Field of the invention

The technical field of the present invention relates to stable oral solution formulation of bisphosphonic acid or its pharmaceutically acceptable salts. More particularly, the present invention relates to stable oral solution formulation of alendronate sodium.

Background of the invention

Various bisphosphonic acid derivatives are well known for use in the treatment of diseases involving bone resorption. These bisphosphonic acids include alendronic acid, risedronic acid, pamidronic acid, ibandronic acid, clodronic acid, etidronic acid, tiludronic acid and other such therapeutic agents belonging to this class of compounds, and their salts and solvates.

Alendronate sodium is chemically known as (4-amino-l-hydroxybutylidene) bisphosphonic acid monosodium salt. Alendronate as disclosed in U.S. 4,621,077, is a specific inhibitor of osteoclast-mediated bone resorption and is indicated for the treatment of urolithiasis and inhibiting bone reabsorption.

Alendronate is commercially available as alendronate sodium trihydrate in the form of tablets and oral solution under the trade name Fosamax® by Merck. Fosamax® oral solution is provided in 70 mg of alendronate sodium/75 ml single dose bottle for once weekly administration for the treatment of osteoporosis. Tablets have certain disadvantage for patients who are unable to swallow tablets readily. To overcome the problem of difficulty in swallowing and to improve the patient compliance, the inventors of US 5,462,932 had developed solution formulation comprising alendronate, in a pharmaceutically acceptable carrier and a sufficient amount of a buffer to maintain a pH of the composition in the range of 2 to 8 and complexing agent to prevent the precipitation of alendronate sodium in aqueous solution. It is further disclosed that citrate buffer acts both as buffer/complexing agent.

Apart from the above, the following patents/patent publications disclose aqueous oral formulations of alendronate.

U.S. 4,814,326 discloses aqueous solution of diphosphonic acid with amino carboxylic acid as stabilizer with pH 4.5-5.65.

U.S. 5,994,329 discloses liquid composition comprising alendronate monosodium trihydrate, sodium propylparaben, sodium butylparaben, sodium citrate dihydrate, citric acid anhydrous, sodium saccharin, sodium hydroxide and water.

In our US patent i.e. US 7,605,148, we disclosed stable aqueous oral formulation comprising alendronate sodium and inorganic acid, wherein the said formulation has pH in the range of about 2 to 5 and is essentially free of buffers and stabilizers.
US 2003/0139378 discloses an oral liquid composition comprising: a) a therapeutically effective amount of at least one bisphosphonate or a pharmaceutically acceptable salt thereof, b) a pharmaceutically acceptable carrier, and c) a pharmaceutically acceptable buffer, wherein a dose of said oral liquid pharmaceutical composition has a buffering capacity sufficient to buffer at least 50 mL of 0.1 N HC1 to a pH of greater than or equal to 3.5.

US 2004/0087550 discloses a composition for prevention of metabolic diseases of bones comprising: at least one bisphosphonate including alendronate sodium, viscosity agents comprising carboxymethylcellulose and xanthan gum; at least one flavoring agent and purified water.

US 2009/0170815 discloses an oral solution comprising alendronate and a liquid carrier, wherein said solution has no buffer and complexing agent.

US 2009/0197837 discloses an oral solution comprising alendronate, deionized water, a sweetener, and a preservative having a pH of 5.5 to 7.5, wherein said solution is free of buffer and complexing agent.

WO 98/14196 discloses an aqueous liquid formulation comprising: alendronic acid; a sufficient amount of a buffer such that the pH of the formulation is between approximately 3.5 and approximately 7.5 and 15 ml of the formulation is able to raise the pH of 50 ml 0.1N HC1 to a pH of at least 3

and optionally, one or more additional agents selected from the group consisting of preservatives, flavoring agents, colorants, and sweeteners.

WO 08/028547 discloses liquid composition for prevention of bone metabolic diseases, comprising alendronic acid or its acceptable pharmaceutical salts, or mixtures thereof, a viscosity agent selected from the group consisting of alginate, propylglycolalginate, arabic gum (acacia), xanthan gum, guar gum, locust bean, carrageenan gum, karaya gum, tragacanth gum, chitosan, sodium carboxymethyl cellulose and carbomer or mixtures thereof, at least one flavoring agent and purified water.

The above prior art references discloses various liquid formulations of alendronate sodium using amino carboxylic acid, citrate buffer, viscosity agents and complexing agent to stabilize alendronate in liquid formulations. However, still there is a need to develop stable solution formulation comprising alendronate wherein said formulation is free of stabilizers. None of the prior art documents disclose the use of sodium acetate and sodium bicarbonate to stabilize the alendronate liquid formulations without the need of adding additional stabilizers or complexing agents.

Objective of the invention

Accordingly, the main objective of the present invention is to provide stable oral solution formulation comprising alendronate sodium.

Yet another objective of the present invention is to provide stable oral solution formulation comprising alendronate sodium in such a way that it will comply with the reference product.

Yet another objective of the present invention is to provide simple process for the preparation of stable oral solution formulation of alendronate sodium.

Summary of the invention

Accordingly, the main embodiment of the present invention is to provide a stable oral solution formulation comprising alendronate sodium, liquid carrier and a salt of weak acid selected from sodium acetate and sodium bicarbonate,

wherein the said formulation has pH in the range of about 5.5 to 8.5, wherein said formulation is essentially free of stabilizers/complexing agents.

Detailed description of the invention

Yet in another embodiment of the present invention, the oral solution further comprises one or more excipients selected from preservatives, sweetening agents and flavoring agents.

To prevent the unwanted growth of bacteria, fungi or yeast preservatives are included in the formulation. Suitable preservatives used according to the present invention are selected from sodium benzoate, potassium sorbate, benzyl alcohol, parabens (p-hydroxybenzoic acids esters) such as methylparaben, ethylparaben, propylparaben, butylparaben and the like or mixtures thereof. The amount of preservative used may be in the range of about 0.02 to about 2% by weight of the composition.

To make the solution palatable and more pleasing to the patient and to mask the taste sweetening agent are added to the formulation. Suitable sweetening agents include saccharin sodium, sodium cyclamate, sorbitol, xylitol, sucrose, glycerol, aspartame and the like. The amount of sweetening agent used may be in the range of about 0.1 to about 2% by weight of the composition.

Suitable flavoring agents include peppermint flavor, spearmint flavor, lime flavor, apple flavor, pear flavor, peach flavor, raspberry flavor, plum flavor, pineapple flavor and the like. The amount of flavorant used may be in the range of about 0.05 to about 5% by weight of the composition.

Suitable liquid carriers include purified water, distilled water, saline solution and the like.

In another embodiment, alendronate sodium used in the present invention is in the form of monosodium trihydrate salt or monosodium monohydrate salt.

In another embodiment, the amount of alendronate sodium used according to the present invention is in the range of about 1% to about 30% by weight of the composition.

In another embodiment, the solution may optionally include a pH adjusting agent to render the final solution to a pH of about 5.5 to 8.5. Suitable pH adjusting agents include sodium hydroxide, potassium hydroxide, hydrochloric acid, sodium carbonate and the like.

In a preferred embodiment, the stable oral solution formulation comprises/contains about 1% to about 30% by weight of alendronate sodium, purified water, about 1% to 2% of salt of weak acid selected from sodium acetate or sodium bicarbonate, about 0.02% to about 2% by weight of preservatives such as methylparaben, ethylparaben, propylparaben and butylparaben; about 0.1% to about 2% by weight of sweetening agents such as saccharin sodium, sodium cyclamate, sorbitol, xylitol; about 0.05% to about 5% by weight of flavoring agents such as peppermint flavor, spearmint flavor and artificial raspberry flavor, wherein the said formulation has pH in the range of about 5.5 to 8.5, wherein said formulation is essentially free of stabilizers/complexing agents.

The solution prepared according to present invention is stable when stored at accelerated conditions i.e. 40°C and 75% relative humidity for three months with the presence of negligible degradation products as shown below in table 1.

In another embodiment of the present invention, there is provided a process for the preparation of stable oral solution formulation comprising alendronate sodium, liquid carrier and a salt of weak acid selected from sodium acetate and sodium bicarbonate, wherein the said formulation has pH in the range of about 5.5 to 8.5, wherein said formulation is essentially free of stabilizers/complexing agents, comprises the steps of: i) dissolving the preservatives and buffering agents in water, ii) adding sweetening agent to the solution of step (i), iii) adding alendronate sodium to the solution of step (ii) and stirring it to get clear solution, iv) adding flavoring agent to the solution of step (iii) and v) adjusting the pH of the solution using hydrochloric acid or sodium hydroxide And vi) finally making up the volume with water to obtain a clear solution.

The stable oral solution of alendronate sodium of the present invention is packed in 75 ml clear transparent 75CC polyethylene container of 33mm.

The stable oral solution of alendronate sodium of the present invention is useful in the therapeutic or prophylactic treatment of disorders in calcium and phosphate metabolism and associated diseases such as osteoporosis which includes post-menopausal osteoporosis, steroid-induced osteoporosis, male osteoporosis, disease-induced osteoporosis, idiopathic osteoporosis, Paget's disorder, abnormally increased bone turnover, periodontal disease, localized bone loss associated with periprosthetic osteolysis and bone fractures.

The following examples further exemplify the invention and are not intended to limit the scope of the invention. It is obvious to those skilled in the art to find out the composition for other dosage forms and substitute the equivalent excipients as described in this specification or with the one known to the industry. Example 1

The processing steps involved in manufacturing a stable aqueous solution given in example 1 are given below: 1.

(i) propylparaben sodium, butylparaben sodium and sodium acetate were dissolved in water under continuous stirring,

(ii) saccharin sodium was added to the solution of step (i) and stirred to obtain
clear solution,

(iii) alendronate sodium was added to the solution of step (ii) and again stirred
to obtain clear solution,

(iv) artificial raspberry flavor was added to the solution obtained in step (iii) and

(v) finally the volume was adjusted with water to make up to 75ml.

The formulations given in example 2 and 3 were prepared using similar procedure described in example 1.

Example 2

Example 3

Stability Data: Alendronate oral solution prepared according to example 1 was stored at 40°C / 75% RH for three months and then tested by HPLC to determine the assay, pH and total amount of impurities. The stability data of is given in table 1.

Table 1

We Claim:

1. A stable oral solution formulation comprising alendronate sodium, liquid carrier and a salt of weak acid selected from sodium acetate and sodium bicarbonate, wherein the said formulation has pH in the range of about 5.5 to 8.5, wherein said formulation is essentially free of stabilizers/complexing agents.

2. The solution of claim 1, further comprise one or more excipients selected from preservatives, sweetening agents and flavoring agents.

3. The solution of claim 2, wherein the preservative is selected from sodium benzoate, potassium sorbate, benzyl alcohol, methylparaben, ethylparaben, propylparaben, butylparaben or mixtures thereof.

4. The solution of claim 2, wherein the sweetening agent is selected from saccharin sodium, sodium cyclamate, sorbitol, xylitol, sucrose, glycerol, aspartame or mixtures thereof.

5. The solution of claim 1, wherein the liquid carrier is selected from purified water, distilled water, saline solution.

6. The stable oral solution formulation comprises/contains about 1% to about 30% by weight of alendronate sodium, purified water, about 1% to 2% of salt of weak acid selected from sodium acetate or sodium bicarbonate, about 0.02% to about 2% by weight of preservatives such as methylparaben, ethylparaben, propylparaben and butylparaben; about 0.1% to about 2% by weight of sweetening agents such as saccharin sodium, sodium cyclamate, sorbitol, xylitol; about 0.05% to about 5% by weight of flavoring agents such as peppermint flavor, spearmint flavor and artificial raspberry flavor, wherein the said formulation has pH in the range of about 5.5 to 8.5, wherein said formulation is essentially free of stabilizers/complexing agents.

7. A process for the preparation of stable oral solution formulation comprising alendronate sodium, liquid carrier and a salt of weak acid selected from sodium acetate and sodium bicarbonate, wherein the said formulation has pH in the range of about 5.5 to 8.5, wherein said formulation is essentially free of stabilizers/complexing agents, comprises the steps of:

i) dissolving the preservatives and buffering agents in water,

ii) adding sweetening agent to the solution of step (i),

iii) adding alendronate sodium to the solution of step (ii) and stirring it to get
clear solution,

iv) adding flavoring agent to the solution of step (iii) and

v) adjusting the pH of the solution using hydrochloric acid or sodium hydroxide
and

vi) finally making up the volume with water to obtain a clear solution.