Field of Invention

The present invention relates to an orally disintegrating pharmaceutical formulation comprising saxagliptin or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

The background of the invention

DPP-IV (dipeptidyl peptidase IV) is an enzyme that catalyzes the conversion of glucagon like peptide-1 (GLP-1 ) from its active form to its inactive form. DPP-IV inhibitors, also commonly known as gliptins, competitively inhibit the enzyme DPP-IV, thereby increasing the endogenous concentration of GLP-1 , which further augments insulin secretion and improves the glycemic profile of patients with diabetes.

DPP-IV inhibitors such as saxagliptin, sitagliptin, vildagliptin, teneligliptin, alogliptin, and linagliptin are available as conventional tablet dosage forms. Conventional tablet dosage forms constitute a preferred route of administration but certain groups of patients including geriatric, bed-ridden, uncooperative, nauseated, on reduced water intake, and patients having dysphagia, difficulty in swallowing, encounter problems while taking these dosage forms. Moreover, patients while travelling may have little or no access to water, limiting the use of conventional tablet dosage forms. As antidiabetic drugs are prescribed chronically, such a problem could lead to a high level of patient non-compliance. In view of this, oral dispersible compositions provide the best alternative over conventional tablet dosage forms. Oral dispersible compositions which rapidly disintegrate on contact with saliva or in a small amount of water, offer increased convenience and ease of administration with the potential to achieve better patient compliance.

However, it is not easy to develop orally disintegrating formulations for all active agents because of several different reasons and requirements such as disintegration, stability, compressibility and taste masking. Further, as DPP-IV inhibitors are generally bitter in taste, conventional tablet dosage forms are available as film-coated tablets in which the outer film coating is used for taste- masking.

Saxagliptin is a dipeptidyl peptidase IV (DPP-IV) inhibitor used for the treatment of type 2 diabetes mellitus. U.S. Patent No. 6,395,767 discloses the compound saxagliptin.

Formula I: Saxagliptin

There are also several patent applications which disclose orally administered saxagliptin formulations, but none of them includes orally disintegrating tablets of saxagliptin.

It is well known in the art that saxagliptin is an unstable compound and it can undergo a thermodynamically favored cyclization to form the corresponding cyclic amidine. This cyclization reaction can occur both in solid state and solution state. The challenge of minimizing or preventing the cyclization reaction during manufacture of saxagliptin formulations is particularly significant because saxagliptin is a low dose drug, which is typically administered in dosage forms containing 2.5 or 5 mg of the drug, and hence the ratio of excipients to drug is high.

Over the past decades, orally disintegrating tablets (ODTs) have gained considerable attention as a preferred alternative to conventional tablets due to improved efficacy, bioavailability, rapid onset of action, better patient compliance and acceptance. ODTs are solid dosage forms containing active ingredients which disintegrate rapidly through buccal mucosa. It is desirable in the treatment of a number of diseases including pediatric and geriatric treatments. However, it is not easy to develop orally disintegrating formulations for all active agents because of several different reasons and requirements such as disintegration, stability, compressibility and taste masking. Dosage form must disintegrate in the oral cavity with the existence of saliva in a short period of time. So, those compositions should have a porous structure. Orally disintegrating tablets are usually pressed with lower compression forces than conventional tablets to obtain a higher porosity. However, these porous characteristics tend to be very sensitive to humidity and may be lead to stability problems.

To fulfill all these requirements, the orally disintegrating tablet formulation of saxagliptin needs to be adapted in particular by a careful excipient selection give a suitable porous structure with suitable disintegrating time and high stability.

As oral dispersible compositions are designed to rapidly disintegrate as the drug comes in direct contact with the tongue, it remains a challenge to the formulators to effectively mask the taste of bitter drugs such as saxagliptin inhibitors to increase the acceptability for these compositions.

Hence, there exists a need in the art for orally disintegrating compositions of saxagliptin thereof to achieve desired dissolution profile and release kinetic while overcoming stability and content uniformity problems. The present invention teaches orally disintegrating compositions of a DPP-IV inhibitor with an acceptable taste.

Detailed description of the invention

The present invention relates to an orally disintegrating pharmaceutical formulation comprising saxagliptin or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

According to one embodiment, saxagliptin or a pharmaceutically acceptable salt used in this present invention is saxagliptin hydrochloride.

Saxagliptin used in the composition of the present invention may be present in its crystalline form, amorphous form, anhydrous form, hydrate form, or mixtures thereof. According to this embodiment, saxagliptin or a pharmaceutically acceptable salt thereof is present in an amount of between 0.10 to 90.00 %, preferably between 0.50 to 50.00 % and more preferably it is 1 .00 to 20.00 % by weight of total formulation.

According to this embodiment, saxagliptin or a pharmaceutically acceptable salt thereof is present in an amount of between 1 mg and 20 mg, preferably 1 mg and 15 mg and more preferably it is between 1 mg and 5 mg.

To develop an orally disintegrating tablet, it is very crucial to achieve superior disintegration time in oral cavity of patients. Formulation must disintegrate in the oral cavity with the existence of saliva in a short period of time. In this invention, for the orally disintegrating formulation comprising saxagliptin or a pharmaceutically acceptable salt thereof, desired disintegration time is achieved.

In one embodiment, the orally disintegrating formulation of saxagliptin or pharmaceutically acceptable salt thereof is disintegrated in less than 1 min.

In one embodiment, the orally disintegrating formulation of this present invention comprises one or more pharmaceutically acceptable excipient selected from the group comprising super-disintegrants, taste masking agents, diluents, glidants, lubricants, binders, glidants, sweeteners, flavouring agents, acidifying agents or alkalizing agents or mixtures thereof.

In one embodiment, the formulation comprises at least two super-disintegrants.

It is difficult to develop orally disintegrating formulations because of several different reasons mentioned above. Those formulations should have a porous structure to achieve rapid disintegration. However, these porous characteristics may be lead to instability problems. A high degree of porosity and a very low overall density are not easily reconciled with strength and durability.

Using super-disintegrant in a specific amount is very important, because it affects density and amount of porous in the structure. Porous structure should both provide rapid disintegration in oral cavity and not to cause stability problems. In this invention, it has been surprisingly found that to achieve these properties, suitable amount of the super- disintegrants is between 0.01 to 10.00 % and preferably 0.01 to 5.00 % and more preferably 0.10 to 5.00 by weight of total formulation.

In one embodiment, synergistically the ratio of saxagliptin to super-disintegrant also affects the compressibility. In the orally disintegrating pharmaceutical formulation of this present invention, the certain ratio of saxagliptin to super-disintegrants is in the range of between 0.01 and 5.00, preferably 0.02 and 2.00 and more preferably 0.2 and 1 .00.

As used herein, the term“super-disintegrant” is defined as the pharmaceutical ingredient that provides improved compressibility, stability as well as achieves disintegration substantially faster than the conventional disintegrants. According to this embodiment, the term “super-disintegrant” is selected from the group comprising crospovidone, croscarmellose sodium, sodium starch glycolate, low-substituted hydroxypropyl cellulose (L-HPC), povidone, alginic acid and alginates, cross-linked alginic acid, sodium carboxymethyl starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, docusate sodium, soy polysaccharide, guar gum, gellan gum, xanthan gum, magnesium alumina silica, polyacrylin potasium, poloxamer, sodium dodecyl sulphate, sodium lauryl sulphate, calcium silicate, sodium glycine carbonate or ion exchange resins or mixtures thereof.

In one embodiment, the super-disintegrants are selected from crospovidone, croscarmellose sodium or mixtures thereof.

Suitable taste-masking agents may include but not limited to PVA (polyvinyl alcohol) based coating, polyvinyl alcohol-polyethylene glycol copolymers (Kollicoat IR), butyl methacrylate and methyl methacrylate (Eudragit E 100) (Poly(butyl methacrylate-co-(2- demethylaminoeethyl)methacrylate-co-methyl methacrylate)), ethylcellulose dispersions (Surelease), Kerry-HPC, polyethylene glycol, polyvinylprolidone, polyvinylprolidone-vinyl acetate copolymer (PVP-VA) and all kinds of OpadryTM, as well as pigments, dyes, titanium dioxide, iron oxide, talc or polymethylmetacrylate copolymers (Eudragit) or mixtures thereof.

Suitable diluents are selected from the group comprising mannitol, xylitol, microcrystalline cellulose (MCC), lactose, corn starch dibasic calcium phosphate, xylitol, spray-dried lactose, sorbitol, sucrose, trehalose, isomalt, LudiFlash® (mannitol, crospovidon and polivinyl acetate), starch, calcium phosphate anhydrate, calcium phosphate dihydrate, calcium phosphate trihydrate, tribasic calcium phosphate, calcium carbonate, calcium sulfate, dicalcium sulfate, sodium chloride, carboxymethyl cellulose calcium, powdered cellulose, cellulose acetate, pregelatinized starch, lactose monohydrate, sodium carbonate, sodium bicarbonate, isomalt, heavy magnesium carbonate, maltodextrine, mixture of sucrose - maltodextrine, dextrose, lactitol, calcium carbonate, sugars, magnesium carbonate, polysaccharides, trehalose, inorganic salts, Pharmaburst® (mannitol, sorbitol, crospovidone and silica; aspartame; and magnesium stearate), Panexcea® (mikrokristalin seluloz, HPMC ve krospovidon), F-Melt® (D-mannitol, xylitol, microcrystalline cellulose, crospovidone, magnesium aluminometasilicate) or mixtures thereof.

Content uniformity problem of the active agent is solved by using diluent. It’s important to choose diluent and use the diluent in a specific amount for providing a good uniformity of content and avoiding stability problems. Since the composition has porous characteristics, it’s sensitive to humidity and fragility which may be lead to stability problems. Furthermore, this stability problem becomes a big challenge due to cyclization reaction problem of saxagliptin.

In one embodiment, the diluent is mannitol.

In this invention, the diluent is in amount of between 50.00% and 90.00%, preferably 60.00% and 80.00% and more preferably between 65.00% and 75.00% by weight of total formulation.

Suitable lubricants are selected from the group comprising sodium stearyl fumarate, magnesium stearate, sodium lauryl sulphate, zinc stearate, calcium stearate, mineral oil, talc, polyethylene glycol, glyceryl monostearate, glyceryl palmitostearate, magnesium lauryl sulphate, fumaric acid, zinc stearate, stearic acid, hydrogenated natural oils, silica, paraffin or mixtures thereof.

In one embodiment, the lubricant is magnesium stearate.

Suitable binders are selected from the group comprising polyvinylpyrrolidone (PVP) (Kollidon) (povidone K30), carnauba wax, hydroxypropyl methyl cellulose (FIPMC), pullulan, polymeth acrylate, glyceryl behenate, hydroxypropyl cellulose (HPC), carboxymethyl cellulose (CMC), methyl cellulose (MC), hydroxyethyl cellulose, sodium carboxymethyl cellulose (Na CMC), carboxymethyl cellulose calcium, ethyl cellulose and other cellulose derivatives, polymetacrylates, polyethylene oxide, polyvinyl alcohol, polycarbophil, polyvinyl acetate and their copolymers, gelatin, starch, xanthan gum, guar gum, alginate, carrageen, kollagen, agar, pectin, hyaluronic acid, carbomer, chitosan, cellulose acetate phthalate, hydroxypropyl starch, hydroxyethyl methyl cellulose, polaxomer, polyethylene glycol (PEG), sugars, glycose syrups, natural gums, tragacanth gum, polyacrylamide, aluminum hydroxide, benthonite, laponite, setostearyl alcohol, polyoxyethylene-alkyl ethers, acacia mucilage, polydextrose or mixtures thereof.

Suitable glidants are selected from the group comprising colloidal anhydrose silica, colloidal silicon dioxide (Aerosil), talc, aluminum silicate, powdered cellulose, calcium phosphate tribasic, hydrophobic colloidal silica, magnesium oxide, magnesium trisilicate, magnesium silicate or mixtures thereof.

In one embodiment, the glidant is colloidal silicon dioxide.

Suitable sweeteners may include but not limited to sucralose, erythritol, thaumatin, mogroside, inuline, acesulfame-K, aspartame, saccharin or its sodium and calcium salts, sodium cyclamate, sucrose, fructose, glucose, sorbitol, menthol, peppermint, cinnamon, chocolate, vanillin and fruit essences such as cherry, orange, strawberry, grape or mixtures thereof.

In one embodiment, the sweetener is sucralose.

In one embodiment, the sweetener is present in an amount of between 0.01% and 5.00% by weight of total formulation.

Taste is one of the most important parameters governing patient compliance. This parameter becomes more evident since the pharmaceutical composition is in the form of orally disintegrating tablets. Using a sweetener improves patient compliance. According to prior art, it is known that aspartame is used mostly as sweetener but contradictory to the prior art we have found that the effect of sucralose as a sweetener in this formulation, not only helped to improve its taste but also increased the efficacy and the conveniency of the formulation because of its positive effects over the glycemic index.

There are lots of disadvantages about aspartame and it has a limited usage if you have to use it every day and also there are several incompatibilities reported in literature and safety problems (Handbook of Pharmaceutical Excipients, Reymond C Rowe, Paul J Sheskey, Marian E Quinn, sixth edition, pages 48-50). Thus, sucralose has an important role in this aspect and even if it is used in low amounts it has a synergistic taste improvement with mannitol which is also very important issue in orally disintegrating tablet formulations.

Suitable flavouring agents may include but not limited menthol, peppermint, cinnamon, chocolate, vanillin and fruit essences such as cherry, orange, strawberry, grape etc. or mixtures thereof.

In one embodiment, the flavouring agent is peppermint.

In one embodiment, the flavouring agent is present in an amount of between 0.0%1 and 5.00% by weight of total formulation.

Suitable acidifying agents may include but not limited to citric acid, fumaric acid, adipic acid, acetic acid, hydrochloric acid, malic acid, nitric acid, phosphoric acid, sulfuric acid, tartaric acid or mixtures thereof.

Suitable alkalizing agents may include but not limited to sodium bicarbonate, sodium glycine carbonate, ammonia solution, ammonium carbonate, diethanolamine, diisopropanolamine, potassium hydroxide, sodium carbonate, sodium borate, sodium hydroxide, trolamine or mixtures thereof.

In this present invention, orally disintegrating formulations comprises; a. 0.10 to 20.00 % saxagliptin

b. 0.01 to 10.00 % super-disintegrant

c. 50.00 to 90.00 % diluent

d. 0.01 to 5.00 % sweetener

e. 0.10 to 5.00 % flavouring agent

f. 0.01 to 5.00 % glidant

g. 0.10 to 10.00 % lubricant Example 1 : Orally disintegrating tablet

Example 2: Orally disintegrating tablet

Example 3: Orally disintegrating tablet

The pharmaceutical compositions mentioned above are prepared by following these steps:

a. mixing saxagliptin or a pharmaceutically acceptable salt thereof, pearlitol (mannitol), croscarmellose sodium, crospovidone, colloidal silicon dioxide, sucralose and peppermint flavor

b. adding sodium magnesium stearate to this mixture and mixing

c. compressing the mixture into tablets