemolyticus. Pasteurella haemolytica

Impaired emptying functions: tamsulosin, trospium chloride, tolterodine, oxybutynin.

Proteins, peptides and drugs: resplicing hormones and homologous hormones, resplicing cytokines, resplicing plasminogens, TNF receptor fusion protein, monoclonal antibodies, nucleic acids, antisense oligonucleotides, oligonucleotides, Glycoproteins and adhesion molecules.

Arthritis in animals: Tepoxalin

Sex hormones and contraceptives:

clomiphene citrate, danazol, desogestrel, ethinyloestradiol, ethynodiol, ethynodiol diacetate, levonorgestrel, medroxyprogesterone acetate, mestranol, methyltestosterone, norethisterone, norethisterone enanthate, norgestrel, estradiol, conjugated estrogens, dydrogesterone, stanozolol, stilboestrol, testosterone, tibolone.

Schizophrenia; Olanzapine, Nicergoline

Sexual dysfunction: Cabergolin, oxytocin, tadalafil, sildenafil, vardenafil

Spermicides: nonoxynol 9.

Stimulants: amphetamine, dexamphetamine, dexfenfluramine, fenfluramine, mazindol, pemoline.

In a specific unbound form, the active ingredient is desmopressin acetate. In this dosage form the dosage form may be used to delay voiding or to treat, treat, or prevent urinary incontinence, nocturia, nocturia, or central incontinence. In one embodiment, the amount of desmopressin acetate in the composition comprises between 0.01 and 2.00% w/w. In another embodiment, the amount of desmopressin acetate in the composition comprises between 0.04 and 1.00% w/w.

In a specific unrestricted embodiment, the active ingredient is loratadine. In this form the dosage form may be used for example to improve nasal or non-nasal symptoms of allergic rhinitis and chronic idiopathic urticaria. In one embodiment, the amount of loratidine in the composition comprises 20-40%w/w. In another embodiment, the amount of loratidine in the composition includes 25-40% w/w.

In a specific unrestricted embodiment, the active ingredient is famotidine. In this dosage form the dosage form can be used, for example, in the treatment of gastroesophageal reflux disease, duodenal and gastric ulcers, pathological hypersecretory conditions (eg Zollinger-Eliison syndrome and multiple endocrine adenomas). In one embodiment, the amount of famotidine in the composition comprises 50-90% w/w. In another embodiment, the amount of famotidine in the composition comprises between 60 and 90% w/w.

In a specific unrestricted embodiment, the active ingredient is montelukast sodium. In this dosage form the dosage form may be used for example in the prevention and treatment of chronic asthma, allergic rhinitis and exercise-induced bronchoconstriction. In one embodiment, the amount of montelukast sodium in the composition comprises 5-40% w/w. In another embodiment, the amount of montelukast sodium in the composition comprises 5-30% w/w.

In a specific unrestricted embodiment, the active ingredient is ondasetron. In this form the dosage form can be used, for example, to prevent postoperative nausea and/or vomiting and also to prevent nausea associated with chemotherapy and radiotherapy for cancer. In one embodiment, the amount of ondansetron in the composition comprises 10-30% w/w. In another embodiment, the amount of ondansetron in the composition comprises about 20% w/w.

The pharmaceutical dosage form of the invention disintegrates, thus releasing the active ingredient, once it comes into contact with a fluid (aqueous medium or saliva).

Typically, the pharmaceutical dosage form of the invention is an orally disintegrating pharmaceutical dosage form that disintegrates in the mouth within 30 seconds, typically 10 seconds or less.

The term “oral disintegration” as used herein should be understood to include a solid dosage form that disintegrates or dissolves in the mouth within (at most) 30 seconds. In other embodiments, the orally disintegrated dosage form disintegrates intraorally within 10, 9, 8, 7, 6, 5, 4, 3, 2 or even 1 second.

A suitable method for administering the dosage form for the particular case of the invention includes oral administration including buccal and sublingual administration. In a specific embodiment, the dosage form is administered sublingually. The dosage images of the invention may also be placed on the tongue or opposite the cheek or gums.

The pharmaceutical dosage forms of the present invention are adapted to supply the active ingredient for example into the oral cavity. The active ingredient may be absorbed across the mucous membrane at the site of administration, e.g. the mucous membrane under the tongue, and/or, in the case of oral administration, from the oral cavity (e.g. via the mucous membranes of the buccal and/or gingiva) and/or From the digestive tract for distribution throughout the body.

The exact dosage and dosage regimen will depend on the therapeutic effect to be achieved and can vary based on the specific active ingredient, the method of administration and the age and condition of the individual to be administered the drug. Sometimes patients may be instructed to take 2 or any other number of FU in a single dose and sometimes only a portion, such as half or a quarter of a FU in a single dose.

The dosage form of the invention achieves a balance of performance: tensile strength, stability and rapid disintegration. It can be produced by well-known freeze-drying techniques. It can be stored (and packaged) in strips but due to its tensile strength, it can also be stored and/or packaged in bottles or consignments. The invention achieves these results in a single processing step, without having to resort to multiple steps involving granulation.

In addition to the components described above, the web may also include other excipients (auxiliary agents, secondary agents) including, but not limited to, fillers, web-forming agents, thickeners (including but not limited to guar gum and xantham gum). ), binders, diluents, lubricants, pH adjusting agents, protecting agents, viscosity improvers, flocculants, non-effervescent flocculants, effervescent flocculants, surfactants, antioxidants, wetting agents, coloring agents, flavoring agents, and flavoring agents. Masking the taste, sweet-flavoring substances, preservatives, and so on.

In one embodiment, a composition of the invention is obtained by solvent sublimation of a liquid preparation comprising an active ingredient, levan and optionally secondary mesh forming agent(s) in a solvent. Typically, the liquid formulation is placed in a mold, for example where a solid formulation, typically in a dosage unit, is sublimated within the mold. The mold may be a granule package by which the solid dosage form is formed within the cavity of the granule package which is then sealed by a thin sealing film or foil foil is placed

In one embodiment, the process includes inserting unit dosage amounts of said composition into special recesses of the open granule package; The preparation is then sublimated to obtain solid dosage forms within the depressions mentioned.

Sublimation may be accomplished by freeze-drying the preparation comprising the active ingredient, levan and optionally secondary mesh forming agent(s) in a solvent. In one embodiment, the solvent is water.

The invention thus discloses a process for preparing rapidly disintegrating dosage forms by freeze-drying a combination of an active ingredient, levan and optionally a secondary tissue network forming agent(s). The rapidly disintegrating dosage form comprises a mesh of the active ingredient, levan carrier and optionally secondary mesh-forming agent(s), the mesh obtained by solvent sublimation of the liquid preparation containing the active ingredient, levan and optional other mesh-forming agents. Said preparation may be a solution, suspension or dispersion. Typically, a primary preparation containing the active ingredient, levan and optionally secondary mesh forming agent(s) is prepared in a solvent, followed by sublimation. Sublimation can be performed by freeze-drying the preparation.

In the freeze-drying procedure, a preparation (in liquid form) comprising an active ingredient, levan and any other optional mesh forming agent in a solvent is filled into molds. Typically, each bar contains a specified amount of the solution in question as well as a specified amount of an active ingredient. The preparation in the mold is then frozen, for example by passing a gaseous cooling medium over the mold. After the preparation solidifies, the solvent is sublimated from it. Freezing is performed in a freeze-drying unit. As a result, an open matrix network is obtained from Levan, optionally combined with other agents to form a matrix network included in the solution, carrying the active ingredient.

The preparation is placed in a mold during the freeze-drying process to obtain a solid image in any desired shape. Prior to the freeze-drying process, the mold can be cooled and frozen (e.g. in a quick freeze tube or the racks of a freeze-drying unit), e.g. using liquid nitrogen or solid carbon dioxide. In one embodiment, the freezing rate ranges from 0.1 to 2 °C/min . In another embodiment, the freezing rate ranges from 0.5 to 1.5°C/min. In yet another embodiment, the freezing rate ranges from 10 to 260°C/min. In another embodiment, the freezing rate ranges from 20 to 260°C/min. In another embodiment, the freezing rate ranges from 20 to 160°C/min.

After lyophilization, the freeze-dried formulations can be removed from the mold as needed or stored in the mold until used. Typically, each mold is designed to produce a unit dosage form of the formulation. Therefore, the resulting composition is highly soluble and decomposes within 30 seconds at most once it comes into contact with a fluid, and typically within less than 10 seconds.

Typically the solvent is water but can optionally also include a co-solvent (such as tert-butyl alcohol) to improve the solubility of the chemical compound.

The composition may include a pH adjusting agent to adjust the pH of the solution from which the dosage form is prepared over a range of 2 to 10, typically 3.5 to 9.5 or 4.5 to 8. Citric acid, sodium hydroxide and sodium carbonate can be used as a pH adjusting agent, but other agents including hydrochloric acid and malic acid can also be used. Non-volatile pH adjusting agents will not be removed by freeze-drying or other sublimation processes and can therefore be present in the final product. When the fast-dissolving dosage form of the invention is prepared using the primary web-forming agent levan without the addition of secondary web-forming agents, an annealing process (temperature shifts) can be used during the freeze-drying process to smooth the surface of the dosage form. The annealing step is performed for technical purposes only and has no effect on the dissolution time or the tensile strength of the resulting dosage form. When secondary web forming agents are present, the aforementioned smoothing annealing step is not needed.

The mold may comprise a series of cylindrical or other shaped cavities, each of a size corresponding to the size of the dosage form required to be formed.

In one embodiment, the die is a cavity in a wafer of thin material. A thin material can have more than one cavity. The thin material may be similar to that used in granule containers used to package oral contraceptive pills and similar dosage forms. For example, the thin material can be made of a thermoplastic material with depressions formed by heat forming or cold forming. A thin layer of polyvinyl chloride can be used as the thin material. Thin material chips can also be used.

Examples

The invention is described in the following examples, which are not in any way limited to the scope of said invention.

Materials used in the examples shown below

Subject

the supplier

Levan (Zymomonas spp.)

RealBiotech, Korea

Levan (Bacillus spp.)

Montana Polysaccharides, USA

Citric acid

Merck, India

Mannitol

Merck, India

Desmopressin acetate

Manufactured by Polypeptide Labs A/S, and supplied by Ferring

Loratadine

Ultratech India Ltd

Famotidine

Exim Pharma International, India

Montelukast Sodium

MSN Pharma Chem Pvt.Ltd., India

Ondansetron base

Cadila Pharma Ltd., India

Guar gum

Merck, India

Sodium lauryl sulphate (SLS)

Merck, India

Xanthan gum

SD Fine Chem Ltd., India

Sodium citrate

Merck, India

Pullulan

Hyashibara, Japan

Glycine

Sigma Aldrich

Hydropropyl methyl cellulose (HPMC)

Shin-Etsu Chemical Co.Japan

Methyl cellulose

Shin-Etsu Chemical Co.Japan

Gum tragacanth

Merck, India

Fish gelatin

Croda Chemicals Pvt.Ltd, India

Sodium methyl paraben

Alta Lab Pvt.Ltd., India

Raffinose

Loba Chemie Pvt.Ltd., India

Trehalose

Loba Chemie Pvt.Ltd., India

Sodium propyl paraben

Prayosha Healthcare, India

Hydroxy propyl b cyclodextrin

Gangwal Chemicals Pvt.Ltd., India

Sodium hydroxide

Merck, India

Neotame

Nutrasweet, USA

Strawberry flavour

Virginia Dare, USA

Cherry flavour

Virginia Dare, USA

How to prepare a satisfactory treatment formula

1) Dissolve levan, and other excipients, if present, in purified water while stirring at 200 to 500 revolutions per minute (rpm).

2) Optionally adjust the pH of the solution using Citric acid or NaOH solution.

3) Make up the final volume of the solution using purified water.

4) Mix the solution and stir at 200 to 500 rpm for 15 minutes.

5) Add the dose of solution into each cavity of the pre-formed granule package flakes (typically using a dispensing pipette).

6) Freezing the filled granule containers at a temperature ranging from -20 to -110°C.

7) Dry the granule packages in a freeze-drying unit

8) Place the granule packing chip containing the dry freeze-drying products. The perforated carrier fabric of the granule packing machine to transport the granule packing chips through the sealing station of the packing machine.

9) Seal the granule packages using foil is placed and place them in the final granule packages.

C1.Formulas

The following formulations were prepared using the method described in Methods Section B above, by freezing the granule packages at a rate of 0.12°C/min in step 6.

Example - 1

Component

Quantity/Unit

%w/w

levan (Bacillus species)

25 mg

100

Purified water

Sufficient quantity: up to 250 microliters

-

Example - 2

Component

Quantity/Unit

%w/w

levan (Zymomonas species)

25 mg

100

Purified water

Sufficient quantity: up to 250 microliters

-

Example - 3

Component

Quantity/Unit

%w/w

levan (Bacillus species)

37.5 mg

100

Purified water

Sufficient quantity: up to 250 microliters

-

Example - 4

Component

Quantity/Unit

%w/w

levan (Zymomonas species)

37.5 mg

100

Purified water

Sufficient quantity: up to 250 microliters

-

Component

Quantity/Unit

%w/w

levan (Zymomonas species)

18.75 mg

100

Purified water

Sufficient quantity: up to 250 microliters

-

Example - 6

Component

Quantity/Unit

%w/w

levan (Zymomonas species)

12.5 mg

100

Purified water

Sufficient quantity: up to 250 microliters

-

Example - 7

Component

Quantity/Unit

%w/w

levan (Zymomonas species)

18.75 mg

99.99

Citric acid (5% w/v)

Sufficient amount up to a pH of 4.5

Sufficient amount up to a pH of 4.5

Purified water

Sufficient quantity: up to 250 microliters

-

Example - 8

Component

Quantity/Unit

%w/w

levan (Zymomonas species)

18.75 mg

99.99

Citric acid (5% w/v)

Sufficient amount up to a pH of 5.0

Sufficient amount up to a pH of 5.0

Purified water

Sufficient quantity: up to 250 microliters

-

Example - 9

Component

Quantity/Unit

%w/w

levan (Zymomonas species)

25 mg

99.99

0.1 N NaOH

Sufficient amount up to pH 7.0

Sufficient amount up to pH 7.0

Purified water

Sufficient quantity: up to 250 microliters

-

Example - 10

Component

Quantity/Unit

%w/w

levan (Zymomonas species)

25 mg

99.99

0.1 N NaOH

Sufficient amount up to pH 8.0

Sufficient amount up to pH 8.0

Purified water

Sufficient quantity: up to 250 microliters

-

Example - 11

Component

Quantity/Unit

%w/w

levan (Zymomonas species)

25 mg

99.99

0.1 N NaOH

Sufficient amount up to a pH of 9.0

Sufficient amount up to a pH of 9.0

Purified water

Sufficient quantity: up to 250 microliters

-

Example 12

Component

Quantity/Unit

%w/w

levan (Zymomonas species)

18.75 mg

75

mannitol

6.25 mg

25

Purified water

Sufficient quantity: up to 250 microliters

-

Example 13

Component

Quantity/Unit

%w/w

levan (Zymomonas species)

12.5 mg

50

mannitol

12.5 mg

50

Purified water

Sufficient quantity: up to 250 microliters

-

C2. Formulas

The following formulas were prepared:

Using the methods described in b above, by freezing the granule packages at a rate of 20-160°C/min for ≤4 minutes in step 6.

Example - 14

Component

Quantity/Unit

%w/w

levan (Zymomonas species)

25 mg

100

Purified water

Sufficient quantity: up to 250 microliters

-

Example 15

Component

Quantity/Unit

%w/w

levan (Zymomonas species)

25 mg

99.99

Citric acid (5% w/v)

Sufficient amount up to a pH of 4.5

Sufficient amount up to a pH of 4.5

Purified water

Sufficient quantity: up to 250 microliters

-

Example 16

Component

Quantity/Unit

%w/w

levan (Zymomonas species)

16.25 mg

64.99

mannitol

8.75 mg

34.99

Citric acid (5% w/v)

Sufficient amount up to a pH of 4.0

Sufficient amount up to a pH of 4.0

Purified water

Sufficient quantity: up to 250 microliters

-

Example 17

Component

Quantity/Unit

%w/w

levan (Zymomonas species)

16.25 mg

64.99

mannitol

8.75 mg

34.99

Citric acid (5% w/v)

Sufficient amount up to a pH of 4.5

Sufficient amount up to a pH of 4.5

Purified water

Sufficient quantity: up to 250 microliters

-

Example 18

Component

Quantity/Unit

%w/w

levan (Zymomonas species)

16.25 mg

64.99

mannitol

8.75 mg

34.99

Citric acid (5% w/v)

Sufficient amount up to a pH of 5.0

Sufficient amount up to a pH of 5.0

Purified water

Sufficient quantity: up to 250 microliters

-

Example 19

Component

Quantity/Unit

%w/w

levan (Zymomonas species)

12.5 mg

49.99

mannitol

12.5 mg

49.99

Citric acid (5% w/v)

Sufficient amount up to a pH of 4.5

Sufficient amount up to a pH of 4.5

Purified water

Sufficient quantity: up to 250 microliters

-

Example 20

Component

Quantity/Unit

%w/w

levan (Zymomonas species)

18.75 mg

74.99

mannitol

6.25 mg

24.99

Citric acid (5% w/v)

Sufficient amount up to a pH of 4.5

Sufficient amount up to a pH of 4.5

Purified water

Sufficient quantity: up to 250 microliters

-

Example - 21

Component

Quantity/Unit

%w/w

levan (Zymomonas species)

18.75 mg

75.0

raffinose

6.25 mg

25.0

Purified water

Sufficient quantity: up to 250 microliters

-

Example 22

Component

Quantity/Unit

%w/w

levan (Zymomonas species)

18.75 mg

74.99

The trehalose

6.25 mg

24.99

Citric acid (5% w/v)

Sufficient amount up to a pH of 4.5

Sufficient amount up to a pH of 4.5

Purified water

Sufficient quantity: up to 250 microliters

-

Dr.. How to prepare dosage forms containing desmopressin

1) Dissolve levan, and other excipients, if present, in purified water while stirring at 200 to 500 rpm;

2) Dissolve desmopressin acetate in purified water and add it to the solution prepared in step 1.

3) Adjust the pH of the solution using Citric acid solution (5% w/v).

4) Make up the final volume of the solution using purified water.

5) Mix the solution and stir at 200 to 500 rpm for an additional period of 5 - 15 minutes.

6) Add the dose of solution into the depressions of the pre-formed pellet pack flakes (typically using a dispensing pipette).

7) Freezing the filled granule containers at a temperature ranging from -20 to -110°C.

8) Dry the granule packages in a freeze-drying unit

9) Place the granule packing chip containing the dry freeze-drying products into the perforated carrier fabric of the granule packing machine, to transport the granule packing chips through the sealing station of the packing machine.

10) Seal the granule packages using foil is placed and place them in the final granule packages.

e. Desmopressin formulas

Desmopressin freeze-dried product formulations were prepared using the method described in D above, by freezing the granule packages at a rate of 0.1 2°C/min or 20 160°C/min in step 7.

Example - 23

Component

Quantity/Unit

%w/w

desmopressin acetate

desmopressin equivalent

240 Microgram

0.63

levan (Bacillus species)

37.5 mg

99.36

Citric acid (5% w/v)

Sufficient amount up to a pH of 4.5

Sufficient amount up to a pH of 4.5

Purified water

Sufficient quantity: up to 250 microliters

-

Example 24

Component

Quantity/Unit

%w/w

desmopressin acetate

desmopressin equivalent

240 Microgram

1.3

levan (Zymomonas species)

18.75 mg

98.7

Citric acid (5% w/v)

Sufficient amount up to a pH of 4.5

Sufficient amount up to a pH of 4.5

Purified water

Sufficient quantity: up to 250 microliters

-

Example 25

Component

Quantity/Unit

%w/w

desmopressin acetate

desmopressin equivalent

240 Microgram

1.3

levan (Zymomonas species)

18.75 mg

98.7

Citric acid (5% w/v)

Sufficient amount up to a pH of 5.0

Sufficient amount up to a pH of 5.0

Purified water

Sufficient quantity: up to 250 microliters

-

Example 26

Component

Quantity/Unit

%w/w

desmopressin acetate

desmopressin equivalent

240 Microgram

0.95

levan (Zymomonas species)

16.25 mg

64.4

mannitol

8.75 mg

34.7

Citric acid (5% w/v)

Sufficient amount up to a pH of 4.5

Sufficient amount up to a pH of 4.5

Purified water

Sufficient quantity: up to 250 microliters

-

Example 27

Component

Quantity/Unit

%w/w

desmopressin acetate

desmopressin equivalent

240 Microgram

1.26

levan (Zymomonas species)

18.75 mg

98.73

sodium citrate (2.5 mM buffer solution)

Sufficient amount up to a pH of 4.5

Sufficient amount up to a pH of 4.5

Purified water

Sufficient quantity: up to 250 microliters

-

Example 28

Component

Quantity/Unit

%w/w

desmopressin acetate

desmopressin equivalent

240 Microgram

1.26

levan (Zymomonas species)

18.75 mg

98.73

sodium citrate (5.0 mM buffer solution)

Sufficient amount up to a pH of 4.5

Sufficient amount up to a pH of 4.5

Purified water

Sufficient quantity: up to 250 microliters

-

Example - 29

Component

Quantity/Unit

%w/w

desmopressin acetate

desmopressin equivalent

240 Microgram

0.79

levan (Zymomonas species)

19.5 mg

64.48

mannitol

10.5 mg

34.72

sodium citrate (5.0 mM buffer solution)

Sufficient amount until Ph reaches 4.5

Sufficient amount up to a pH of 4.5

Purified water

Sufficient quantity: up to 250 microliters

-

Example 30

Component

Quantity/Unit

%w/w

desmopressin acetate

desmopressin equivalent

60 Microgram

0.19

levan (Zymomonas species)

19.5 mg

64.87

mannitol

10.5 mg

34.93

Citric acid (5% w/v)

Sufficient amount up to a pH of 4.5

Sufficient amount up to a pH of 4.5

Purified water

Sufficient quantity: up to 250 microliters

-

Example 31

Component

Quantity/Unit

%w/w

desmopressin acetate

desmopressin equivalent

25 Microgram

0.08

levan (Zymomonas species)

19.5 mg

64.94

mannitol

10.5 mg

34.97

Citric acid (5% w/v)

Sufficient amount up to a pH of 4.5

Sufficient amount up to a pH of 4.5

Purified water

Sufficient quantity: up to 250 microliters

-

Example 32

Component

Quantity/Unit

%w/w

desmopressin acetate

desmopressin equivalent

10 Microgram

0.03

levan (Zymomonas species)

19.5 mg

64.97

mannitol

10.5 mg

34.99

Citric acid (5% w/v)

Sufficient amount up to a pH of 4.5

Sufficient amount up to a pH of 4.5

Purified water

Sufficient quantity: up to 250 microliters

-

And the. Methods of preparing dosage forms containing Loratadine

1) Disperse guar gum in purified water while stirring.

2) Prepare a solution of levan and other excipients in water while stirring, and add this solution to the guar gum solution obtained in step 1 while stirring at 200-500 rpm.

3) Add loratadine to the solution obtained in step 2 by stirring continuously until 200 - 500 rpm.

4) The loratadine suspension is homogenized for a period of 10-20 minutes to obtain a uniform suspension.

5) Adjust the pH of the suspension using Citric acid solution (5% w/v).

6) Form the final volume of the suspension using purified water .

7) Mix the suspension and stir at 200 to 500 rpm for an additional period of 5 - 15 minutes.

8) Add the prepared dose of suspension into each cavity of the pre-formed granule package chips while stirring the suspension moderately to maintain uniformity.

9) Freezing the filled granule containers at a temperature ranging from -20 to -110°C.

10) Dry the granule packages in a freeze-drying unit

11) Place the granule packing chip containing dry freeze-drying products into the perforated carrier fabric of the granule packing machine, to transport the granule packing chip through the sealing station of the packing machine.

12) Seal the granule packages using foil is placed and place them in the final granule packages.

g. Loratadine Formulations The following loratidine freeze-drying product formulations were prepared using the method described in F above, by freezing the granule packages at a rate of 0.1-2°C/min or 20-160°C/min in step 9.

Example 33

Component

Quantity/Unit

%w/w

Loratadine

10 mg

28.5

levan (Zymomonas species)

25 mg

70.5

Guar gum

0.437 mg

0.01

Citric acid (5% w/v)

Sufficient amount up to a pH of 4.3

Sufficient amount up to a pH of 4.3

Purified water

Sufficient quantity up to 350 microliter

-

Example 34

Component

Quantity/Unit

%w/w

Loratadine

10 mg

35.8

levan (Zymomonas species)

17.5 mg

62.6

Guar gum

0.437 mg

0.01

Citric acid (5% w/v)

Sufficient amount up to a pH of 4.8

Sufficient amount up to a pH of 4.8

Purified water

A sufficient amount of 350 microliters

-

Example 35

Component

Quantity/Unit

%w/w

Loratadine

10 mg

35.7

levan (Zymomonas species)

17.5 mg

62.4

Guar gum

0.437 mg

0.01

SLS

0.087 mg

0.003

Citric acid (5% w/v)

Sufficient amount up to a pH of 4.8

Sufficient amount up to a pH of 4.8

Purified water

A sufficient amount of 350 microliters

-

H. Methods of preparing dosage forms containing famotidine

1) Disperse xanthan gum or guar gum in purified water and stir.

2) Dissolve levan in the solution obtained in step 1 while stirring at 200 - 500 rpm.

3) Add famotidine to the solution of step 2 with continuous stirring at 200 - 500 rpm until a suitable suspension is obtained.

4) The famotidine suspension obtained in step 3 is homogenized for 10 minutes to obtain a uniform suspension.

5) Adjust the pH of the suspension using 0.1 N NaOH.

6) Form the final volume of the suspension using purified water.

7) Mix the suspension and stir at 200 to 500 rpm for an additional period of 5 - 15 minutes.

8) Add the prepared dose of suspension into each cavity of the pre-formed granule package chips while stirring the suspension moderately to maintain uniformity.

9) Freezing the filled granule containers at a temperature ranging from -20 to -110°C.

10) Dry the granule packages in a freeze-drying unit

11) Place the granule packing chip containing dry freeze-drying products into the perforated carrier fabric of the granule packing machine, to transport the granule packing chip through the sealing station of the packing machine.

12) Seal the granule packages using foil is placed and place them in the final granule packages.

i. Famotidine formulas

The following famotidine orally disintegrating dosage forms were prepared using the method described above in H, by freezing the granule packages at a rate of 0.1°C/min or 20-160°C/min in step 9.

Component

Quantity/Unit

%w/w

famotidine

20 mg

65.5

levan (Zymomonas species)

10.5 mg

34.4

Xanthan gum

0.023 mg

0.07

0.1 N NaOH

Sufficient amount up to pH 8.0

Sufficient amount up to pH 8.0

Purified water

A sufficient amount of 250 microliters

-

Component

Quantity/Unit

%w/w

famotidine

20 mg

60.8

levan (Zymomonas species)

12.5 mg

38.0

Xanthan gum

0.37 mg

1.1

0.1 N NaOH

Sufficient amount up to pH 8.0

Sufficient amount up to pH 8.0

Purified water

A sufficient amount of 250 microliters

-

Component

Quantity/Unit

%w/w

famotidine

20 mg

65.10

levan (Zymomonas species)

10.5 mg

34.18

Xanthan gum

0.219 mg

0.71

0.1 N NaOH

Sufficient amount up to pH 8.0

Sufficient amount up to pH 8.0

Purified water

A sufficient amount of 250 microliters

-

Component

Quantity/Unit

%w/w

famotidine

40 mg

88.03

levan (Zymomonas species)

5 mg

11.00

Guar gum

0.437 mg

0.96

0.1 N NaOH

Sufficient amount up to pH 8.0

Sufficient amount up to pH 8.0

Purified water

A sufficient amount of 250 microliters

-

Y. Methods of preparing dosage forms containing montelukast sodium

1) Dissolve montelukast in purified water while stirring.

2) Dissolve levan, and other excipients if present, in the montelukast solution of Step 1 while stirring at 200 - 500 rpm.

3) Make up the final volume of the solution using purified water.

4) Mix the solution and stir at 200 to 500 rpm for an additional 15 minutes.

5) Add the dose of solution into each cavity of the pre-formed granules package.

6) Freeze the filled granule containers at a temperature ranging from -60 to -80 degrees Celsius.

7) Dry the granule packages in a freeze-drying unit

8) Place the granule packing chip containing dry freeze-drying products into the perforated carrier fabric of the granule packing machine, to transport the granule packing chips through the sealing station of the packing machine.

9) Seal the granule packages using foil is placed and place them in the final granule packages.

K. Formulations of montelukast sodium The following oral disintegrating dosage form of montelukast was prepared using the method described in “j” above, by freezing granule packages at a rate of 0.1-2°C/min or 20-160°C/min in step 6.

Example - 40

Component

Quantity/Unit

%w/w

montelukast sodium

montelukast equivalent

10 mg

28.57

levan

25 mg

71.42

Purified water

Sufficient quantity: up to 250 microliters

-

Example 41

Component

Quantity/Unit

%w/w

montelukast sodium

montelukast equivalent

10 mg

28.57

levan

18.75 mg

53.57

mannitol

6.25 mg

17.85

Purified water

Sufficient quantity: up to 250 microliters

-

Example 42

Component

Quantity/Unit

%w/w

montelukast sodium

montelukast equivalent

10 mg

27.93

levan

18.75 mg

52.37

mannitol

6.25 mg

17.45

neotame

0.3 mg

0.83

Cherry flavour

0.5 mg

1.39

Purified water

Sufficient quantity: up to 250 microliters

-

Example 43

Component

Quantity/Unit

%w/w

montelukast sodium

montelukast equivalent

10 mg

27.93

levan

18.75 mg

52.37

mannitol

13.5 mg

17.45

Hydroxypropyl b-cyclodextrin

11.3 mg

neotame

0.3 mg

0.83

Cherry flavour

0.5 mg

1.39

Purified water

Sufficient quantity: up to 250 microliters

-

Example 44

Component

Quantity/Unit

%w/w

montelukast sodium

montelukast equivalent

10 mg

17.84

levan

18.75 mg

33.45

mannitol

14.0 mg

24.97

The trehalose

12.5 mg

22.30

neotame

0.3 mg

0.53

Cherry flavour

0.5 mg

0.89

Purified water

Sufficient quantity: up to 250 microliters

-

Example 45

Component

Quantity/Unit

%w/w

montelukast sodium

montelukast equivalent

4.0 mg

13.64

levan

18.75 mg

63.94

mannitol

6.25 mg

21.31

neotame

0.12 mg

0.41

Cherry flavour

0.2 mg

0.68

Purified water

Sufficient quantity: up to 250 microliters

-

Example 46

Component

Quantity/Unit

%w/w

montelukast sodium

montelukast equivalent

4.0 mg

8.06

levan

18.75 mg

37.82

mannitol

14.0 mg

28.24

trehalose

12.5 mg

25.21

neotame

0.12 mg

0.24

Cherry flavour

0.2 mg

0.41

Purified water

Sufficient quantity: up to 250 microliters

-

Example 47

Component

Quantity/Unit

%w/w

montelukast sodium

montelukast equivalent

5.0 mg

9.89

levan

18.75 mg

37.08

mannitol

14.0 mg

27.68

trehalose

12.5 mg

24.72

neotame

0.12 mg

0.23

Cherry flavour

0.2 mg

0.39

Purified water

Sufficient quantity: up to 250 microliters

-

to. Methods of preparing dosage forms containing ondansetron

1) Dissolve levan, mannitol, methyl parabens, propyl parabens, pH adjusting agent, sweeteners and/or flavoring agents in purified water while stirring.

2) Disperse Ondansetron with stirring at 200 - 500 rpm in the solution obtained in step 1.

3) Make up the final volume of the solution using purified water.

4) Mix the solution and stir at 200 to 500 rpm for an additional 15 minutes.

5) Add the dose of solution into each cavity of the pre-formed granules package.

6) Freeze the filled granule containers at a temperature ranging from -60 to -80 degrees Celsius.

7) Dry the granule packages in a freeze-drying unit.

8) Place the granule packing chip containing dry freeze-drying products into the perforated carrier fabric of the granule packing machine, to transport the granule packing chips through the sealing station of the packing machine.

9) Seal the granule packages using foil is placed and place them in the final granule packages.

M. ondansetron formulas

The following ondansetron orally disintegrating dosage forms were prepared using the method described in L above, by freezing the granule packages at a rate of 0.1-2°C/min or 20-160°C/min in step 6.

Example 48

Component

Quantity/Unit

%w/w

Ondansetron

8.0 mg

20.64

Levan

24.0 mg

61.94

Mannitol

6.25 mg

16.12

Methylparaben

0.133 mg

0.34

Propylparaben

0.016 mg

0.04

Neotame

0.1 mg

0.26

Strawberry flavour

0.25 mg

0.64

Purified water

Sufficient quantity: up to 250 microliters

-

Example - 49

Component

Quantity/Unit

%w/w

Ondansetron

8.0 mg

20.72

Levan

24.0 mg

62.18

Mannitol

6.25 mg

16.19

Neotame

0.1 mg

0.26

Strawberry flavour

0.25 mg

0.65

0.1 N NaOH

Sufficient amount up to pH of 8.0

Sufficient amount up to pH of 8.0

Purified water

Sufficient quantity: up to 250 microliters

-

n. Comparative examples

Example - 50

Comparative freeze-drying products were prepared according to the method described in B above, but pullulan was used instead of levan and the granule packages were frozen at a rate of 20-260°C/min for ≤4 minutes in step 6.

Component

Quantity/Unit

%w/w

pullulan

25 mg

100

Purified water

A sufficient amount of 250 microliters

-

Example - 51

Comparative freeze-drying products were prepared according to the method described in b above, but HPMC was used instead of levan and the granule packages were frozen at a rate of 0.1–2°C/min in step 6.

Component

Quantity/Unit

%w/w

HPMC

25 mg

100

Purified water

A sufficient amount of 250 microliters

-

Example - 52

Comparative freeze-drying products were prepared according to the method described in b above, but HPMC was used instead of:

levan and freeze the granule packages at a rate ranging from 20 - 160 °C/min in less than or equal to 4 minutes in step 6.

Component

Quantity/Unit

%w/w

HPMC

25 mg

100

Purified water

A sufficient amount of 250 microliters

-

Example - 53

Comparable freeze-drying products were prepared according to the method described in B above, but methyl cellulose was used instead of levan and the granule packages were frozen at a rate of 0.1 to 2°C/min in step 6.

Component

Quantity/Unit

%w/w

methyl cellulose

25 mg

100

Purified water

A sufficient amount of 250 microliters

-

Example - 54

Comparative freeze-drying products were prepared according to the method described in b above, but methyl cellulose was used instead of levan and the granule packages were frozen at a rate of 20–160°C/min for ≤4 minutes in step 6.

Component

Quantity/Unit

%w/w

methyl cellulose

25 mg

100

Purified water

A sufficient amount of 250 microliters

-

Comparative freeze-drying products were prepared according to the method described in b above, but tragacanth gum was used instead of levan and the granule packages were frozen at a rate of 0.1 to 2°C/min in step 6.

Component

Quantity/Unit

%w/w

Tragacanth gum

25 mg

100

Purified water

A sufficient amount of 250 microliters

-

Comparable freeze-drying products were prepared according to the method described in b above, but using tragacanth gum instead of levan and the granule packages were frozen at a rate of 20–160°C/min for ≤4 minutes in step 6.

Component

Quantity/Unit

%w/w

Tragacanth gum

25 mg

100

Purified water

A sufficient amount of 250 microliters

-

Example - 57 Comparative freeze-drying products were prepared according to the method described in b above, but fish gelatin was used instead of levan and the granule packages were frozen at a rate of 0.1 to 2°C/min in step 6.

Component

Quantity/Unit

%w/w

Fish gelatin

25 mg

100

Purified water

A sufficient amount of 250 microliters

-

The freeze-drying products obtained were very brittle and broke into smaller pieces. No additional analysis can be performed.

Example - 58

Comparative freeze-drying products were prepared according to the method described in b above, but fish gelatin was used instead of levan and the granule packages were frozen at a rate of 20–160°C/min for ≤4 minutes in step 6.

Component

Quantity/Unit

%w/w

Fish gelatin

25 mg

100

Purified water

A sufficient amount of 250 microliters

-

Comparable freeze-drying products were prepared according to the method described in b above, but fish gelatin was used instead of levan and the granule packages were frozen at a rate of 0.1–2°C/min in step 6.

Component

Quantity/Unit

%w/w

Fish gelatin

12.5 mg

50

mannitol

12.5 mg

50

Purified water

A sufficient amount of 250 microliters

-

Example - 60

Comparative freeze-drying products were prepared according to the method described in b above, but fish gelatin was used instead of levan and the granule packages were frozen at a rate of 20–160°C/min for ≤4 minutes in step 6.

Component

Quantity/Unit

%w/w

Fish gelatin

12.5 mg

50

mannitol

12.5 mg

50

Purified water

A sufficient amount of 250 microliters

-

s. Fragmentation tests

Sa. Test for fragmentation in a petri dish

This test measures the expected disintegration time of the composition of the invention in an aqueous medium, which is an indication of its disintegration time in saliva.

The disintegration rate of all freeze-drying products on wet filter paper was determined according to the method described in International Application No. 2009002084, page 12, paragraph 129, where the test was performed at a temperature of approximately 25°C.

S-B. Measurement of the oral dissolution time (ODT) of a satisfactory treatment

The melting time of the freeze-drying products for sedation therapy in the oral cavity was determined according to the method described in International Application No. 2009002084, page 12, paragraph 132, whereby the freeze-drying products were placed on the tongue of a healthy adult human and then the time was measured until they completely melted while the Rub the cooling products by drying between the tongue and the roof of the mouth. The average ODT was measured from data obtained from 5 healthy adult humans.

A. Disintegration time test method (DT in the laboratory)

This test measures the disintegration time of the compositions of the invention in an aqueous medium, which indicates the disintegration time in saliva.

Equipment: Electrolab, Model: ED2 SAPO

Procedure: The method was followed according to:

USP 31-NF 26 (General Chapters, <701>Disintegration)

And

Ph Eur. 1997 (2.9.1. Disintegration of tablets and capsules).

The beaker was filled with water and its temperature was set at 37°C (0.5°C) using a water bath. The drying quenching product was placed in a submersible made of a copper wire about 0.5 mm in diameter (0.05 mM) and about 15 mm long. The drying cooling products were then placed in a basket of the basket rack assembly and a tool was placed on top of it. The fragmentation time was noted in seconds.

F. Tensile strength test method

Equipment: Engineering Systems (NOTTM) Ltd, Model: 5 kN Testing Machine

Action: The tensile strength determination method is fed into the tool. The variables of test speed (15 mm/min), crack pattern, unit (Newton, [N]), crack percentage (80%), minimum (0.1) and distance between load-bearing edges (4.5 mM) were set in the instrument . A 10 kg load cell was used and the tensile strength was calculated using the following formula:

Newton/mm2 = 3 Average (N) distance between two bearing axes in mm

2 (Thickness in millimolar)2 (Diameter in millimolar)

Thickness and diameter were determined using a vernier thickness measuring machine.

The tensile strength of commercially available Nimulid-MD, for an orally disintegrating tablet of Nimesulide, was found to be

It was prepared by a conventional compression technique of 1.14 N/mm2.

s. Dissolution method

This test measures the solubility (%) of an active ingredient of the composition of the invention in an aqueous medium, which indicates the rate of release of the active ingredient from the composition.

Equipment: Varian, Model: VK7025

Procedure: The dissolution time of cryogenic products containing an active ingredient was measured as follows: The method was followed in accordance with USP 32-NF 27 (General Chapters, <711>Dissolution). The dissolution media (0.1 N HCl, phosphate buffer pH 6.8, acetate buffer pH 4.5, or 0.5% SLS in water) were chosen on the basis of the active ingredient in the formulation. The dissolution baths were filled with an appropriate media volume (500 ml or 900 ml) based on the active ingredient in the formulation and the media temperature was maintained at 37 0.5 °C using a water bath. The device used was a USP type II (stirrer) and was set at the required rpm (50 rpm) according to the test procedure. Samples were drawn according to the time point (5 min, 10 min, 15 min and 30 min) specified in the testing procedure. Samples were analyzed by chromatography or UV according to the test procedure and the percentage release was calculated.

Data on fragmentation rates, ODT, in vitro DT, and tensile and melting strengths for quench-drying products prepared according to Examples 1 through 37 and Comparative Examples 38 through 48 are shown in Table 1.

Table 1

Example number

Petri dish fragmentation test (sec)

It melts in the mouth (seconds)

DT in the lab

(second)

Tensile strength

(Newton/mm2)

Dissolution

(5/15 min)(%)

7

5

5

1.07

Not applicable

2

4

6

2

1.58

Not applicable

3

5

6

4

1.41

Not applicable

4

8

7

5

1.38

Not applicable

5

3

5

4

0.61

Not applicable

6

2

2

3

0.22

Not applicable

7

4

5

3

0.64

Not applicable

8

5

5

3

0.73

Not applicable

9

2

3

4

0.22

Not applicable

10

2

4

4

0.21

Not applicable

11

2

4

5

0.18

Not applicable

12

3

4

3

0.44

Not applicable

13

5

4

2

0.23

Not applicable

14

2

4

3

0.32

Not applicable

15

4

6

2

0.27

Not applicable

16

2

4

4

0.09

Not applicable

17

3

3

3

0.07

Not applicable

18

4

3

3

0.09

Not applicable

19

5

4

3

0.07

Not applicable

20

2

4

4

0.16

Not applicable

21

2

2

2

0.16

Not applicable

22

2

3

4

0.10

Not applicable

23

2

Not applicable

3

0.32

98/99

24

6

Not applicable

4

0.78

85/96

25

6

Not applicable

3

0.64

99/99

26

4

Not applicable

3

0.10

76/92

27

4

Not applicable

3

0.84

87/95

28

4

Not applicable

3

0.53

102/102

29

3

Not applicable

3

0.09

102/92

30

3

Not applicable

2

0.15

99/101

31

3

Not applicable

2

0.13

93/95

32

3

Not applicable

2

0.17

103/103

33

6

Not applicable

7

0.68

102/103

34

3

Not applicable

6

0.37

100/101

35

2

Not applicable

3

0.19

100/102

36

6

Not applicable

8

0.34

69/89

37

5

Not applicable

2

0.34

68/85

38

6

Not applicable

2

0.38

61/92

39

5

Not applicable

9

0.19

51/75

40

6

Not applicable

9

0.28

97/100

41

5

Not applicable

6

0.12

93/92

42

4

Not applicable

4

0.08

97/97

43

4

Not applicable

2

0.14

97/97

44

5

Not applicable

2

0.16

97/97

45

3

Not applicable

2

0.08

97/98

46

4

Not applicable

2

0.12

99/98

47

3

Not applicable

2

0.20

96/96

48

2

Not applicable

2

0.09

101/12

49

2

Not applicable

2

0.10

101/19

50

32

30

196

0.80

Not applicable

51

150

39

124

0.97

Not applicable

52

35

51

128

0.27

Not applicable

53

> 300

190

> 30 minutes

< 0.05

Not applicable

54

> 300

192

> 30 minutes

< 0.05

Not applicable

55

25

22

40

< 0.05

Not applicable

56

36

30

20

<0.05

Not applicable

58

2

5

< 2

<0.05

Not applicable

59

2

3

< 2

0.15

Not applicable

60

2

4

< 2

0.06

Not applicable

NA is not applicable for Column 3 where the melt-in-mouth time was measured for satisfactory freeze-drying products only.

NA is not applicable for Column 6 as the dissolution time was measured for freeze-drying product containing drug substances only.

Q. Pharmacokinetic test:

A comparative test was performed to evaluate the pharmacokinetic profile of the composition given in Example 26 (240 mcg of desmopressin acetate, levan and mannitol) (test composition) with a reference composition comprising 240 mcg of desmopressin acetate, fish gelatin and mannitol (Minirin Melt). Testing was performed in parallel by administering a single sublingual dose of the relevant formulation to 8 New Zealand rabbits in each treatment group.

Blood samples were taken at specific time intervals from each treatment group and analyzed for Desmopressin content.

Pharmacokinetic variables were calculated for rabbits individually using unpaired analysis. The rate and extent of Desmopressin absorption were similar in the test and reference formulations. The reference Cmax (peak or maximum concentration) and AUClast (area under the curve to final sampling time) were within the 20% range of the reference sample. In addition, Cmax was The test formulation was higher compared to the reference formulation.