CLIAMS:We Claim:

1. An orally disintegrating composition comprising granules of phentermine or salts thereof and at least one organic acid, wherein the granules are prepared by wet granulation and are devoid of organic acid.

2. An orally disintegrating composition of claim 1, wherein the organic acid is selected from the group comprising of citric acid, tartaric acid, fumaric acid, lactic acid, maleic acid and succinic acid.

3. An orally disintegrating composition of claim 1, wherein phentermine is in the form of phentermine hydrochloride.

4. An orally disintegrating composition of claim 1, wherein the composition is in the form of orally disintegrating tablet.

5. An orally disintegrating composition of claim 1, wherein granules of phentermine or salts thereof comprises one or more polyalcohols selected from the group of arabitol, erythritol, propylene glycol, glycerin, galactitol, sorbitol, mannitol, ribulose, xylitol, sorbose, riboflavin, sucrose, dextrose, maltose, lactose, lactulose, ribose, mannose, galactose, fructose and diethanolamine, triethanolamine.

6. An orally disintegrating composition of claim 1, wherein the weight ratio of mannitol to phentermine or salts thereof is in the range of between 1:1 and 30:1 by weight, preferably in the range of between 10:1 and 15:1 by weight.

7. An orally disintegrating tablet of claim 4, wherein the friability of the orally disintegrating tablet is less than 1.0%.

8. An orally disintegrating composition of claim 1, wherein the weight ratio of phentermine or salts thereof to organic acid is in the range of between 1:0.1 and 1:10 (w/w), preferably it is in the range of between 1:0.5 and 1:2 (w/w).

9. An orally disintegrating tablet prepared by the process comprising steps of:
(a) mixing phentermine or salts thereof with at least one polyalcohol to form homogenous powder blend;
(b) granulating the powder blend with aqueous solution of water soluble polymer in a rapid mixer granulator to form granules;
(c) mixing organic acid with the granules formed in step (b);
(d) optionally, mixing granules with at least one pharmaceutically acceptable excipient selected from the category of diluent, water soluble binder, disintegrant, surfactant, flavoring agent and lubricant.
(e) compressing the blend from step (c) or (d) to form orally disintegrating tablet.

10. An orally disintegrating composition of claim 4, wherein the tablet retains at least 90% w/w of the potency of the phentermine or salts thereof when stored at 25°C and 40% relative humidity or at 40ºC and 25% relative humidity for 3 months.

11. An orally disintegrating composition of any of the preceding claim, wherein the composition may provide anorectic action for weight reduction when administered to a patient in need thereof.
,TagSPECI:4. Description

The present invention relates to improved orally disintegrating compositions of phentermine or salts thereof. In particular, the invention relates to orally disintegrating compositions comprising granules of phentermine or salts thereof and at least one organic acid, wherein the granules are devoid of organic acid. The granules of phentermine or salts thereof are prepared by wet granulation. The granules thus prepared by wet granulation are mixed with at least one organic acid, optionally with one or more pharmaceutically acceptable excipients and compressed to form orally disintegrating tablet. Further, the invention also provides process for preparation of orally disintegrating tablet of phentermine or salts thereof.

Phentermine hydrochloride is a sympathomimetic amine anorectic available in the form of orally disintegrating tablet (ODT) which is marketed under the brand name of Suprenza®. Its chemical name is α,α,dimethylphenethylamine hydrochloride with a following structural formula:

Orally disintegrating formulations are becoming an increasingly important issue in the area of better patient compliance comparative to the conventional solid dosage forms for oral administration such as capsules and tablets, which are the most commonly used. In particular pediatric and geriatric patients and patients with mental problems such as depression, often experience difficulties in swallowing solid dosage forms. Moreover, the progressive ageing of population is one of the changes occurring in modern society. Swallowing difficulty is a phenomenon accompanied by the onset of degenerative pathologies involving difficulties in coordination and in swallowing the traditional oral forms such as tablets or capsules. Approximately 10 million Americans are evaluated each year with swallowing difficulties.

The conventional solution to such a problem is usually provided by water-soluble effervescent tablets. In this case, the patient ingests the aqueous solution resulting from the disintegration of the tablet in water so that the active ingredient already dissolved or dispersed in water is in a highly bio-available form.

ODTs are solid unit dosage form which dissolve or disintegrate rapidly in the mouth without water or chewing and are easily taken by elderly people, children and patients that have difficulty swallowing. They are attracting attention as formulations that improve quality of life because administration without water is possible.

A satisfied orally disintegrating dosage form needs to meet number of requirements. Firstly, it has to disintegrate in the oral cavity rapidly. Moreover, a premature release in the mouth could also lead to problems due to the often unpleasant taste of the active ingredient. Besides, these compositions should be very porous and should not be very hard. These porous compositions tend to be very sensitive to humidity.

Various formulations and methods are already known for the preparation of orally disintegrating formulations. However, orally disintegrating formulations are becoming an increasingly important issue in the area of better patient compliance comparative to the conventional solid dosage forms for oral administration such as capsules and tablets.

Various technologies have been developed which enable the preparation of compositions that disintegrate quickly in the oral cavity. These technologies include, fluidized bed, spray drying, freeze drying and floss formation.

US patent number US 6,149,938 discloses a process for making a granulate composition of phentermine hydrochloride suitable for preparation of ODT. The process involves granulating in a fluidized bed a polyalcohol, API and citric acid with aqueous solution or aqueous dispersion of a water-soluble or water-dispersible polymer. The process further involves drying granulate in a fluidized bed.

EP patent number EP 1,246,668 B1 discloses a fast acting oral pharmaceutical composition and particularly relates to fast-acting, freeze-dried pharmaceutical composition of zolmitriptan.

US patent number US 5,178,878 discloses a rapidly dissolving oral formulation that requires incorporation of effervescent agent into a tableted matrix in order to achieve rapid oral disintegration. However, tablets which include effervescent pairs are highly sensitive to moisture and require costly and special handling equipment, controlled-humidity environments, as well as special moisture resistant packaging. Moreover, such preparations have an unpleasant mouth feel.

US patent number US 5,958,471 discloses spray drying technology as another orally disintegrating technique, which includes preparing an aqueous solution of more than 80% of one or more non-hygroscopic polyols, and spraying the resulting mixture into an air stream.

EP patent number EP 1,145,711 B1 describes the preparation of flash-melt dosage forms that disintegrate in the mouth in less than 25 second.

The spray drying technique involves spraying the drug and excipients into a chamber maintained at a high temperature. As a result, this technique is not suitable for application to thermo-labile drugs. Additionally, spray drying technology leads only to very poor output and is very expensive.

The dosage forms based on freeze-drying technology are significantly more costly to produce and are time-consuming. In addition, the effectiveness of a freeze-drying process depends on the physico-chemical parameters of the active substances used.

Thus, there exists an enduring need to develop a robust, simple and economical process, which eliminates the need of additional steps, expensive specialty excipients and sophisticated techniques for developing orally disintegrating compositions.

The main object of the present invention is to provide an improved orally disintegrating compositions of phentermine or salts thereof which overcomes above described problems and which further provide the advantageous property of allowing the active medicament to disintegrate rapidly in the oral cavity without remaining substantial amounts of the active ingredient and which have a pleasant mouth feel.

Another objective of the present invention is to provide a simple, cost-effective and time saving process for the preparation of orally disintegrating composition of phentermine or salts thereof. Also the object of the present invention is to provide an orally disintegrating composition of phentermine or salts thereof which have good mechanical strength (such as adequate hardness and low friability) enough to be processed in high speed tableting machines and shipped in low cost packages.

Orally disintegrating pharmaceutical composition includes the compositions which disintegrate/dissolve in the mouth rapidly without administering, providing the convenience of a tablet formulation while allowing the ease of swallowing provided by a liquid formulation. Such dosage forms due to their ease of administration and pleasant mouth feel may encourage patients who have difficulty in swallowing conventional tablets to adhere to daily medication regimens. Such tablets also serve useful where water may not be readily available to assist in swallowing the tablet in specific conditions like while traveling or patient is not in a condition to use water and swallow the conventional tablet.

It was reported in the prior art that the granules prepared by fluid bed processor are porous in nature only when phentermine is processed (granulation) with at least one organic acid. The porous nature of granules, according to the prior art, is necessary to achieve shorter disintegration time. But the inventors of the present invention have surprisingly found that orally disintegrating compositions of phentermine or salts thereof can be prepared without using sophisticated technique such as fluid bed processor and without using organic acid during granulation. In other words, improved orally disintegrating compositions of phentermine or salts thereof can be prepared by conventional wet granulation.

According to the present invention, orally disintegrating pharmaceutical compositions are disintegrated in less than three minutes in oral cavity. More preferably, the pharmaceutical formulations are disintegrated in an oral cavity in less than two minutes and most preferably the pharmaceutical formulations are disintegrated in oral cavity in less than one minute.

In one general aspect, there is provided an orally disintegrating composition comprising granules of phentermine or salts thereof and at least one organic acid.

In another general aspect, there is provided an orally disintegrating tablet, wherein the granules are prepared by wet granulation in rapid mixer granulator.

In one general aspect, there is provided a composition in the form of orally disintegrating tablet.

The orally disintegrating composition described in the present invention comprises granules of phentermine or salts thereof and at least one organic acid, wherein the granules are prepared by wet granulation and the said granules are devoid of organic acid.

In another general aspect, there is provided a process for preparation of orally disintegrating composition of phentermine or salts thereof which process comprises of steps:
(a) mixing phentermine or salts thereof with at least one polyalcohol to form homogenous powder blend;
(b) granulating the powder blend with aqueous solution of water soluble polymer in a rapid mixer granulator to form granules;
(c) mixing organic acid with the granules formed in step (b);
(d) optionally, mixing granules with at least one pharmaceutically acceptable excipient selected from the category of diluent, water soluble binder, disintegrant, surfactant, flavoring agent and lubricant;
(e) processing the granules of step (c) or (d) in to a suitable orally disintegrating composition.

In another general aspect, there is provided a process for preparation of orally disintegrating tablet of phentermine or salts thereof which process comprises of steps:
(f) mixing phentermine or salts thereof with at least one polyalcohol to form homogenous powder blend;
(g) granulating the powder blend with aqueous solution of water soluble polymer in a rapid mixer granulator to form granules;
(h) mixing organic acid with the granules formed in step (b);
(i) optionally, mixing granules with at least one pharmaceutically acceptable excipient selected from the category of diluent, water soluble binder, disintegrant, surfactant, flavoring agent and lubricant;
(j) compressing the granules of step (c) or (d) to orally disintegrating composition.

In another general aspect, there is provided a process for preparation of orally disintegrating tablet of phentermine or salts thereof which process comprises of steps:
(a) mixing phentermine or salts thereof with mannitol to form homogenous powder blend;
(b) granulating the powder blend with aqueous solution of polyvinyl pyrrolidone in a rapid mixer granulator to form granules;
(c) mixing granules formed in step (b) with citric acid, mannitol, crospovidone, sodium lauryl sulfate, peppermint flavor, talc and magnesium stearate.
(d) compressing the blend from step (c) to form orally disintegrating tablet.

In another general aspect of the invention, the weight ratio of mannitol to phentermine or salts thereof is in the range of between 1:1 and 30:1 (w/w), preferably it is in the range of between 10:1 and 15:1 (w/w). The said amount makes it possible to significantly improve compressibility and reduce friability. Higher quantities may have negative mechanichal strength of the formulation and lower quantities may worsen the disintegration time.

In another general aspect, the hardness of the orally disintegrating tablet is between 5 N to 100 N, preferably it is between 20 N to 50 N; and the friability of the orally disintegrating tablet is less than 1.0%.

In another general aspect, the composition comprises the weight ratio of phentermine or salts thereof to organic acid is in the range of between 1:0.1 and 1:10 (w/w), preferably it is in the range of between 1:0.5 and 1:2 (w/w).

In another general aspect, the composition comprises phentermine or salts thereof, wherein the dosage form retains at least 90% w/w of the potency of phentermine or salts thereof when stored at 25°C and 40% relative humidity or at 40ºC and 25% relative humidity for 3 months.

The term "pharmaceutically acceptable excipients" includes a pharmaceutically acceptable material, composition or vehicle, suitable for administering an active pharmaceutical ingredient. Each excipient should be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Excipients include diluents, binders, disintegrants, glidants, lubricants, flavoring, and others.

The term “granulation” used throughout the specification refers to a process in which primary powder particles are made to adhere to form larger, multiparticle entities called granules, free-flowing compositions, having sufficient cohesive properties for compression into tablets. In other words, it is the process of collecting particles together by creating bonds between them. Bonds may be formed by compression or by using a binding agent. Generally, the granulation process involves treating dry powders with agents that increase the adhesive properties of the particles resulting in stable agglomerations of the powder particles. Wet granulation is the most widely used method. In wet granulation, the dry powder components are blended in a suitable mixer followed by addition of a binding agent and further mixing to achieve the desired consistency. After drying, the granulated compositions typically have a free flowing, sand-like texture. Granulation provides the required cohesiveness and compactability for compression into tablets of satisfactory hardness and friability. Wet granulation using substantial amounts of wetting agent is the method which is most commonly used in the pharmaceutical industry, as it provides better prospects in terms of ease of processing, especially with respect to the required flow and cohesive properties, and presumably fewer problems associated with physical characteristics of various ingredients in the formulation.

The term “polyalcohols” as used herein, refers to a chemical compound having two or more hydroxyl groups bonded to one or more carbon atoms.

In an embodiment, there is provided an orally disintegrating composition comprising phentermine or salts thereof and at least one organic acid.

In another embodiment, there is provided an orally disintegrating composition in the form of a tablet.

In another embodiment, there is provided an orally disintegrating tablet comprising granules of phentermine or salts thereof and at least one organic acid, wherein the granules are devoid of organic acid.

The orally disintegrating tablet composition comprising phentermine or salts thereof and at least one organic acid can be prepared by wet granulation in rapid mixer granulator. The important aspect of the invention is that organic acid do not present in the granules i.e. organic acid is mixed with the formed granules as an extragranular part.

As such phentermine hydrochloride has low density, therefore to increase its compressibility a diluent needed to be used, where mannitol is selected as diluent. The weight ratio of mannitol to phentermine or salts thereof is in the range of between 1:1 and 30:1 (w/w), preferably it is in the range of between 10:1 and 15:1 (w/w). The said amount makes it possible to significantly improve compressibility and reduce friability.

According to this object of the present invention, the hardness of the orally disintegrating tablet is between 5 N to 100 N, preferably it is between 20 N to 50 N; and the friability of the orally disintegrating tablet is less than 1.0%.

In another embodiment, the composition in accordance of the present invention comprises the weight ratio of phentermine or salts thereof to organic acid is in the range of between 1:0.1 and 1:10 (w/w), preferably it is in the range of between 1:0.5 and 1:2 (w/w). The said amount makes it possible to significantly improve the formulation and achieve a substantial reduction in disintegration time. The said amount makes it possible to significantly improve the formulation and achieve a substantial reduction in disintegration time.

In another embodiment, the orally disintegrating composition prepared by the process comprising steps of:
(a) mixing phentermine or salts thereof with at least one polyalcohol to form homogenous powder blend;
(b) granulating the powder blend with aqueous solution of water soluble polymer in a rapid mixer granulator to form granules;
(c) mixing organic acid with the granules formed in step (b);
(d) optionally, mixing granules with at least one pharmaceutically acceptable excipient;
(e) processing the blend from step (c) or (d) in to a suitable dosage form.

In another embodiment, the orally disintegrating tablet prepared by the process of comprising steps of:
(a) mixing phentermine or salts thereof with mannitol to form homogenous powder blend;
(b) granulating the powder blend with aqueous solution of povidone k-30 in a rapid mixer granulator to form granules;
(c) mixing granules formed in step (b) with citric acid, mannitol, crospovidone, SLS, peppermint flavor, talc and magnesium stearate.
(d) compressing the blend from step (c) to form orally disintegrating tablet.

In another embodiment, the composition in accordance of the present invention comprising phentermine or salts thereof, wherein the dosage form retains at least 90% w/w of the potency of the phentermine or salts thereof when stored at 25°C and 40% relative humidity or at 40ºC and 25% relative humidity for 3 months.

Polyalcohols useful in this invention include, without limitation, alkyl polyalcohols, amine polyalcohols, polyamine polyalcohols, and mixtures thereof. Particular polyalcohols useful in this invention include, without limitation, adonitol, arabitol, erythritol, propylene glycol, glycerin, galactitol, sorbitol, mannitol, ribulose, xylitol, sorbose, riboflavin, sucrose, dextrose, maltose, lactose, lactulose, ribose, mannose, galactose, fructose, diethanolamine, triethanolamine, (bis(2-hydroxyethyl)amino-2-propanol, tromethamine, 2-bis(2-hydroxyethyl)-amino-2- (hydroxymethy I)- 1,3 -propanediol, l,3-bis[tris(hydroxymethyl)methyl amino] propane, and glucosamine.

Diluents increase the bulk of a solid pharmaceutical composition. Exemplary diluents for solid compositions include, but are not limited to, microcrystalline cellulose, microfine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates, potassium chloride, powdered cellulose, sodium chloride, sorbitol and talc.

Disintegrants increase the dissolution rate of a compacted solid pharmaceutical composition in the patient's stomach, for example. Exemplary disintegrants include, but are not limited to, alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, colloidal silicon dioxide, croscarmellose sodium, crospovidone, guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate and starch.

A lubricant can be added to the composition to reduce adhesion and ease the release of the product from the dye. Exemplary lubricants include, but are not limited to, magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc and zinc stearate.

A stabilizing agent can be added to the composition to stabilize the product during production and during storage of the formulation. Exemplary stabilizing agent include butylated hydroxy anisole, butylated hydroxy toluene, citric acid anhydrous or hydrous, benzoic acid, lanoline, sulphated derivatives, Ortho-phosphoric acid alone or in combinations there of.

An antioxidant can be added to the composition to eliminate or reduce oxidation of the product during production and during storage of the formulation. Exemplary antioxidant include butylated hydroxytoluene, butylated hydroxyanisole, DL-alpha-tocopherol, propyl gallate, octyl gallate, ethylenediamine tetraacetate, ascorbyl palmitate, acetyl cysteine, ascorbic acid, sodium ascorbate, fumaric acid, lecithin and the like and mixtures thereof. The antioxidant in the dosage form ranges from 0.1% to 15% by weight of the composition.

The composition of the present invention may comprise one or more pharmaceutically acceptable excipients selected from the class of, but not limited to, diluent, disintegrant, glidant, lubricant, coloring agent, flavoring agent, antioxidant and stabilizing agent.

The present invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

Example 1:
Table 1
Sr. No Ingredients % w/w
1. Phentermine Hydrochloride 2-20
2. Mannitol 30-90
3. Crospovidone 5-40
4. Povidone k-30 0.1-10
5. Purified Water qs
6. Citric acid 1-20
7. SLS 0.1-5
8. Sucralose 0.5-5
9. Peppermint flavour 0.01-2
10. Talc 0.1-5
11. Mag steatrate 0.1-5
Total 100

Process:
Phentermine or salt thereof was mixed with mannitol to form homogenous powder blend, which was granulated with aqueous solution of povidone k-30 in a rapid mixer granulator to form granules. These granules were mixed with citric acid, mannitol, crospovidone, SLS, peppermint flavor, talc and magnesium stearate and compressed to form orally disintegrating tablet.
The tablet prepared in the example 1 has disintegration time of less than 1 minute.