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Title:
TABLET
Document Type and Number:
WIPO Patent Application WO/2011/058336
Kind Code:
A2
Abstract:
A tablet comprising: a pharmaceutically active agent; Gum Arabic; an agent selected from a saccharide, a polyol, an amino acid and mixtures of two or more thereof; and wherein the tablet comprises at least 30% by weight of Gum Arabic based on the total weight of the tablet.

Inventors:
MOHAMMED, Afzal, Rahman (Birmingham B4 7ET, GB)
ALHUSBAN, Farhan (Birmingham B4 7ET, GB)
PERRIE, Yvonne (Birmingham B4 7ET, GB)
Application Number:
GB2010/002109
Publication Date:
May 19, 2011
Filing Date:
November 16, 2010
Export Citation:
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Assignee:
ASTON UNIVERSITY (Business Partnership Unit, Aston Triangle, Birmingham B4 7ET, GB)
MOHAMMED, Afzal, Rahman (Birmingham B4 7ET, GB)
ALHUSBAN, Farhan (Birmingham B4 7ET, GB)
PERRIE, Yvonne (Birmingham B4 7ET, GB)
International Classes:
A61K9/20
Attorney, Agent or Firm:
CHUNG, Hsu Min et al. (Boult Wade Tennant, Verulam Gardens70 Gray's Inn Road, London WC1 X 8BT, GB)
Download PDF:
Claims:
CLAIMS

1. A tablet comprising:

a pharmaceutically active agent;

Gum Arabic;

an agent selected from a saccharide, a polyol, an amino acid and mixtures of two or more thereof; and

wherein the tablet comprises at least 30% by weight of Gum Arabic based on the total weight of the tablet .

2. The tablet according to claim 1 comprising at least 50 % by weight of Gum Arabic based on the total weight of the tablet .

3. A tablet comprising:

a pharmaceutically active agent;

Gelatin and/or Gum Arabic;

a divalent salt and/or a monovalent salt;

an agent selected from a saccharide, a polyol, an amino acid and mixtures of two or more thereof.

4. The tablet of claim 3 wherein the tablet comprises at least 30% by weight of Gelatin and/or Arabic Gum based on the total weight of the tablet.

5. The tablet according to claim 4 comprising at least 50 % by weight of Gelatin and/or Gum Arabic based on the total weight of the tablet.

6. The tablet according to any one of claims 3 to 5

wherein the divalent salt is selected from one or more of CaCl2 and MgCl2. The tablet according to any one of claims 3 to 6 wherein the tablet comprises at least 5% by weight of divalent salt based on the total weight of the tablet.

The tablet according to any one of the preceding claims wherein the saccharide is a monosaccharide selected from galactose, glucose, D-mannose, trehalose, sorbose, and mixtures of two or more thereof .

The tablet according to any one of the preceding claims wherein the saccharide is a disaccharide selected from lactose, sucrose, trehalose, cellobiose, and mixtures of two or more thereof .

The tablet according to any one of the preceding claims wherein the saccharide is a polysaccharide selected from raffinose, melezitose, maltodextrins , dextrans, starches, and mixtures of two or more thereof.

The tablet according to any one of the preceding claims wherein the polyol is selected from mannitol, xylitol, maltitol, lactitol, xylitol, sorbitol (glucitol) , pyranosyl sorbitol, myoinositol and mixtures of two or more thereof .

The tablet according to any one of the preceding claims wherein the amino acid is selected from lysine,

alanine, glutamine, histidine, proline, serine,

cysteine and mixtures of two or more thereof .

13. The tablet according to any one of the preceding claims wherein the ratio of the agent selected from a

saccharide, a polyol, an amino acid and mixtures of two or more thereof: divalent salt is in the range of from 1:2 to 3:1 by weight.

14. The tablet according to any one of the preceding

claims wherein the ratio of the Arabic gum: the agent selected from a saccharide, a polyol, a amino acid and mixtures of two or more thereof is in the range of from 1:1 to 4:1 by weight.

15. The tablet according to any one of the preceding

claims wherein the tablet comprises at least 9% by weight of the agent selected from a saccharide, a polyol, an amino acid and mixtures of two or more thereof based on the total weight of the tablet.

16. The tablet according to any one of the preceding

claims wherein the tablet is an orally disintegrating tablet .

17. The tablet according to any one of the preceding claims wherein the pharmaceutically active agent is selected from an analgesic or anti-inflammatory agent, an anthelmintic, an an i-arrhythmic agent, an anticoagulant, an anti-depressant , an anti-diabetic agent, an anti-epileptic agent, an anti-fungal agent, an anti- gout agent, an anti-hypertension agent, an antimalarial, an anti-migraine agent, an anti-muscarinic agent, an anti-neoplastic agent, an anti-protozoal agent, an anti-thyroid agent, an anxiolytic, a sedative, a hypnotic agent or a neuroleptic agent, a corticosteroid, a diuretic, an anti-Parkinsonian agent, a gastro- intestinal agent, a histamine Hl-receptor antagonist, a lipid regulating agent, an anti-anginal agent, a thyroid agent, a nutritional agent, an

antipyretic agent, an antibacterial agent, an

immunosuppressant, an antiviral agent, hypothalmic or a pituitory hormone, a sex hormone, a prostaglandin, a vaccine, a cough suppresant, a local anaesthetic, an antisera, an opioid analgesic, a stimulant, a viral vector for gene therapy, an anti allergic agent, a cardio protective agent, an anti obesity agent, an oral contraceptive, an anti dementia, a fertility agent, a cholinesterase inhibitor, and an anti cholinergic agent or a therapeutic mixture thereof .

The tablet according to any one of the preceding claims comprising from 0.0001% to 55% by weight of a

pharmaceutically active agent based on the total weight of the tablet.

The tablet as defined in any one of the preceding claims for use in a method of treatment of the human or animal body by therapy.

The tablet as defined in any one of claims 1 to 18 for use in the treatment of constipation, depression, drug addiction, diabetes, diarrhoea, epilepsy, fungal infection, headache, heart burn, gout, GORD,

hypertension, malaria, migraines, Parkinson's disease, cancer, viral infections, bacterial infections, eczema, local or systemic pain, elevated cholesterol, inflammation, insomnia, protozoal infections, tapeworm infection, arrhymia, thrombosis, angina, allergic reaction, thyroid imbalance, water retention, gastrointestinal infection, and/or erectile dysfunction, motion sickness, irritable bowel syndrome, alzheimer, psychotic diseases, osteoporosis, heart failure, autoimmune diseases, endocrine disorder, and obesity.

A tablet as defined in any one of claims 1 to 18 for use in the manufacture of a medicament for treating constipation, depression, diabetes, diarrhoea, drug addiction, epilepsy, fungal infection, gout, GORD, headache, heart burn, hypertension, malaria, migraines, Parkinson's disease, cancer, viral infections,

bacterial infections, eczema, local or systemic pain, elevated cholesterol, inflammation, insomnia, protozoal infections, tapeworm infection, arrhymia, thrombosis, angina, allergic reaction, thyroid imbalance, water retention, gastro- intestinal infection, erectile dysfunction, motion sickness, irritable bowel syndrome, alzheimer, psychotic diseases, osteoporosis, heart failure, autoimmune diseases, endocrine disorder, and/or obesity.

The tablet as defined in any of the preceding claims, which is a freeze-dried tablet.

A method of preparing the tablet as defined in any one of claims 1 to 18, the method comprising;

(a) (i) wherein the claims are dependent on claim 1, mixing the pharmaceutically active agent; Gum Arabic,- the agent selected from a saccharide, a polyol, an amino acid and mixtures of two or more thereof; and a solvent to form a solution or suspension; (ii) wherein the claims are dependent on claim 3, mixing the pharmaceutically active agent; Gelatin and/or Arabic Gum; the divalent salt and/or monovalent salt; the agent selected from a saccharide, a polyol, an amino acid and mixtures of two or more thereof; and a solvent to form a solution or suspension;

(b) freezing the solution or suspension;

(c) lyophilizing the frozen solution or

suspension to remove the solvent and form a solid.

The method of claim 23 wherein prior to freezing the solution or suspension; a crystallising excipient is added to the solution or suspension.

The method of claim 23 or 24 wherein after freezing the solution or suspension, the frozen solution or

suspension is annealed, preferably in the presence of the crystallising excipient.

The method according to claim 25 wherein the frozen solution or suspension is annealed at a temperature of from -40°C to -10°C for at least 10 hours.

The method according to any one of claims 24 to 26 wherein the crystallising excipient is selected from serine, alanine, mannitol, glycine, cysteine,

asparagine and mixtures of two or more thereof .

28. A method of treating depression, diabetes, diarrhoea, drug addiction, constipation, epilepsy, fungal

infection, GORD, gout, headache, heart burn,

hypertension, malaria, migraines, Parkinson's disease, cancer, viral infections, bacterial infections, eczema, local or systemic pain, elevated cholesterol,

inflammation, insomnia, protozoal infections, tapeworm infection, arrhymia, thrombosis, angina, allergic reaction, thyroid imbalance, water retention, gastrointestinal infection erectile dysfunction, motion sickness, irritable bowel syndrome, alzheimer,

psychotic diseases, osteoporosis, heart failure, autoimmune diseases, endocrine disorder, and/or

obesity, the method comprising orally administering the tablet as defined in any one of claims 1 to 18.

Description:
TABLET

The present invention relates to a tablet, and preferably an orally disintegrating tablet, a process for making the tablet, and the use of the tablet in a method of treatment of the human or animal body by therapy.

Pill-swallowing difficulty affects a significant proportion of people, and in particular affects geriatric and

paediatric populations. In order to address this problem, orally disintegrating tablets have been developed.

Orally disintegrating tablets are typically solid unit dosage forms which disintegrate or dissolve in the mouth without chewing or the necessity to add water. Orally disintegrating tablets are also known as fast-dissolving tablets .

In December 2008 the US Department of Health and Human

Services, Food and Drug Administration issued a "Guidance for Industry: Orally Disintegrating Tablets" . In the

Guidance, orally disintegrating tablets are considered to be solid oral preparations which disintegrate rapidly in the oral cavity with an in vivo disintegration time of

approximately 30 seconds or less, when based on the USP disintegration test method or alternative (see

http : //www. fda . gov/downloads/Drugs/GuidanceComplianceRegulat orylnformation/Guidances/ucm070578. pdf) and USP 29, <701> Disintegration, pp. 2670-2672.

Orally disintegrating tablets have many advantages over both solid and liquid dosage forms. Such tablets remain solid until administration. This aids the stability of the pharmaceutically active agent, the dose accuracy, and storage of the tablets. Upon contact of the tablet with the oral cavity, the tablets transform into a liquid within a short time period (typically less than 30 seconds after administration) which allows the pharmaceutically active agent to be easily swallowed/transferred transdermally to the patient. US 2007/0092564 discloses an orally disintegrating

formulation, comprising an effective amount of an

pharmaceutically active ingredient and a matrix, wherein the matrix comprises pullan. This document also discloses a process for preparing the orally disintegrating

formulations, comprising the steps of:

(a) formulating the pharmaceutically active ingredient, pullan, amino acid and solvent into a solution or suspension;

(b) freezing the solution or suspension at a low

temperature;

(c) lyophilizing the solution or suspension to remove the solvent and the solid formulation is obtained.

It is advantageous for orally disintegrating tablets to be hard so that the integrity of the tablet is not damaged during storage. It is also advantageous for orally

disintegrating tablets to have a low friability, or high fracturability, so that the tablets do not fragment before use. Moreover, it is advantageous for orally disintegrating tablets to have fast disintegration times so that when the tablet is placed in the oral cavity it dissolves quickly, preferably in less than 30 seconds, more preferably in less than 20 seconds using the USP Distingretion test (USP 29, <701> Disintegration, pp. 2670-2672) .

It is an object of the present invention to address at least some of the problems and disadvantages of the prior art and to provide a tablet have improved properties for use an orally disintegrating tablet.

Accordingly, in one aspect the present invention provides a tablet comprising:

a pharmaceutically active agent;

Gum Arabic;

an agent selected from a saccharide, a polyol, an amino acid and mixtures of two or more thereof; and

wherein the tablet comprises at least 30% by weight of Gum Arabic based on the total weight of the tablet.

In a further aspect the present invention provides a tablet comprising :

a pharmaceutically active agent;

Gelatin and/or Gum Arabic;

a divalent salt and/or a monovalent salt;

an agent selected from a saccharide, a polyol, an amino acid and mixtures of two or more thereof .

In another aspect the present invention there is provided a tablet as defined herein for use in a method of treatment of the human or animal body by therapy. In another aspect of the present invention there is provided a tablet as described herein for use in the treatment of constipation, depression, drug addiction, diabetes, diarrhea, epilepsy, fungal infection, headache, heart burn, gout, GORD, hypertension, malaria, migraines, Parkinsons disease, cancer, viral infections, bacterial infections, eczema, local or systemic pain, elevated cholesterol, inflammation, insomnia, protozoal infections, tapeworm infection, arrhymia, thrombosis, angina, allergic reaction, thyroid imbalance, water retention gastro-intestinal

infection, erectile dysfunction, motion sickness, irritable bowel syndrome, alzheimer, psychotic diseases, osteoporosis, heart failure, autoimmune diseases, endocrine disorder, and/or obesity.

In another aspect of the present invention there is provided the use of the tablet as described herein for the

manufacture of a medicament for treating constipation, depression, diabetes, diarrhea, drug addiction, epilepsy, fungal infection, gout, GORD, headache, heart burn,

hypertension, malaria, migraines, Parkinsons disease, cancer, viral infections, bacterial infections, eczema, local or systemic pain, elevated cholesterol, inflammation, insomnia, protozoal infections, tapeworm infection,

arrhymia, thrombosis, angina, allergic reaction, thyroid imbalance, water retention, gastro- intestinal infection, erectile dysfunction, motion sickness, irritable bowel syndrome, alzheimer, psychotic diseases, osteoporosis, heart failure, autoimmune diseases, endocrine disorder, and/or obesity.

In another aspect of the present invention there is provided a method of preparing the tablet as described herein, the method comprising; (a) mixing the pharmaceutically active agent; Gum Arabic; the agent selected from a saccharide, a polyol, an amino acid and mixtures of two or more thereof ; and a solvent to form a solution or suspension;

(b) freezing the solution or suspension;

(c) lyophilizing the frozen solution or

suspension to remove the solvent and form a solid.

In a further aspect of the present invention there is provided a method of preparing the tablet as described herein, the method comprising;

(a) mixing the pharmaceutically active agent;

Gelatin and/or Arabic Gum; the divalent salt and/or the monovalent salt; the agent

selected from a saccharide, a polyol, an amino acid and mixtures of two or more thereof; and a solvent to form a solution or suspension;

(b) freezing the solution or suspension;

(c) lyophilizing the frozen solution or

suspension to remove the solvent and form a solid.

Gelatin, and in particular hydrolysed Gelatin, is known to be of used in forming orally disintegrating tablets as a drug carrier and a matrix- forming agent. The use of Gelatin allows the easy formation of a tablet with a suitable hardness for packaging of the tablet. Gelatin typically comes from the hydrolysed product of animal collagen

tissues, such as skin, tendon, ligament and bones. In recent years the emergence of diseases such as mad cow disease, foot and mouth disease and scrapie have led to safety concerns being raised about Gelatin. Moreover, the use of Gelatin in tablets may be unacceptable for example to Vegetarian and/or to people with certain religious beliefs. Accordingly, there is a desire to provide a tablet, and in particular, an orally disintegrating tablet which has the desired combination of features, for example, hardness and strength (so that it will not disintegrate during

storage/transport etc) , but which disintegrates quickly in the mouth. Preferably, also the tablet is formed from components which are ethically and morally acceptable to the end users. The present inventors have surprisingly found that a tablet comprising:

a pharmaceutically active agent;

Gum Arabic- an agent selected from a saccharide, a polyol, an amino acid and mixtures of two or more thereof; and

wherein the tablet comprises at least 30% by weight of Gum Arabic based on the total weight of the tablet overcomes at least some of the problems of known tablets, while providing tablets having suitable strength for storage and transport and which disintegrates quickly in the mouth. Although Gum Arabic, which is also known as Arabic Gum, has been known to be used in tablets (but not for orally disintegrating tablets), its use is not known in such high concentrations. Without wishing to be bound by any particular theory, in the tablet of the present invention comprising at least 30% by weight of Gum Arabic based on the total weight of the tablet, it is thought that the Gum Arabic acts as a binder or provides a matrix within which the pharmaceutically active agent is contained. The present inventors have also found that using a high proportion (at least 30% by weight of Gum Arabic based on the total weight of the tablet) in the formation of

lyophilised tablets has a number of further advantages over using Gelatin. The present inventors have found that tablets comprising high levels of Gum Arabic may be prepared using a shorter freeze drying cycles than those with

Gelatin. A further advantage is that the method of the present invention reduces need, or eliminates the need, for a heating step to be used in the tablet formation process. Gum Arabic is also thought to act as an emulisifer and/or suspending agent for pharmaceutically active agents, thus the need to include additional emulisifers and/or suspending agents in the formulation of the tablet is reduced/

eliminated.

The use of gum arabic in an amount of at least 30 percent by weight of the total weight of the tablet may also allow the incorporation of higher dose of drugs (hydrophobic drugs) without compromising the homogeneity of the formulation and the disintegration profile of the tablet. Furthermore, gum arabic has desirable thermal properties that may reduce the risk of the tablet being damaged by over-heating, for example, during the manufacturing process. During

manufacture e.g. by freeze-drying, heat is applied to the tablet during the sublimation step. By using gum Arabic in accordance with the present invention, the risk of damage to the tablet by overheating is reduced due to gum arable's desirable thermal properties. (freeze drying profile)

The present inventors have also surprising found that a tablet comprising the combination of a pharmaceutically active agent, Gelatin and/or Gum Arabic, a divalent salt and/or monovalent salt; an agent selected from a saccharide, a polyol, an amino acid and mixtures of two or more thereof provides a tablet which is suitable for use as an orally disintegrating tablet. Such tablets have been found to have an advantageous combination of properties which include having the desired hardness and ability to disintegrate quickly in the mouth. Without wishing to be bound by any particular theory, it is thought that the presence of the divalent salt and/or monovalent salt in the tablet increases the friability and/or wettability of the tablets, and thus leads to a decrease in the disintegration time without significantly (or not) altering the mechanical properties of the tablets, compared to tablets not comprising divalent or monovalent salts.

Each aspect as defined herein may be combined with any other aspect or aspects unless clearly indicated to the contrary. In particular any feature indicated as being preferred or advantageous may be combined with any other feature or features indicated as being preferred or advantageous.

In one embodiment of the present invention, the tablet comprises at least 30% by weight of Gum Arabic based on the total weight of the tablet. More preferably, the tablet comprises at least 35%, at least 40%, at least 50%, at least 55%, at least 60%, at least 70%, at least 75% by weight of Gum Arabic based on the total weight of the tablet.

Preferably, the tablet comprises 85% or less, or 80% or less by weight of Gum Arabic based on the total weight of the tablet. When the tablet comprises a divalent salt, preferably the tablet comprises at least 30% by weight of Gelatin based on the total weight of the tablet. More preferably, the tablet comprises at least 35%, at least 40%, at least 50%, at least 55%, at least 60%, at least 70%, at least 75% by weight of Gelatin based on the total weight of the tablet.

Preferably, the tablet comprises 85% or less, or 80% or less by weight of Gelatin based on the total weight of the tablet.

When the tablet comprises a divalent salt, preferably the tablet comprises at least 30% by weight of Arabic Gum based on the total weight of the tablet. More preferably, the tablet comprises at least 35%, at least 40%, at least 50%, at least 55%, at least 60%, at least 70%, at least 75% by weight of Arabic Gum based on the total weight of the tablet. When the tablet comprises a divalent salt,

preferably the tablet comprises 85% or less, or 80% or less by weight of Arabic Gum based on the total weight of the tablet.

The tablets of the present invention may comprise both Gum Arabic and Gelatin. However, preferably the tablets

comprise Gum Arabic or Gelatin.

When the tablet comprises a divalent salt, the tablet may comprise at least 30% by weight of Arabic Gum and/or Gelatin based on the total weight of the tablet. More preferably, the tablet comprises at least 35%, at least 40%, at least 50%, at least 55%, at least 60%, at least 70%, at least 75%, at least 90% by weight of Arabic Gum and/or Gelatin based on the total weight of the tablet. When the tablet comprises a divalent salt, preferably the tablet comprises 85% or less, or 80% or less by weight of Arabic Gum and/or Gelatin based on the total weight of the tablet. The pharmaceutically active agent is preferably present in the tablet in a pharmaceutically effective amount.

Preferably, the tablet comprises from 0.0001% to 55% by weight of pharmaceutically active agent based on the total weight of the tablet. More preferably, the tablet comprises from 5% to 50%, from 10% to 40%, or from 20% to 30% by weight of pharmaceutically active agent based on the total weight of the tablet. Preferably the pharmaceutically active agent is present in the tablet in unit dosage form. The pharmaceutically active agent may be present in the tablet in half dosage form.

Any suitable pharmaceutically active agent may be used in the tablets of the present invention. The pharmaceutically active agent may be selected from an analgesic or antiinflammatory agent, an anthelmintic, an anti-arrhythmic agent, an anti-coagulant , an anti-depressant, an antidiabetic agent, an anti-epileptic agent, an anti-fungal agent, an anti-gout agent, an anti-hypertension agent, an anti-malarial , an anti-migraine agent, an anti-muscarinic agent, an anti-neoplastic agent, an anti-protozoal agent, an anti-thyroid agent, an anxiolytic, a sedative, a hypnotic agent or a neuroleptic agent, a corticosteroid, a diuretic, an anti-Parkinsonian agent, a gastro- intestinal agent, a histamine Hl-receptor antagonist, a lipid regulating agent (such as a nutritional supplement, e.g. vitamins, minerals, proteins, carbohydrates) , an anti-anginal agent, a thyroid agent, a nutritional agent, an antipyretic agent, an

antibacterial agent, an immunosuppressant, an antiviral agent, hypothalmic or a pituitory hormone, a sex hormone, a prostaglandin, a vaccine, a cough suppresant, a local anaesthetic, an antisera, an opioid analgesic, a stimulant, a viral vector for gene therapy, an anti allergic agent, a cardio protective agent, an anti obesity agent, an oral contraceptive, an anti dementia, a fertility agent, a cholinesterase inhibitor, and an anti cholinergic agent or a therapeutic mixture thereof .

Examples of pharmaceutically active agents which may be used in the present invention include the following:

Analgesics and anti-inflammatory agents: aloxiprin, auranofin, azapropazone , benorylate, diflunisal, etodolac, fenbufen, fenoprofen calcium, flurbiprofen, ibuprofen, indomethacin, ketoprofen, mefenamic acid, nabumetone, naproxen, oxyphenbutazone , phenylbutazone, piroxicam, sulindac .

Anthelmintics: albendazole, bephenium

hydroxynaphthoate , dichlorophen, ivermectin, mebendazole, oxfendazole, oxantel embonate, praziquantel, pyrantel embonate, thiabendazole.

Anti-arrhythmic agents: amiodarone HC1 , disopyramide , quinidine sulphate.

Anti-bacterial agents: benethamine penicillin,

cinoxacin, ciprofloxacin HC1, clarithromycin, clofazimine, cloxacillin, doxycycline, erythromycin, ethionamide,

imipenem, nalidixic acid, nitrofurantoin, rifampicin, spiramycin, sulphabenzamide , sulphadoxine , sulphamerazine , sulphacetamide, sulphadiazine , sulphafurazole,

sulphamethoxazole, sulphapyridine, tetracycline,

trimethoprim.

Anti-coagulants : dicoumarol, dipyridamole, nicoumalone, phenindione .

Anti-constipation: docusate sodium, sodium

picosulphate , sennosides, tegaserod maleate.

Anti-depressants : amoxapine, maprotiline HC1,

trimipramine maleate.

Anti-diabetics : acetohexamide, chlorpropamide,

glibenclamide, gliclazide, glipizide, tolazamide, insulin tolbutamide .

Anti-diarrhoea: loperamide HCL, Bismuth subsalicylate.

Anti-epileptics : beclamide, carbamazepine, clonazepam, ethotoin, methoin, methsuximide, methylphenobarbxtone, phenacemide, phenobarbitone, phenytoin, phensuximide , primidone, sulthiame, valproic acid.

Anti-fungal agents: amphotericin, butoconazole nitrate, clotrimazole, econazole nitrate, fluconazole,

griseofulvin, itraconazole, ketoconazole, miconazole, natamycin, nystatin, sulconazole nitrate, terbinafine HC1, terconazole, tioconazole, undecenoic acid. Anti-gout agents: allopurinol, probenecid, sulphin- pyrazone . Anti-gastro-oesophageal reflux disease (GORD) :

rabeprazole sodium, esomeprazole magnesium, famotidine, Omeprazole magnesium.

Anti-heart burn: Omeprazole magnesium, famotidine, Cimetidine, Ranitidine HC1.

Anti-headache : Paracetamol/metoclopramide

hydrochloride . An i-hypertensive agents: amlodipine, diazoxide, felodipine, isradipine, minoxidil, nicardipine HCl,

nifedipine, nimodipine, prazosin HCl, reserpine, benazepril, Verapamil hydrochloride. Anti-malarials : amodiaquine, chloroquine, halofantrine

HCl, mefloquine HCl, proguanil HCl, pyrimethamine, quinine sulphate .

Anti-migraine agents: dihydroergotamine mesylate, ergotamine tartrate, methysergide maleate, pizotifen

maleate .

Anti-muscarinic agents: atropine, benzhexol HCl, biperiden, hyoscyamine, mepenzolate bromide, tropicamide.

Anti-neoplastic agents and Immunosuppressants:

aminoglutethimide , azathioprine, busulphan, chlorambucil, cyclosporin, dacarbazine, etoposide, lomustine, melphalan, mercaptopurine , methotrexate, mitomycin, mitotane, tamoxifen citrate, testolactone . Anti-protazoal agents: clioquinol,

diiodohydroxyquinoline , diloxanide furoate, dinitolmide, furzolidone, metronidazole, nitrofurazone , tinidazole.

Anti-thyroid agents: carbimazole, propylthiouracil.

Anxiolytic, sedatives, hypnotics and neuroleptics:

alprazolam, amylobarbitone , barbitone, bromazepam,

bromperidol, brotizolam, butobarbitone, carbromal,

chlordiazepoxide , chlormethiazole, chlorpromazine , clobazam, clozapine, diazepam, droperidol, ethinamate, fluanisone, flunitrazepam, fluopromazine, flupenthixol decanoate, fluphenazine decanoate, flurazepam, haloperidol, lorazepam, lormetazepam, medazepam, meprobamate, methaqualone ,

midazolam, nitrazepam, oxazepam, pentobarbitone,

perphenazine pimozide, prochlorperazine, sulpiride,

temazepam, thioridazine, triazolam, zopiclone. β-Blockers: nadolol, pindolol. Cardiac Inotropic agents: digitoxin, digoxin,

lanatoside C, medigoxin.

Corticosteroids: beclomethasone, betamethasone,

budesonide, cortisone acetate, desoxymethasone,

dexamethasone, fludrocortisone acetate, flunisolide,

flucortolone, fluticasone propionate, hydrocortisone, methylprednisolone , prednisolone, prednisone, triamcinolone. Diuretics: acetazolamide, amiloride, bendrofluazide , bumetanide, chlorothiazide, chlorthalidone, ethacrynic acid, frusemide, metolazone, spironolactone, triamterene.

Anti -parkinsonian agents: bromocriptine mesylate.

Gastro- intestinal agents: bisacodyl, cimetidine, cisapride, diphenoxylate HCl, domperidone, famotidine, loperamide, mesalazine, omeprazole, sulphasalazine .

Histamine H, -Receptor Antagonists: astemizole,

cinnarizine, cyclizine, cyproheptadine HCl, dimenhydrinate , meclozine HCl, oxatomide, terfenadine.

Lipid regulating agents: bezafibrate, clofibrate, fenofibrate, gemfibrozil, probucol, atorvastatin calcium, ezetimibe, simvastatin.

Nitrates and other anti -anginal agents: amyl nitrate, glyceryl trinitrate, isosorbide dinitrate, pentaerythritol tetranitrate .

Nutritional agents: betacarotene , vitamin A, vitamin B2, vitamin D, vitamin E, vitamin K.

Opioid analgesics: codeine, dextropropyoxyphene , diamorphine, dihydrocodeine, meptazinol, morphine,

pentazocine .

Sex hormones: clomiphene citrate, danazol, ethinyl estradiol, medroxyprogesterone acetate, mestranol, methyltestosterone, norethisterone, norgestrel, estradiol, conjugated oestrogens, progesterone, stanozolol, stibestrol, testosterone, tibolone. Stimulants: dexamphetamine, dexfenfluramine, mazindol, nicotine .

The viral vector may be a retrovirus (such as Moloney murine leukaemia virus), a lentivirus, an adenovirus, an adeno-associated virus (AAV) or a nanoengineered substance such as Ormosil.

Anti allergic agent: promethazine HCl, Chlorpheniramine maleate, diphenhydramine HCl, loratadine .

Cardio protective agent: aspirin, dexrazoxane.

Anti obesity agent: orlistat, sibutramine HCl,

methamphetamine HCl, phentermine HCl.

Oral contraceptive: levonorgestrel , norgestrel, ethinyl estradiol, drospirenone .

Anti dementia: donepezil HCl, rivastigmine tartrate, memantine HCl.

Cholinesterase inhibitor: donepezil hydrochloride, galantamine hydrobromide .

Anti cholinergic agent: Benzhexol, ipratropium bromide.

Vaccine: typhoid Vaccine, OPV (oral polio vaccine) Pharmaceutically acceptable salts, isomers and derivatives thereof may be substituted for these drugs. Mixtures of pharmaceutically active agents may be used where

therapeutically effective.

The tablets comprise an agent selected from a saccharide, a polyol, an amino acid and mixtures of two or more thereof. Without wishing to be bound by any particular theory, it is thought that the presence of an agent selected from a saccharide, a polyol, an amino acid and mixtures of two or more thereof based on the total weight of the tablet aids in shortening the disintegration time of the tablet, enhancing the mechanical properties, and/or protecting the

pharmaceutically active agent from the effects of freezing and lyophilisation process. It also aids in enhancing the solubility for poorly water soluble drugs. The replacement of saccharides with amino acids enables administration of these dosage forms to diabetics and children. Thus, in a preferred embodiment the tablets comprise at least one amino acid.

Preferably, the tablet comprises at least 9%, or at least 10%, by weight of an agent selected from a saccharide, a polyol, an amino acid and mixtures of two or more thereof based on the total weight of the tablet.

Preferably, the tablet comprises from 9% to 50%, or from 10% to 50%, by weight of an agent selected from a saccharide, a polyol, an amino acid and mixtures of two or more thereof based on the total weight of the tablet. More preferably, the tablet comprises from 15% to 45%, from 20% to 40%, or from 25% to 35% by weight of an agent selected from a saccharide, a polyol, an amino acid and mixtures of two or more thereof based on the total weight of the tablet .

The saccharide may be a monosaccharide, a disaccharide, a polysaccharide and mixtures of two or more thereof . Any suitable monosaccharide, disaccharide, and polysaccharide may be used.

The monosaccharide may be selected from galactose, glucose, D-mannose, sorbose, and mixtures of two or more thereof.

Preferably, the monosaccharide is glucose and/or galactose. More preferably the monosaccharide is glucose.

The disaccharide selected may be from lactose, sucrose, trehalose, cellobiose, and mixtures of two or more thereof. Preferably the disaccharide is trehalose and/or lactose. More preferably the disaccharide is trehalose.

The polysaccharide may be selected from raffinose,

melezitose, maltodextrins , dextrans, starches, maltotriose, and mixtures of two or more thereof. Preferably the

polysaccharide is a maltodextrins and/or a starch. More preferably the polysaccharide is a starch.

Preferably, the tablet comprises from 9% to 50%, or from 10% to 50%, by weight of a saccharide based on the total weight of the tablet. More preferably, the tablet comprises from

15% to 45%, from 20% to 40%, or from 25% to 35% by weight of a saccharide, based on the total weight of the tablet. Any suitable polyol may be used in the tablet of the present invention. Suitable polyols may be selected from mannitol, xylitol, maltitol, lactitol, xylitol, sorbitol (glucitol) , pyranosyl sorbitol, myoinositol and mixtures of two or more thereof . Preferably the polyol is mannitol and/or sorbitol . More preferably the polyol is mannitol.

Preferably, the tablet comprises from 9% to 50%, or from 10 to 50% by weight of a polyol based on the total weight of the tablet. More preferably, the tablet comprises from 15% to 45%, from 20% to 40%, or from 25% to 35% by weight of a polyol based on the total weight of the tablet. Any amino acid may be used, for example, isoleucine,

alanine, leucine, asparagine, lysine, aspartic acid,

methionine, cysteine, phenylalanine, glutamic acid,

threonine, glutamine, tryptophan, glycine, valine, proline, serine, tyrosine, arginine, histidine and mixtures of two or more thereof. Preferably, the amino acid is selected from lysine, alanine, glutamine, histidine, glycine, serine, proline and mixtures of two or more thereof. More

preferably the amino acid is alanine, glycine and/or

proline. Most preferably the amino acid is alanine.

Preferably, the tablet comprises from 9% to 50%, or from 10 to 50% by weight of an amino acid based on the total weight of the tablet. More preferably, the tablet comprises from 15% to 45%, from 20% to 40%, or from 25% to 35% by weight of an amino acid based on the total weight of the tablet. Preferably the tablets comprise a divalent salt. It will be understood that in the tablet the divalent salts may be present as divalent ions. The divalent salt may be a salt of Be, g, Ca, Sr and/or Ba. Preferably the divalent salt is selected from one or more of CaCl 2 and MgCl 2 . Most preferably the divalent salt is MgCl 2 . Mixtures of one or more divalent salts may be used in the tablet.

The tablets may comprise a monovalent salt. It will be understood that in the tablet the monovalent salts may be present as monovalent ions. The monovalent salt may be a salt of Na and/or K. Preferably the monovalent salt is selected from one or more of NaCl and KC1. Most preferably the divalent salt is NaCl. Mixtures of one or more

monovalent salts may be used in the tablet.

The tablet may comprise at least one monovalent and at least one divalent salt. The monovalent or divalent salt may be a halide, such as a chloride, bromide or iodide. Chlorides are preferred.

As outlined above, without wishing to be bound by any particular theory, it is thought that the presence of the divalent salt and/or monovalent salt in the tablet does not alter the mechanical properties of the tablets. The presence of a divalent salt increases the wettability of the tablets, and thus leads to a decrease in the disintegration time, whilst the hardness and fracturability of the tablets is not compromised. Divalent salts, such as MgCl 2 and CaCl 2 are preferred. Most preferred is MgCl 2 . Preferably, the tablet comprises at least 5% by weight of divalent salt and/or monovalent salt based on the total weight of the tablet. Preferably, the tablet comprises from 5% to 45% by weight of divalent salt and/or monovalent salt based on the total weight of the tablet. More preferably, the tablet comprises from 10% to 40%, from 15% to 35%, or from 20% to 30% by weight of divalent salt and/or monovalent salt based on the total weight of the tablet. Preferably the tablet comprises a divalent salt.

When the tablet comprises a divalent salt and/or monovalent salt, preferably, the the ratio of the agent selected from a saccharide, a polyol, an amino acid and mixtures of two or more thereof: divalent salt is in the range of from 1:2 to 3:1 by weight. More preferably, the ratio of the agent selected from a saccharide, a polyol, an amino acid and mixtures of two or more thereof: divalent salt is in the range of from 1:1 to 2:1 by weight .

When Gum Arabic is present in the tablet, preferably, the ratio of the Gum Arabic: the agent selected from a

saccharide, a polyol, a amino acid and mixtures of two or more thereof is in the range of from 1:1 to 4:1 by weight. More preferably, the ratio of the Gum Arabic: the agent selected from a saccharide, a polyol, a amino acid and mixtures of two or more thereof is in the range of from 2:1 to 3:1 by weight . When Gelatin is present in the tablet, preferably, the ratio of the Gelatin: the agent selected from a saccharide, a polyol, a amino acid and mixtures of two or more thereof is in the range of from 1:1 to 4:1 by weight. More preferably, the ratio of the Gelatin: the agent selected from a

saccharide, a polyol, a amino acid and mixtures of two or more thereof is in the range of from 2:1 to 3:1 by weight.

When Gelatin and Gum Arabic are present in the tablet, preferably, the ratio of the Gelatin and Gum Arabic: the agent selected from a saccharide, a polyol, a amino acid and mixtures of two or more thereof is in the range of from 1:1 to 4:1 by weight. More preferably, the ratio of the Gelatin and Gum Arabic: the agent selected from a saccharide, a polyol, an amino acid and mixtures of two or more thereof is in the range of from 2:1 to 3:1 by weight. Preferably the tablet is an orally disintegrating tablet. As used herein the term orally disintegrating tablet means that the tablet dissolves and/or disintegrates in the mouth upon contact with saliva and may be easily swallowed with or without drinking water.

Preferably the orally disintegrating tablet dissolves and/or disintegrates in the mouth of a user in less than 30

seconds. More preferably, the orally disintegrating tablet dissolves and/or disintegrates in the mouth of a user in less than 20 seconds, less than 15 seconds, less than 10 seconds, or more preferably less than 5 seconds.

Preferably the orally disintegrating tablet completely dissolves and/or disintegrates in the mouth of a user without the addition of water. Preferably, the tablets of the present invention have low hygroscopicity, so that the storage life of the tablets is increased. In one embodiment of the present invention the tablet comprises :

a pharmaceutically active agent,

Gum Arabic,

an agent selected from glycine, trehalose, mannitol, glucose, alanine, histidine, serine, proline and mixtures of two or more thereof; and

wherein the tablet comprises at least 30% by weight of Gum Arabic based on the total weight of the tablet. In another embodiment of the present invention the tablet comprises :

a pharmaceutically active agent;

Gelatin and/or Gum Arabic;

a divalent salt and/or monovalent salt;

an agent selected from glycine, trehalose, mannitol, glucose, alanine, histidine, serine, proline and mixtures of two or more thereof .

Preferably the tablet comprises a divalent salt.

Preferably, the divalent salt is MgCl 2 and or CaCl 2 . More preferably the divalent salt is MgCl 2 . Preferably the tablet comprises at least 30% by weight of Gelatin and/or Gum

Arabic based on the total weight of the tablet.

The tablet as described herein may be for use in a method of treatment of the human or animal body by therapy.

The tablet described herein may be for use in the treatment of constipation, depression, drug addiction, diabetes, diarrhea, epilepsy, fungal infection, headache, heart burn, gout, GORD, hypertension, malaria, migraines, Parkinsons disease, cancer, viral infections, bacterial infections, eczema, local or systemic pain, elevated cholesterol, inflammation, insomnia, protozoal infections, tapeworm infection, arrhymia, thrombosis, angina, allergic reaction, thyroid imbalance, water retention, gastro- intestinal infection, erectile dysfunction, motion sickness, irritable bowel syndrome, alzheimer, psychotic diseases, osteoporosis, heart failure, autoimmune diseases, endocrine disorder, and/or obesity.

In one embodiment of the present invention there is provided the use of the tablet as described herein may be for the manufacture of a medicament for treating constipation, depression, diabetes, diarrhea, drug addiction, epilepsy, fungal infection, gout, GORD, headache, heart burn,

hypertension, malaria, migraines, Parkinsons disease, cancer, viral infections, bacterial infections, eczema, local or systemic pain, elevated cholesterol, inflammation, insomnia, protozoal infections, tapeworm infection,

arrhymia, thrombosis, angina, allergic reaction, thyroid imbalance, water retention, gastro- intestinal infection, erectile dysfunction, motion sickness, irritable bowel syndrome, alzheimer, psychotic diseases, osteoporosis, heart failure, autoimmune diseases, endocrine disorder, and/or obesity.

In another embodiment of the present invention there is provided a method of treating depression, diabetes,

diarrhea, drug addiction, constipation, epilepsy, fungal infection, GORD, gout, headache, heart burn, hypertension, malaria, migraines, Parkinsons disease, cancer, viral infections, bacterial infections, eczema, local or systemic pain, elevated cholesterol, inflammation, insomnia,

protozoal infections, tapeworm infection, arrhymia,

thrombosis, angina, allergic reaction, thyroid imbalance, water retention, gastro- intestinal infection, erectile dysfunction, motion sickness, irritable bowel syndrome, alzheimer, psychotic diseases, osteoporosis, heart failure, autoimmune diseases, endocrine disorder, and/or obesity, the method comprising orally administering the tablet as

described herein.

The tablet may further comprise one or more pharmaceutically acceptable excipients, for example, thickening agents, stabilizers, surfactants, antioxidants, sweetners,

flavouring agents, preservative, taste-masking agents, absorption enhancers, pH modifying agents, bacteriostatic agents etc and mixtures of two or more thereof. Colouring agents may be included in the tablet. These may include, for example, natural food colors and dyes suitable for drug applications, and may be present in amounts from 0.01% to 2% by weight, or from 0.1% to 1% by weight based on the total weight of the tablet.

Artificial and/or natural flavouring agents may be included in the tablet. The flavouring agents may include, for example, essential oils, synthetic flavours or mixtures, including but not limited to, oils delivered from plants and fruits such as citrus oils, fruit essences, peppermint oil, spearmint oil, other mint oils, clove oils, oil of

wintergreen, anise and the like, menthol, eucalyptol, thymol and combinations thereof. The tablet may comprise from 0.1% to 1.5% by weight, or from 0.5% to 1% by weight of

artificial and/or natural flavouring agents based on the total weight of the tablet.

In one embodiment of the present invention there is provided a packaging comprising a tablet as described herein. The packing may comprise a plurality of tablets as described herein.

The tablets of the present invention may be made by a method comprising;

(a) mixing the pharmaceutically active agent; Gum Arabic; the agent selected from a saccharide, a polyol, an amino acid and mixtures of two or more thereof ; and a solvent to form a solution or suspension;

(b) freezing the solution or suspension;

(c) lyophilizing the frozen solution or suspension to remove the solvent and form a solid.

The tablets of the present invention may be made by a method comprising;

(a) mixing the pharmaceutically active agent;

Gelatin and/or Arabic Gum; the divalent salt and/or the monovalent salt, the agent

selected from a saccharide, a polyol, an amino acid and mixtures of two or more thereof; and a solvent to form a solution or suspension;

(b) freezing the solution or suspension; (c) lyophilizing the frozen solution or

suspension to remove the solvent and form a solid. Any suitable pharmaceutically acceptable solvent may be used to form the tablets. Suitable solvents include water, isopropanol, glycol and/or acetone.

Prior to freezing the solution or suspension; a

crystallising excipient may be added to the solution or suspension. Adding the crystallising excipient to the solution or suspension modifies the thermal profile of the frozen material. The modified thermal profile allows freeze drying at higher temperatures and consequently decreases the primary drying time.

Preferably, after freezing the solution or suspension, the frozen solution or suspension is annealed, optionally in the presence of the crystallising excipient. The combination of the presence of crystallising excipient and the annealing step aids the freeze drying of the amorphous material . The modified formulation enables the stability of the materials to be enhanced during the freeze drying steps, and aids the formation of an intact product.

The crystallising excipient may be selected from suitable saccharide, a polyol, an amino acid and mixtures of two or more thereof. Suitable agents examples of saccharides, polyols, amino acids are given above.

Preferably, the frozen solution or suspension is annealed at a temperature of from -70°C to -5°C for at least 5 hours. More preferably, the frozen solution or suspension is annealed at a temperature of from -40°C to -10°C for at least 5 hours. Preferably, the frozen solution or

suspension is annealed at a temperature of from -30°C to -10°C for at least 10 hours. Annealing the frozen solution or suspension leads to the formation of an improved product.

The crystallising excipient is preferably selected from serine, alanine, mannitol, glycine, cysteine, lactose, asparagine, and mixtures of two or more thereof.

These and other aspects of the invention will now be described with reference to the accompanying Examples

Figures and, in which:

Figure 1 shows overlaid DSC heating curves of frozen gelatin stock solution (5%) with 70% (solid materials) of Proline: serine (25:75) without annealing (curve 1 and 2) and with annealing (curves 3 and 4) . The collapse temperature of a formulation is 1 to 3 °C higher than their Tg (glass

transition) . The annealing step vanishes the glass

transition step (Tg) and consequently increase the collapse temperature, which allows successful freeze drying at higher temperature .

Figure 2 shows a photograph of collapsed freeze dried tablets based on 5% gelatin stock solution with 70% (solid materials) of Proline: serine (25:75) without annealing. The collapse is a result of the low collapse temperature. Figure 3 shows a photograph of intact freeze dried tablets based on 5% gelatin stock solution with 70% (solid

materials) of Proline: serine (25:75) after annealing at -13°C for 10 hours.

Figure 4 shows a bar chart of the results on the hardness of the tablets based on 5% gelatin stock solution and agent selected from a saccharide, a polyol, and an amino acid at varied concentration (total solid material) with or without the inclusion of MgCl 2 in the formulations.

Figure 5 shows a bar chart of the results on the

fracturability of the tablets based on 5% gelatin stock solution and agent selected from a saccharide, a polyol, and an amino acid at varied concentration (total solid material) with or without the inclusion of MgCl 2 in the formulations.

Figure 6 shows a bar chart of the results on the

disintegration time (based on the USP disintegration test) of the tablets based on 5% gelatin stock solution and agent selected from a saccharide, a polyol, and an amino acid at varied concentration (total solid material) with or without the inclusion of MgCl 2 in the formulations. Figure 7 shows a bar chart of a mathematical representation of improvement in the tablets properties. A high value is associated with improved hardness and short disintegration times . Figure 8 shows the temperature profiles of tablets based on Gum Arabic and gelatin during their freeze drying cycles. The results suggest that Gum Arabic has a significantly shorter primary drying time compared to gelatin.

Figure 9 shows a bar chart showing the mechanical strength in terms of the harness and fracturability of tablets based on varied concentration of Gum Arabic stock solution.

Figure 10 shows a bar chart showing the disintegration time of tablets based on varied concentration of Gum Arabic stock solution.

Figure 11 shows a bar chart showing the mechanical strength of tablets formed using 15% Gum Arabic stock solution and agent selected from a saccharide, a polyol, and an amino acid at varied concentration (total solid material) .

Figure 12 shows a bar chart showing the disintegration time tablets formed using 15% Gum Arabic stock solution and agent selected from a saccharide, a polyol, an amino acid at varied concentration (total solid material) .

Example 1

The inventors have found that freeze drying of amorphous materials may be facilitated by modifying the thermal profile of the frozen material by adding a readily

crystallising excipient and by applying an annealing step. The modified formulation ensures the stability during the freeze drying steps and formation of intact and elegant product. Additionally, the modified thermal profile allows freeze drying at higher temperature and consequently

decreasing the primary drying time significantly (increasing the formulation's critical freeze drying temperature). One application of that was shortening the disintegration time of lyophilised tablets by inclusion of high wettable materials in the formulation of lyophilised orally

disintegrating tablets. It is thought that the fast disintegration profile of the lyophilised tablets is directly related to the wettability profile of the excipient used in the formulation. Proline is a highly wettable excipient, however, its inclusion in lyophilised fast disintegrating tablets is limited due to the low glass transition temperature (amorphous) and consequently its collapse temperature. Addition of readily crystallising materials such as serine and alanine and applying annealing step result in protecting the formulation from collapsing.

Figure 1 shows Overlaid DSC heating curves of frozen gelatin stock solution (5%) with 70% (solid materials) of Proline: serine (25:75) without annealing (curve 1 and 2) and with annealing (curves 3 and 4) . The collapse temperature of a formulation is 1 to 3 °C higher than their Tg (glass transition) , which appear as thermal step in the baseline (curve 1 and 2) . The annealing step vanishes the glass transition step (Tg) (curves 3 and 4) and consequently increase the collapse temperature, which allows successful freeze drying at higher temperature.

Example 2

Tablets having the components listed in Table 1 below were made using the following method. Gelatin (60 bloom

strength) was dissolved in double distilled water at 40 °C to obtain a concentration of 5% w/w. After complete dissolution of gelatin, an agent selected from a saccharide, a polyol, an amino acid at varied concentration (total solid material) was added along varied concentration of MgCl 2 .

1.5 g of the solution was poured into a mould, frozen at -80°C for about 60 minutes and freeze-dried (ADVANTAGE

Freeze-dryer, VIRTIS) according to an optimized regime

(primary drying for 48 hours at shelf temperature of -40°C and secondary drying for 8 hours at shelf temperature of 20°C and vacuum of 50 m Torr. All the formulations were prepared in triplicate from three independent batches.

Formulation g of g of added g of added Concentration Mass of Molar code added gelatin (X) of (X) added ratio water material material (% MgCl 2 (g) (X:

( g) w/w) MgCl 2)

FDGG001 23.75 1.25 0.3125 20 0.165 1:1

(Glucose)

FDGT001 23.75 1.25 0.3125 20 0.0869 1:1

(Trehalose)

FDGT002 23.75 1.25 0.3125 20 0.165 1:1.9

(Trehalose)

FDGL001 23.75 1.25 0.3125 20 0.2035 1:1

(Lysine)

FDGL002 23.75 1.25 0.3125 20 0.165 1:0.8

(Lysine)

FDGL003 23.75 1.25 1.25 50 0.814 1 : 1

(Lysine)

FDGL004 23.75 1.25 1.25 50 0.407 2 : 1

(Lysine)

FDGM001 23.75 1.25 0.5357 30 0.280 1:1

(Mannitol)

FDGM002 23.75 1.25 0.5357 30 0.165 1:0.59

(Mannitol)

FDGMO03 23.75 1.25 1.25 50 0.653 1 : 1

(Mannitol)

FDGM004 23.75 1.25 1.25 50 0.327 2:1

(Mannitol)

FDGA1001 23.75 1.25 1.25 50 0.668 1:1

(Alanine)

FDGA1002 23.75 1.25 1.25 50 0.165

(Alanine)

FDGH001 23.75 1.25 0.5357 30 0.329 1:1

(Histidine)

FDGH002 23.75 1.25 0.5357 30 0.165

(Histidine)

Table 1 A series of experiments were conducted on the tablets formed to show the effect of using magnesium chloride (MgCl 2 ) as a disintegration enhancer in the formulation of lyophilised fast disintegrating tablets.

The hardness of the tablets was measured using the method and apparatus outlined below.

Figure 4 shows a bar chart of the results on the hardness of the tablets based on 5% gelatin stock solution and agent selected from a saccharide, a polyol, an amino acid at varied concentration (total solid material) with or without the inclusion of MgCl 2 in the formulations. The fracturability of the tablets was measured using the method and apparatus outlined below.

Figure 5 shows a bar chart of the results on the

fracturability of the tablets based on 5% gelatin stock solution and agent selected from a saccharide, a polyol, an amino acid at varied concentration (total solid material) with or without the inclusion of MgCl 2 in the formulations.

The disintegration of the tablets was measured using the method and apparatus outlined below.

Figure 6 shows a bar chart of the results on the

disintegration time of the tablets based on 5% gelatin stock solution and agent selected from a saccharide, a polyol, an amino acid at varied concentration (total solid

material) with or without the inclusion of MgCl 2 in the formulations . The RLTI of the tablets were measure in the following way. RLTI = (H/DT) ÷ (H°/DT°)

Where H: hardness of the tested tablet, DT: disintegration time of the tested tablet, H° : hardness of the control tablets (5% gelatin only), DT° : disintegration time of the control tablet (5% gelatin only) .

Figure 7 shows a bar chart of a mathematical representation of improvement in the tablets properties . A high value is associated with improved hardness and short disintegration times .

The results suggested that inclusion of MgCl 2 in the tablet improves the overall tablets properties, because inclusion of MgCl 2 decreases the disintegration time without altering the mechanical properties of the tablets, and consequently results in higher RLTI .

Example 3

Figure 8 shows the temperature profiles of tablets based on Gum Arabic and gelatin during their freeze drying cycles . The results suggest that Gum Arabic has a significantly shorter primary drying time compared to gelatin.

Example 4

Preparation of lyophilized tablets

This example was carried out in order to access the

influence of gum Arabic concentration on the mechanical properties and disintegration time of lyophilised orally disintegrating tablets. Gum arabic was dissolved in double distilled water at room temperature to obtain a concentration of 5, 10, 15 and 20% w/w. 1.5 g of the solution was poured into a mould, frozen at -80°C for about 60 minutes and freeze-dried (ADVANTAGE Freeze-drye , VIRTIS) according to an optimized regime

(primary drying for 24 hours at shelf temperature of -40°C and secondary drying for 4 hours at shelf temperature of 20°C and vacuum of 50 m Torr. All the formulations were prepared in triplicate from three independent batches.

Inclusion of mannitol, L- lanine and L-glutamine.

Mannitol, L-alanine and L-glutamine were added individually to 15 % (w/w) gum Arabic stock solutions at concentration of 30 and 50 of total solid material. 1.5g of the solution was poured into a mould, frozen at -80°C for about 60 minutes and freeze-dried (ADVANTAGE Freeze-dryer, VIRTIS) according to the optimized regime (primary drying for 24 hours at shelf temperature of -40°C and secondary drying for 4 hours at shelf temperature of 20 °C and vacuum of 50 m Torr. All the formulations were prepared in triplicate from three independent batches .

Differential scanning calorimetry studies.

Differential scanning calorimetry (Pyris Diamond DSC and Intracooler 2P: Perkin Elmer, Wellessey, USA) was employed to determine glass transition temperature (Tg) and

crystallisation event of the formulation in their liquid state (before freeze drying) . 10-15 mg of the liquid samples were loaded into aluminium pans, cooled to -65°C and then heated to 20°C at 5°C/min with a nitrogen purge of

20ml/min. An empty aluminium pan was used as reference for all measurements. The resulting graphs were analysed by Pyris manager

software. Tg value was determined from the intersection of relative tangents to the baseline. All the measurements were done in triplicate of independently prepared samples. The DSC was calibrated for temperature and heat flow using standard samples of indium (melting point: 156.6 °C, AHm: 28.42 J/g) and Zinc (melting point: 419.5°C, AHm: 108.26 J/g) · Mechanical properties of the tablets.

The mechanical properties of the tablets (hardness and fracturability) were investigated with a texture analyzer (QTS 25: Brookfield, Essex, UK) equipped with a 25kg load cell. The instrument was calibrated by standard weight of 500g and 5kg. The tablet was placed in a holder with a cylindrical hole. The hardness was taken as the peak force after 1mm penetration of 5mm diameter probe at a speed of 6 mm/min. Fracturability was the peak force after 3mm penetration of 1mm diameter probe at a speed of 6mm/min. The results were average of three measurements from

independently prepared batches.

Disintegration time of the tablets.

The disintegration time of the tablets was measured using a USP disintegration tester (Erweka, ZT3) . Distilled water (800 ml) kept at 37 °C was used as a medium and the basket was raised and lowered at a fixed frequency of 30

cycles/min. One tablet was evaluated from each lot. All the formulations were evaluated in triplicate and standard deviation was calculated. Results

Thermal properties of the formulation.

Table 2

Figure 9 shows a bar chart showing the mechanical strength in terms of the harness and fracturability of lyophilised tablets based on varied concentration of Gum Arabic stock solution.

Figure 10 shows a bar chart showing the disintegration time of tablets based on varied concentration of Gum Arabic stock solution.

Figure 11 shows the effects of the presence of mannitol, alanine, glutamine, mannitol and alanine on the mechanical strength of the tablets. Figure 12 shows the effects of the presence of mannitol, alanine, glutamine, mannitol and alanine on the

disintegration time of the tablets. Gum Arabic LTI RLTI (to 5% concentration (hardness/disintegration gelatine) (%w/w) time)

5 0.28 0.59

10 0.40 0.86

15 0.56 1.18

20 0.36 0.78

Table 3

Table 3 shows the lyophilised tablet index

(hardness/disintegration time) and the relative lyophilised tablet index (relative to 5% gelatine) of lyophilised tablets based on varied concentration of gum Arabic. The RLTI value provided a ratio indicative of whether the prepared gum Arabic formulation was better than the gelatin only formulation. Values greater than 1 indicate

superiority over the gelatin formulation, whereas lower values suggest retardation in the overall tablet properties (disintegration time and hardness) . Example 5: ODTs of phenytoin (50 mg)

1. Formulation

Gum Arabic was dissolved in double distilled water at room temperature to obtain a concentration of 15% w/w. Alanine was added to the solution at a concentration of 40% w/w as a percentage of the dissolved gum Arabic. With constant stirring on a magnetic stirrer, phenytoin was added slowly at a concentration of 30% w/w, as a percentage of the dissolved gum Arabic. The resulted formulation was subjected to shear homogenisation at 5000 rpm for 10 min to obtain a uniform suspension. Accurate mass of the homogenised formulation required to obtain the therapeutic dose was poured in a tablet mould with internal diameter of 18 mm, frozen at -80°C for about 60 minutes, annealed in -20°C pre-cooled freezer for 12 hours and then transferred back to the -80°C freezer. The frozen formulation was freeze-dried (ADVANTAGE Freeze-drye , VIRTIS) according to an optimized regime (primary drying for 16 hours at shelf temperature of -35°C and secondary drying for 1 hour at shelf temperature of 10 °C and vacuum of 50 mTorr) .

2. Characterisations and stability study of the prepared ODTs

The lyophilised ODTs of phenytoin were subject to short term stability studies. Whereas no change were noticed in appearance or smell, the results (table 4) indicated that no significant change in moisture content, disintegration time, drug content and mechanical properties suggesting that the formulation were chemically and physically stable. Table 4. Characterisation of the prepared lyophilised ODTs after 0 and 3 months. Results are means + SD, n=3.

Time interval (months)

Parameters

0 3

Moisture content

2.04 ± 0.47 2.25 ± 0.32 (%)

Disintegration time

5 ± 1 6 ± 1

(s)

Hardness (N) 6.41 ± 0.56 6.28 ± 0.42

Friability (%) 10.45 ± 2.75 9.2 ± 1.83

Drug content (%) 101.24 ± 3.89 99.12 ± 4.02 3. Dissolution study

The dissolution profiles of the prepared lyophilised tablets and commercial chewable tablets (Epanutin ® Infatabs) that contain 50 mg 5, 5diphenylhydantoin (phenytoin) are presented in Figure 13. According to the US Pharmacopeia, not less than 70% of the dose should be dissolved within 120 min under the prescribed dissolution conditions. Bear in mind, that the chewable tablets were crushed to fine powder before performing the dissolution test and the instant

disintegration of the lyophilised tablets, both products satisfied the USP criteria by far and showed fast

dissolution rate with about 60% of the drug released in less than 5 min. However, the lyophilised tablets showed higher dissolution efficiency with complete drug release in about 10 min (figure 13) .

Example 6: ODTs of ranitidine HCl (75 mg) .

1. Formulation

Gum Arabic was dissolved in double distilled water at room temperature to obtain a concentration of 15 % w/w. Alanine was added to the solution at a concentration of 40% w/w as a percentage of the dissolved gum Arabic. With constant stirring on a magnetic stirrer, ranitidine HCl was added slowly at a concentration of 15% w/w, as a percentage of the dissolved gum Arabic. The resulted formulation was

subjected to shear homogenisation at 5000 rpm for 10 min to obtain a uniform solution. Accurate mass of the homogenised formulation required to obtain the therapeutic dose was poured in a tablet mould with internal diameter of 20 mm, frozen at -80°C for about 60 minutes, annealed in -20°C pre-cooled freezer for 12 hours and then transferred back to the -80°C freezer. The frozen formulation was freeze-dried (ADVANTAGE Freeze-dryer, VIRTIS) according to an optimized regime (primary drying for 16 hours at shelf temperature of -35°C and secondary drying for 1 hour at shelf temperature of 10 °C and vacuum of 50 mTorr) .

2. Characterisations and stability study of the prepared ODTs Short term stability studies of the lyophilised ODTs of ranitidine HCl are summarised in table 5. The results indicated no significant change in appearance, moisture content, disintegration time, drug content and mechanical properties, suggesting that the formulation was chemically and physically stable.

Table 5. Characterisation of the prepared lyophilised ODTs after 0 and 3 months. Results are means + SD, n=3.

3. Dissolution profile

The dissolution profiles of the prepared lyophilised tablets and commercial compressed tablets (Zantac™ Relief) that contain 75 mg ranitidine HCl are presented in Figure 14.

According to the USP, not less than 80% of the drug should dissolve within 45 min under the prescribed dissolution conditions. The results showed that both products satisfied the USP criteria with complete dissolution in less than 45 min. However, the lyophilised tablets showed faster dissolution rate with 100% drug release in about 5 min compared to 20 min was required by the compressed tablets (figure 14) . Example 7: ODTs of ibuprofen (200 mg) .

1. Formulation

Gum Arabic was dissolved in double distilled water at room temperature to obtain a concentration of 15 % w/w. Alanine was added to the solution at a concentration of 40% w/w as a percentage of the dissolved gum Arabic. With constant stirring on a magnetic stirrer, ibuprofen was added slowly at a concentration of 40% w/w, as a percentage of the dissolved gum Arabic. The resulted formulation was

subjected to shear homogenisation at 5000 rpm for 10 min to obtain a uniform suspension. Accurate mass of the

homogenised formulation required to obtain the therapeutic dose was poured in a tablet mould with internal diameter of 20 mm, frozen at -80°C for about 60 minutes, annealed in -20°C pre-cooled freezer for 12 hours and then transferred back to the -80°C freezer. The frozen formulation was freeze-dried (ADVANTAGE Freeze-dryer , VIRTIS) according to an optimized regime (primary drying for 16 hours at shelf temperature of -35 °C and secondary drying for 1 hour at shelf temperature of 10°C and vacuum of 50 mTorr) .

2. Characterisations and stability study of the prepared ODTs

The results from short term stability studies of the

lyophilised ODTs are summarised in Table 3. The results indicated that no significant change in appearance, moisture content, disintegration time, drug content and mechanical properties was observed, which may suggests that the

formulation were chemically and physically stable.

Table 6. Characterisation of the prepared lyophilised after 0 and 3 months. Results are means ± SD, n=3.

3. Dissolution profile

The dissolution profiles of the prepared lyophilised tablets and commercial compressed ODTS (Nurofen Meltlets) that contain 200 mg ibuprofen are presented in Figure 15.

According to the US Pharmacopeia, not less than 70% of the dose should be dissolved within 120 min under the prescribed dissolution conditions. The results showed that both products satisfied the USP criteria confidently as the required 70% release was reached in less than 10 min, which could be attributed to their fast disintegration in the dissolution medium. However, the lyophilised tablets showed faster dissolution rate, about 90% drug release after 5 min compared to about 50% in case of the compressed ODTs (figure 15) .

Example 8: ODTs of loperamide HC1 (2 mg) .

1. Formulation Gum Arabic was dissolved in double distilled water at room temperature to obtain a concentration of 15% w/w. Alanine was added to the solution at a concentration of 40% w/w as a percentage of the dissolved gum Arabic. With constant stirring on a magnetic stirrer, loperamide HCl was added slowly at a concentration of 1% w/w, as a percentage of the dissolved gum Arabic . The resulted formulation was

subjected to shear homogenisation at 5000 rpm for 10 min to obtain a uniform suspension. Accurate mass of the

homogenised formulation required to obtain the therapeutic dose was poured in a tablet mould with internal diameter of 13.50 mm, frozen at -80°C for about 60 minutes, annealed in -20°C pre-cooled freezer for 12 hours and then transferred back to the -80°C freezer. The frozen formulation was freeze-dried (ADVANTAGE Freeze-dryer, VIRTIS) according to an optimized regime (primary drying for 16 hours at shelf temperature of -35°C and secondary drying for 1 hour at shelf temperature of 10°C and vacuum of 50 mTorr) . 2. Characterisations and stability study of the prepared

ODTs

The short term stability studies of the prepared ODTs are summarised in table 7. The results indicated that no significant change in appearance, moisture content,

disintegration time, drug content and mechanical properties was observed suggesting that the formulation was chemically and physically stable. Table 7. Characterisation of the prepared lyophilised ODTs after 0 and 3 months. Results are means + SD, n=3.

3. Dissolution profiles

The dissolution profiles of the prepared lyophilised tablets and commercial lyophilised ODTs (Imodium ® Instant) that contain 2 mg loperamide HC1 are presented in Figure 16.

According to the US Pharmacopeia, not less than 80% of the dose should be dissolved within 30 min under the prescribed dissolution conditions.

All the tested ODTs from both formulations showed instant disintegration in the dissolution medium. Our lyophilised ODTs showed very fast dissolution rate, about 70% drug release in just 2 min, and achieved the mandatory drug release (80%) within 10 min. On the other hand, the

commercial lyophilised ODTs showed huge variation in their dissolution rate, especially in the first 6 min, and needed 25 min to release 80% of the dose. Moreover, the prepared ODTs displayed more efficient dissolution with cumulative drug release of more than 90% at the end of the experiment compared to a maximum cumulative release of 80% for the commercial ODTs .