SK42999A3 - Aqueous liquid pharmaceutical formulation, process for the preparation and use thereof - Google Patents

Abstract

A liquid formulation of alendronic acid, or pharmaceutically acceptable salt has enough buffer so that the pH of the formulation is 4-7.5, and 15 ml of the formulation is able to raise the pH of 50 ml of 0.1N HC1 from 1 to at least 3, and preferably 4.

Description

Aqueous liquid pharmaceutical composition, process for its preparation and use thereof

Technical field

The invention relates to aqueous liquid pharmaceutical compositions containing alendronic acid or a pharmaceutically acceptable salt thereof, and in particular those containing a buffer which can control the gastric pH.

The present invention relates to prior U.S. patent applications Serial Nos. 60/026765 and 60/036002, filed October 4, 1996 and January 22, 1997, the contents of which are incorporated herein by reference.

BACKGROUND OF THE INVENTION

Sodium alendronate, 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid trihydrate, has been approved by various regulatory agencies, including the FDA (Food and Drug Administration) in the United States, for the oral treatment of osteoporosis in postmenopausal women. The currently marketed formulation is in the form of a tablet and patients are instructed to take the tablet with a full glass of water in the morning, at least half an hour before eating or drinking.

Many people suffer from heartburn, often caused by reflux of gastric acid into the esophagus. This may cause a burning sensation. The population of patients in need of alendronate treatment overlaps with the population of those suffering from heartburn or similar symptoms.

Therefore, it would be desirable to provide a composition that allows oral administration of a bisphosphonate such as alendronate sodium and which has the additional benefit of alleviating heartburn symptoms.

SUMMARY OF THE INVENTION

The present invention provides an aqueous liquid pharmaceutical composition comprising: alendronic acid or a pharmaceutically acceptable salt thereof as an active ingredient, a sufficient amount of a buffer such that:

2A. the pH of the composition is between about 3.5 and about 7.5, and

B. 15 ml of the composition is capable of raising the pH of 50 ml of 0.1 N HCl (pH about 1) to a pH of at least 3.0, and optionally, one or more additional agents including those selected from the group consisting of preservatives, flavoring agents , dyes and sweeteners.

Another embodiment of the invention is a pharmaceutical composition formed by mixing said active ingredients, a buffer and an optional agent or agents.

The type of buffer that can be used in this composition is not a key issue as long as its buffer capacity is such that a relatively small volume of buffer can sufficiently raise the pH of the acidic solution. Exemplary buffer systems include those selected from the group consisting of citrate, tartrate, fumarate, phosphate, acetate, and mixtures thereof. Typically, 0.2 to 3.0 g of salt or free acid and base will be used to form a buffer salt combination (per 15 mL dose). Generally, a 15 ml dose of the composition of the invention will contain 0.2 to 3 g of at least one of sodium phosphate, sodium citrate dihydrate, sodium tartrate dihydrate, or sodium formate. A suitable buffer system is, for example, a citrate buffer comprising anhydrous citric acid and sodium citrate dihydrate present in a molar ratio of about 1: 1 to 350, more preferably 1:50 to 150, and most preferably about 1:81.

In addition to the aforementioned buffers, various basic compounds such as sodium hydroxide, potassium hydroxide, ammonium hydroxide and the like can be used to further adjust the buffer system.

Another embodiment of the invention is to provide a buffered environment for the active ingredient alendronic acid so that it is not exposed to a pH of less than about 3.0, more preferably 3.5, and most preferably about 4.0 under in vivo conditions. Thus, the present invention encompasses a method of inhibiting bone resorption comprising administering to a patient a pharmaceutical composition comprising alendronic acid and a buffer such that alendronic acid is not exposed to the gastrointestinal environment having a pH of less than about 3.0. The bioavailability of the active ingredient is believed to be increased at a pH greater than about 3.0.

Another embodiment of the present invention is an aqueous liquid pharmaceutical composition comprising before mixing:

alendronic acid or a pharmaceutically acceptable salt thereof as an active ingredient, a sufficient amount of a buffer such that A. the pH of the composition is between about 3.5 and about 7.5; and B. 15 ml of the composition is capable of raising the pH of 50 ml of 0.1 N HCl to a pH of at least 3; and optionally one or more accessory agents selected from the group consisting of preservatives, flavoring agents, coloring agents and sweeteners.

Another embodiment of the present invention is an aqueous liquid pharmaceutical composition prepared by combining:

alendronic acid or a pharmaceutically acceptable salt thereof as an active ingredient; sufficient buffer so that the pH of the composition is between about 3.5 and about 7.5; and B. 15 ml of the composition is capable of raising the pH of 50 ml of 0.1 N HCl to a pH of at least 3; and optionally one or more accessory agents selected from the group consisting of preservatives, flavoring agents, coloring agents and sweeteners.

Another embodiment relates to a process for the manufacture of an aqueous liquid pharmaceutical composition comprising the step of combining alendronic acid or a pharmaceutically acceptable salt as an active ingredient;

sufficient buffer so that the pH of the composition is between about 3.5 and about 7.5; and B. 15 ml of the composition is capable of raising the pH of 50 ml of 0.1 N HCl to a pH of at least 3; and optionally one or more accessory agents selected from the group consisting of preservatives, flavoring agents, coloring agents and sweeteners.

As used herein and in the claims, the term "alendronic acid" includes the corresponding forms of bisphosphonic acid, pharmaceutically acceptable salt forms, and equilibrium mixtures of these compounds. Included are crystalline, hydrated crystalline and amorphous forms of alendronic acid, and pharmaceutically acceptable salts thereof. Included in particular are alendronate sodium and its hydrate, also known as alendronate sodium trihydrate.

"Pharmaceutically acceptable salt forms are those commonly used in pharmaceutical formulations, such as alkali metal (Na *,

-4CA ² * and Mg ² *), organic bases (such as N-methylglycamine) and amino acids (such as lysine).

Methods for producing alendronic acid and alendronic salt trihydrate are known. In particular, processes for producing alendronic acid and theirs are possible

Also pharmaceutically acceptable salts can be found in U.S. Patents 4,922,007, 5,019,651 and 5,510,517, each of which is incorporated herein by reference.

The concentration of alendronic acid or sodium alendronate or other alendronate salts in the composition will be in the range of about 0.05 mg / ml to 2 mg / ml based on alendronic acid; and preferably from about 0.1 to 0.9 mg / ml based on alendronic acid. Particularly preferred concentrations are 0.13, 0.33 and 0.67 mg / ml based on alendronic acid, since one tablespoon (approximately 15 ml) of such a solution would correspond to a dose of approximately 2.5 and 10 g based on alendronic acid. . Such an amount could be mixed in water (about 60 to 200 ml) and swallowed. Alternatively, if greater than 20 mg daily doses of alendronic acid are desired, the patient may mix two tablespoons (approximately 30 ml) of the solution in water to provide a dose of 10 ml, based on alendronic acid, per tablespoon. that the diluted solution will be administered once a day, but if desired, additional dosages may be provided, or alternatively, dosages may be provided less frequently than once a day.

In an alternative dosing method, the composition which may contain water is not diluted by the patient prior to use. In this case, the patient swallows only a small amount of fluid (approximately 15 ml).

The composition of the invention has many distinct advantages. The preferred form of the composition is supplied as a concentrate with respect to the benefits for the manufacturer and the pharmacist. For example, a monthly supply (containing, for example, 31 doses of one tablespoon each) is only about 473 ml of liquid. This allows easy handling and storage. The composition may be readily diluted by the patient prior to use.

In addition, the liquid formulation is advantageous in that alendronate sodium is often prescribed to the elderly, who may have difficulty swallowing tablets or capsules, but may more easily swallow the liquid formulation, the liquid formulation.

The dosing means also allows for the inclusion of a flavoring agent that can improve patient compliance. Further, the bioavailability of the active ingredient appears to be increased in this formulation compared to prior art tablet forms.

The buffering agent also negates the need for the patient to also take liquid additional anticidal agents to suppress acid reflux, heartburn, and other stomach complaints.

Incorporating a relatively large amount of buffer is a key feature of the present invention. The amount of buffer should be sufficient that A) the pH of the composition lies between about 3.5 and about 7.5, preferably between about 4 and about 7, and most preferably between about 4 and about 5.5; and B) 15 ml of the composition was able to raise the pH of 50 ml of 0.1 N HCl (pH about 1) to a pH of at least 3.5 and preferably about 4. The pH of the composition itself is important because at pH 3.5 to 5, 5 there is a minimal possibility of gastric irritation for vomiting.

The ability of the composition to buffer about 50 ml of strong acid is important because the composition has the ability to buffer stomach acid. Reflux of gastric acid to the esophagus can cause irritation and even disturbance of the esophagus. Typically, a human has about 50 ml of gastric juice at a pH of about 1 in the stomach. Using the aledronate composition of the invention, the gastric acid is buffered to at least pH 3.5, preferably about 4. In animal models in accordance with the invention alendronate sodium and gastric acid at pH 3.5 is not irritating to esophageal tissues. If the patient experiences reflux, it will not result in esophageal irritation.

The preservatives which may be used to provide multiple dosing may be any of the known pharmaceutically acceptable preservatives, active in a liquid having a pH between 3.5 and 7.5 and not adversely affecting each other with the active ingredient. They can be used in their usual concentrations. Preferred preservatives include sodium benzoate, potassium sorbate, benzyl alcohol, butylparaben, ethylparaben, methylparaben, propylparaben and the like, as well as a mixture of such substances. In a typical embodiment, sodium benzoate is used at concentrations of 1.0-2.0 mg / ml.

It may also be desirable to incorporate flavor enhancers such as sweeteners and colorants, although their inclusion in the composition is strictly optional. Suitable sweeteners include various sugars, sorbitol, xylitol, sucrose or the like. The preferred concentration of sorbitol or xylitol is between about 100 to 700 mg / ml and preferably between about 200 and 500 mg / ml. Another suitable sweetener is sodium saccharin, which may be used at a concentration of about 0.1 to 1.0 mg / ml, preferably about 0.5 to 0.7 mg / ml. Combinations of one or more sweeteners may also be used.

The additional optional agent is a flavoring agent. Flavors that have been verified as suitable (considering the clarity of the product) include "Orange" # 782 (Virginia Dare), "tutti-Frutti" (Fermenich / 51.880-CE), "Artificial Berry" # 491 (Fermenich) and " Arteficial Strawberry (Fermenich / 57.883-C). Other flavors include, but are not limited to, natural and artificial orange, strawberry, all citrus flavors, tomato, apple and tuti-fruti. Typical concentrations are from 10 to 50 mg / ml, but at least about 10 mg / ml.

The following non-limiting examples are provided to better illustrate the invention.

DETAILED DESCRIPTION OF THE INVENTION

Example 1 sodium alendrontate trihydrate 0.87 * mg sodium benzoate 1.3 mg orange flavor (Virginia Dare # 792) 10 mg sodium citrate dihydrate 100 mg anhydrous citric acid 0.45 mg xylitol 250 mg purified water as needed 1 ml

The total citrate (mol.l ^-1 ) is 0.50 mol.l ^-1 . The pH of the composition is 4.8. When 15 ml of the composition is added to 50 ml of 0.1 N HCl, the pH is 4.04.

* Corresponds to 0.67 mg / ml alendronic acid.

Example 2 sodium alendonate trihydrate 0.87 * mg sodium benzoate 1.3 mg potassium sorbate 1 mg xylitol 400 mg sodium citrate dihydrate 100 mg anhydrous citric acid 0.45 mg flavor 10 mg purified water if necessary, 1 ml * Corresponds to 0.67 mg / ml alendronic acid. Example 3 sodium alendonate trihydrate 0.87 * mg potassium sorbate 1.3 mg xylitol 400 mg sodium citrate dihydrate 100 mg anhydrous citric acid 0.45 mg purified water if necessary, 1 ml * Corresponds to 0.67 mg / ml alendronic acid. Example 4 sodium alendonate trihydrate 0.87 * mg sodium citrate dihydrate 100 mg anhydrous citric acid 0.45 mg xylitol 400 mg purified water if necessary, 1 ml * Corresponds to 0.67 mg / ml alendronic acid.

-8Example 5 sodium alendonate trihydrate tartaric acid, non-flammable sodium hydroxide in granules, non-flammable xylitol sodium benzoate, non-flammable flavor N&A # 782 Orange purified water

0.87 * mg 75 mg 38.5 mg 400 mg 1.3 mg 10 mg as needed 1 ml * Corresponds to 0.67 mg / ml alendronic acid.

Example 6 sodium alendonate trihydrate tartaric acid, non-flammable sodium hydroxide in pellets, non-flammable sodium xylitol benzoate, non-flammable flavor N&A # 782 Orange purified water

0.87 * mg 70 mg 36 mg 400 mg 1.3 mg 10 mg as needed 1 ml * Corresponds to 0.67 mg / ml alendronic acid.

Example 7 sodium alendonate trihydrate 0.87 * mg tartaric acid, non-flammable 75 mg sodium hydroxide in pellets, non-flammable 38.5 mg xylitol 50 mg sodium saccharin 0.7 mg sodium methyl paraben 1.3 mg

-9 flavor N&A # 782 Orange 10 mg purified water as needed 1 ml * Corresponds to 0.67 mg / ml alendronic acid.

Example 8 sodium alendronate citric acid sodium citrate xylitol saccharin sodium flavor N&A # 782 Orange purified water

0.87 * mg 70.59 mg 0.57 mg 50 mg 0.5 mg 10 mg as needed 1 ml * Corresponds to 0.67 mg / ml alendronic acid.

Example 9 Sodium alendonate trihydrate tartaric acid, non-flammable sodium hydroxide in granules, non-flammable sodium saccharin methyl paraben sodium flavor N&A # 782 Orange purified water

0.87 * mg 75 mg 38.5 mg 0.7 mg 1.3 mg 10 mg as needed 1 ml * Corresponds to 0.67 mg / ml alendronic acid.

Claims (17)

PATENT CLAIMS An aqueous liquid pharmaceutical composition comprising: alendronic acid or a pharmaceutically acceptable salt thereof as an active ingredient, a sufficient amount of a buffer such that: A. the pH of the composition is between about 3.5 and about 7.5, and B. 15 ml of the composition is capable of raising the pH of 50 ml of 0.1 N HCl (pH about 1) to a pH of at least 3.0, and optionally, one or more additional agents selected from the group consisting of preservatives, flavoring agents, coloring agents and sweeteners. Aqueous liquid pharmaceutical composition according to claim 1, characterized in that the buffer is a citric acid / sodium citrate or tartaric / sodium tartrate buffer system. I ’ Aqueous liquid pharmaceutical composition according to claim 2, characterized in that the concentration of sodium alendronate trihydrate is 0.1 to 0.9 mg / ml based on alendronic acid. The aqueous liquid pharmaceutical composition of claim 3, wherein the concentration of sodium alendronate trihydrate is 0.133 or 0.67 mg / ml based on alendronic acid. The aqueous liquid pharmaceutical composition according to claim 2, wherein the concentration of citric acid and sodium citrate present in the composition is 0.06 to 0.65 mol.l ^-1 , the pH of the composition is 3.5 to 7. 5 and a pH of 50 ml of 0.1 N HCl exceeds 3 after addition of 15 ml of the composition. 6. An aqueous liquid pharmaceutical composition comprising (in mg / ml): -11 sodium alendronate trihydrate 0.2 to 0.9 (based on alendronic acid) sodium benzoate 1.0 to 2.0 sodium citrate dihydrate 75 to 125 anhydrous citric acid 0.3 to 40 xylitol 100 to 640 wherein the concentration of citric acid; and the sodium citrate present in the composition is 0.06 to 0.65 mol.l ^-1 , the pH of the composition is 3.5 to 7.5, and the pH of 50 ml of 0.1 N HCl exceeds 3 after the addition of 15 ml of the composition. Aqueous liquid pharmaceutical composition according to claim 6, characterized by characterized in that it contains (in mg / ml): alendronate sodium trihydrate 0.1 to 0.9 (based on alendronic acid) sodium benzoate 1.0 to 2.0 xylitol 400 artificial flavor 5 to 50 sodium citrate dihydrate 75 to 125 anhydrous citric acid 0.3 to 40 The aqueous liquid pharmaceutical composition of claim 6, wherein the alendronate sodium trihydrate is present in an amount of 0.33 to 0.67 mg / ml relative to alendronic acid. The aqueous liquid pharmaceutical composition according to claim 6, characterized by containing (in mg / ml): alendronate sodium trihydrate 0.2 to 0.9 (based on alendronic acid) tartaric acid, non - flammable 70 to 140 Sodium hydroxide in pellets, non - flammable 36 to 72 xylitol 100 to 640 sodium benzoate, non - flammable 0až3 -12 flavor N&A # 782 Orange 0 to 100. The aqueous liquid pharmaceutical composition of claim 9, wherein the alendronate sodium trihydrate is present at a concentration of 0.13 to 0.67 mg / ml based on alendronic acid. 11. The aqueous liquid pharmaceutical composition of claim 2 wherein the sum of the total amount of citric acid and sodium citrate present in the composition is at least about 50 mg / ml. 12. The aqueous liquid pharmaceutical composition of claim 8, wherein the sum of the total amount of citric acid and sodium citrate present in the composition is at least about 75 mg / ml. 13. A formulation according to claim 8, characterized uj account whether the characterized _(in that the sum total amount of citric acid and sodium citrate present in the composition is at least about 100 mg / ml. 14. An aqueous liquid pharmaceutical composition comprising before mixing: alendronic acid or a pharmaceutically acceptable salt thereof as an active ingredient, a sufficient amount of a buffer such that: A. the pH of the composition is between about 3.5 and about 7.5, and B. 15 ml of the composition is capable of raising the pH of 50 ml of 0.1 N HCl to a pH of at least 3.0, and optionally, one or more additional agents selected from the group consisting of preservatives, flavoring agents, coloring agents and sweeteners. 15. An aqueous liquid pharmaceutical composition prepared by mixing: alendronic acid or a pharmaceutically acceptable salt thereof as an active ingredient, a sufficient amount of a buffer such that: A. the pH of the composition lies between about 3.5 and about 7.5, and B. 15 ml of the formulation is capable of raising the pH of 50 ml of 0.1 N HCl to a pH of at least 3.0, -13a optionally, one or more accessory agents selected from the group consisting of preservatives, flavoring agents, coloring agents and sweeteners. 16. A process for the manufacture of an aqueous liquid pharmaceutical composition comprising the step of mixing alendronic acid or a pharmaceutically acceptable salt thereof as an active ingredient with a sufficient amount of a buffer such that: A. the pH of the composition is between about 3.5 and about 7.5, and B. 15 ml of the composition is capable of raising the pH of 50 ml of 0.1 N HCl to a pH of at least 3.0, and optionally, one or more additional agents selected from the group consisting of preservatives, flavoring agents, coloring agents and sweeteners. An aqueous liquid pharmaceutical composition comprising alendronic acid or a pharmaceutically acceptable salt thereof and a buffer for use in inhibiting bone resorption such that alendronic acid is not exposed to the gastrointestinal environment having a pH below 3.5,