EA001213B1 - Liquid alendronate formulations - Google Patents

Abstract

1. An aqueous liquid pharmaceutical formulation comprising: alendronic acid or a pharmaceutically acceptable salts as na active ingredient; a sufficient amount of a buffer such that: A) the pH of the formulation is between approximately 3.5 and approximately 7.5; and B) 15 ml of the formulation is able to raise the pH of 50 ml 0.1N HCl 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. 2. A formulation according to claim 1, wherein the buffer is a critic acid/sodium citrate or a tartaric acid/sodium tartrate buffer system. 3. A formulation according to claim 2 wherein the concentration of alendronate monosodium trihydrate is 0.1-0.9 mg/ml on an alendronic acid basis. 4. A formulation according to claim 3 wherein the concentration of alendronate monosodium trihydrate is 0.133 or 0.67 mg/ml on an alendronic acid basis. 5. A formulation according to claim 2, wherein the concentration of citric acid and sodium citrate present is 0.06-0.65 M, the pH of the formulation is 3.5-7.5, and the pH of 50 ml of 0.1N HCl when 15 ml of the formulation is added is above pH 3. 6. An aqueous liquid pharmaceutical formulation comprising (in mg/ml): alendronate monosodium trihydrate (on an alendronic acid basis) 0.2-0.9 sodium benzoate 1.0-2.0 sodium citrate dehydrate 75-125 citric acid anhydrous 0.3-40 xylitol 100-640 wherein the citric acid and sodium citrate present in the invention is 0.06-0.65M, the pH of the formulation is 3.5-7.5 and the pH of 50 ml of 0.1N HCl when 15 ml of the formulation is added is above pH 3. 7. A liquid pharmaceutical formulation according to claim 6 comprising (in mg/ml): alendronate monosodium trihydrate (on an alendronic acid basis) 0.1-0.9 sodium benzoate 1.0-2.0 potassium sorbate 1.0-2.0 xylitol 400 artificial flavoring 5-50 sodium citrate dehydrate 75-125 citric acid, anhydrous 0.3-40 8. A pharmaceutical formulation according to claim 6 wherein the alendronate monosodium trihydrate is present at 0.33 to 0.67 mg/ml on an alendronic acid basis. 9. An aqueous liquid pharmaceutical formulation comprising (in mg/ml): alendronate monosodium trihydrate (on an alendronic acid basis) 0.1-0.9 tartaric acid, NF 70-140 sodium hydroxide pellets, NF 36-72 xylitol 100-640 sodium benzoate NF 0-3 flavor N & A #782 Orange 0-100 10. A pharmaceutical formulation according to claim 9 wherein the alendronate monosodium trihydrate is present at a concentration of 0.13 to 0.67 mg/ml on an alendronic acid basis. 11. A pharmaceutical formulation according to claim 2 wherein the sum total amount of citric acid and sodium citrate present in the formulation is at least about 50 mg/ml. 12. A pharmaceutical formulation according to claim 8 wherein the sum total amount of citric acid and sodium citrate present in the formulation is at least about 75 mg/ml. 13. A pharmaceutical formulation according to claim 8 wherein the sum total amount of citric acid and sodium citrate present in the formulation is at least about 100 mg/ml. 14. A method of inhibiting bone resorption comprising administering an aqueous liquid formulation of alendronic acid or pharmaceutically acceptable salt and a buffer so that the alendronic acid is not exposed to a gastro-intestinal environment which has a pH below about 3.5. 15. An aqueous liquid pharmaceutical formulation prior to mixing comprising: alendronic acid or a pharmaceutically acceptable salt as an active ingredient; a sufficient amount of a buffer such that: A) the pH of the formulation is between approximately 3.5 and approximately 7.5; and B) 15 ml of the formulation is able to raise the pH of 50 ml 0.1N HCl 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. 16. An aqueous liquid pharmaceutical formulation prepared by combining: alendronic acid or a pharmaceutically acceptable salt as an active ingredient; a sufficient amount of a buffer such that: A) the pH of the formulation is between approximately 3.5 and approximately 7.5; and B) 15 ml of the formulation is able to raise the pH of 50 ml 0.1N HCl 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. 17. A method of preparing an aqueous liquid pharmaceutical composition comprising the step of combining alendronic acid or a pharmaceutically acceptable salt as an active ingredient; a sufficient amount of a buffer such that: A) the pH of the formulation is between approximately 3.5 and approximately 7.5; and B) 15 ml of the formulation is able to raise the pH of 50 m1 0.1N HCl 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.

Description

The present invention relates to liquid pharmaceutical formulations of alendronic acid or its pharmaceutically acceptable salt and, in particular, to formulations containing a buffer that can control gastric pH.

BACKGROUND OF THE INVENTION

Sodium alendronate (4-amino-1-hydroxy-butylidene 1,1-bisphosphonic acid monosodium trihydrate) has been approved by various regulatory agencies, including the US Department of Food and Drug Administration, as a treatment for osteoporosis in postmenopausal women. The currently sold formulation is a tablet, and the patient is instructed to take the tablet in the morning with a full glass of water, at least half an hour before eating or drinking.

Many people suffer from heartburn, often due to the reverse flow of stomach acid into the esophagus. It may cause a burning sensation. There is a relationship between the number of patients who need alendronate therapy and who experience heartburn or similar symptoms.

Therefore, it would be desirable to develop a formulation that would allow oral administration of a bisphosphonate, such as sodium alendronate, and that would have the added benefit of alleviating the symptoms of heartburn.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a liquid pharmaceutical composition comprising: alendronic acid or a pharmaceutically acceptable salt as an active ingredient; a sufficient amount of buffer so that:

A) the pH of the composition is between about 3.5 and about 7.5; and

B) 15 ml of the composition can increase the pH of 50 ml of 0.1 n HCl (pH approximately 1) to a pH of at least 3; and optionally, one or more additional substances selected from the group consisting of preservatives, flavors, colorants and sweeteners. Another aspect of the present invention is a pharmaceutical composition prepared by mixing the aforementioned active ingredients, a buffer and an optional substance (or substances).

The type of buffer that can be used in this formulation is not critical since its buffering capacity is such that a relatively small volume can sufficiently increase the pH of the acid solution. Examples of buffer systems include systems selected from the group consisting of citrate, tartrate, fumarate, phosphate, acetate, and mixtures thereof. Typically, 0.2 to 3 g of salt or free acid and base will be used to prepare the buffer salt composition (per 15 ml dosage). In general, 15 ml of a dosage of the formulation of the present invention will contain from 0.2 to 3 g of at least one of the following salts: disodium phosphate, disodium citrate dihydrated, disodium tartrate dihydrated, or disodium formate. For example, a useful buffering system is a citrate buffer comprising anhydrous citric acid and trisodium dihydrated citrate, which are present in a molar proportion of about 1: 1-350, preferably 1: 50-150, and more preferably about 1:81.

In addition to the buffers mentioned, various bases, for example sodium hydroxide, potassium hydroxide, ammonium hydroxide and the like, can be used to further control the buffer system.

Another aspect of the present invention is the provision of a buffer medium for the active ingredient of alendronic acid so that while it is ίη νίνο, it would not be exposed to a pH of less than about 3.0, preferably about 3.5, and more preferably about 4.0. Thus, the present invention also includes a method for inhibiting bone resorption, which comprises administering to a patient a pharmaceutical formulation comprising alendronic acid and a buffer such that alendronic acid is not exposed to a gastrointestinal environment that has a pH below about 3.0. It is believed that the bioavailability of the active ingredient increases at a pH that is greater than about 3.0.

Another aspect of the present invention is an aqueous liquid pharmaceutical composition, which before mixing includes: alendronic acid or a pharmaceutically acceptable salt as an active ingredient; a sufficient amount of buffer so that:

A) the pH of the formulation is between about 3.5 and about 7.5; and

B) 15 ml of the formulation may increase the pH of 50 ml of 0.1 n HCl to a pH of at least 3; and optionally, one or more additional reagents selected from the group consisting of preservatives, flavors, colorants and sweeteners.

Another aspect of the present invention is an aqueous liquid pharmaceutical composition prepared by combining alendronic acid or a pharmaceutically acceptable salt as an active ingredient and a sufficient amount of a buffer such that

A) the pH of the formulation is between about 3.5 and about 7.5; and

B) 15 ml of the formulation may increase the pH of 50 ml of 0.1 n HCl to a pH of at least 3; and optionally, one or more additional reagents selected from the group consisting of preservatives, flavors, colorants and sweeteners.

Another aspect of the present invention relates to methods for preparing an aqueous liquid pharmaceutical composition, comprising the step of combining alendronic acid or a pharmaceutically acceptable salt as an active ingredient; enough buffer so that

A) the pH of the formulation is between about 3.5 and about 7.5; and

B) 15 ml of the formulation may increase the pH of 50 ml of 0.1 n HCl to a pH of at least 3; and optionally, one or more additional substances selected from the group consisting of preservatives, flavors, colorants and sweeteners.

As used throughout the specification and claims, the term “alendronic acid” includes related forms of bisphosphonic acid, pharmaceutically acceptable salt forms, and equilibrium mixtures thereof. It includes crystalline, crystalline hydrate and amorphous forms of alendronic acid and its pharmaceutically acceptable salts. It specifically includes sodium alendronate and its hydrate, also known as trihydrated monosodium alendronate.

“Pharmaceutically acceptable salt forms” means those forms which are commonly used in pharmaceutical formulations, such as, for example, alkali metal salts (Na ⁺ , Ca ²⁺ , K ⁺ and Md ²⁴ ) of organic bases (such as метил-methylglucamine) and amino acids ( such as lysine).

Methods for the preparation of alendronic acid and sodium alendronate trihydrate are known in the art. In particular, methods for the preparation of alendronic acid and its pharmaceutically acceptable salts can be found in US 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 this formulation will be in the range of about 0.05 to 2 mg / ml for alendronic acid, and preferably about 0.1 to 0.9 mg / ml for alendronic acid.

Particularly useful concentrations are 0.13, 0.33 and 0.67 mg / ml for alendronic acid, while one tablespoon (approximately 15 ml) of such a solution would correspond to a dose of approximately 2, 5 and 10 mg, respectively, for alendronic acid . It is mixed with water (approximately 60-200 ml) and taken orally. Conversely, if larger daily doses, such as 20 mg alendronic acid, are considered desirable, the patient can mix two tablespoons (approximately 30 ml) of the solution that provide a 10 mg dose of alendronic acid per tablespoon in water. It appears that the diluted solution will be taken once a day, but additional dosages can be provided if desired; or, conversely, dosages less than once a day may be provided.

In an alternative dosing method, a formulation that may contain water is not diluted with water before the patient takes it inside. In this embodiment, the patient swallows only a small amount of liquid (approximately 15 ml).

The formulation of the present invention has many distinct advantages. A preferred formulation is supplied as a concentrate, which provides convenience to the manufacturer and pharmacist. For example, a monthly supply (containing, for example, 31 tablespoons of dosages) is equal to only about one pint of liquid (473 ml). This makes it easy to handle and store. It can be easily diluted by the patient before oral administration.

In addition, the liquid formulation has the advantage that sodium alendronate is often prescribed to elderly patients who may have difficulty swallowing tablets or capsules, but may more easily swallow the liquid formulation. A liquid dosage formulation also allows the inclusion of a taste enhancer that can facilitate patient administration. Further, the bioavailability of the active ingredient, as it turned out, is increased in the present formulation, compared with the previous available tablet forms.

In addition, the buffer reagent avoids the patient taking various additional antacids to combat acid backflow, heartburn, or other stomach problems.

The inclusion of a relatively large amount of buffer solution is a key feature of the present invention. The amount of buffer should be sufficient so that

A) the pH of the formulation is between about 3.5 and about 5, preferably between about 4 and about 7, and more preferably between about 4 and about 5.5; and

C) 15 ml of the formulation can increase the pH of 50 ml of 0.1 n HCl (pH of about 1) to a pH of at least 3.5 and preferably to 4. The pH of the formulation itself is important because at pH 3.5-5, 5 The potential for additional gastric irritation is minimal.

The ability of a formulation to serve as a buffer for approximately 50 ml of strong acid is important because it has the ability to serve as a buffer for stomach acid. The return flow of gastric acid into the esophagus can cause irritation and even erosion of the esophagus. Typically, the human body contains about 50 ml of gastric juice in the stomach with a pH of about 1. After taking the alendronate formulation of the present invention, the gastric juice under the action of a buffer has a pH of at least 3.5 and preferably up to about 4. It was found that in animal models in accordance with the present invention, that a mixture of sodium alendronate and stomach acid at a pH of at least 3.5 is not irritating to the tissues of the esophagus. Thus, if the patient experiences a reverse current, then irritation of the esophagus will not occur.

Preservatives that can be used to provide multiple dosages can be any known pharmacologically acceptable preservatives that are active in a liquid having a pH of 3.5-7.5 and which do not irreversibly react with the active ingredient. They should be used at their usual concentrations. Preferred preservatives include sodium benzoate, potassium sorbate, benzyl alcohol, butyl paraben, ethyl paraben, methyl paraben, propyl paraben, the like compounds and mixtures thereof. In a typical embodiment, sodium benzoate is used at a concentration of 1.0-2.0 mg / ml.

The inclusion of flavoring agents, such as sweeteners and coloring agents, may be desirable, although their inclusion in the formulation is not strictly required. Suitable sweeteners include various sugars, sorbitol, xylitol, sucrose or the like. A useful concentration of sorbitol or xylitol is between about 100-700 mg / ml and preferably about 200-500 mg / ml. Saccharin sodium is another useful sweetener and can be used at a concentration of about 0.1-1.0 mg / ml and preferably about 0.5-0.7 mg / ml. Combinations of one or more sweeteners may also be used.

An additional optional ingredient is a flavor. Flavors that have been found to be suitable (in terms of purity of formulation) include Orange # 782 (

Eags). TISH-RGISH (Regtesh / 51.880-SE), Artificial Berry # 491 (Regtesh) and Artificial Strawberry (Regtesh / 57.883-С). Other flavors include, but are not limited to, natural and artificial orange, strawberries, all citrus flavors, tomato, apple, and tutti-frutti. Typical concentrations are 10-50 mg / ml, in particular about 10 mg / ml.

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

EXAMPLE 1

Monone Alendronate Trihydrate - triya 0.87 * mg Sodium benzoate 1.3 mg Orange flavor (νίΓβίηία Jage # 792) 10 mg Dihydrated citrate triya 100 mg Citric Acid Anhydrous 0.45 mg Xylitol 250 mg Purified water Up to 1 ml Total citrate concentration (M) is equal to

0.50 M. The pH of the formulation is 4.8. When 15 ml of the formulation 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

Mono- Alendronate Trihydrate sodium 0.87 * mg Sodium benzoate 1.3 mg Potassium sorbate 1.3 mg Xylitol 400 mg Dihydrated citrate sodium 100 mg Citric Acid Anhydrous 0.45 mg Flavoring 10 mg Purified water Up to 1 ml * Corresponds to 0.67 mg / ml alendron acids. EXAMPLE 3 Mono- Alendronate Trihydrate sodium 0.87 * mg Potassium sorbate 1, 3 mg Xylitol 400 mg Dihydrated citrate sodium 100 mg Citric Acid Anhydrous 0.45 mg Purified water Up to 1 ml * Corresponds to 0.67 mg / ml alendron acids. EXAMPLE 4 Mono- Alendronate Trihydrate sodium 0.87 * mg Dihydrated citrate sodium 100 mg Citric Acid Anhydrous 0.45 mg Xylitol 400 mg Purified water Up to 1 ml

* Corresponds to 0.67 mg / ml alendronic acid.

EXAMPLE 5 Alendronate trihydrate mo- nonatria 0.87 * mg Tartaric acid, ΝΕ 75 mg Sodium hydroxide granules, ΝΡ 38.5 mg Xylitol 400 mg Sodium Benzoate ΝΡ 1.3 mg Fragrance Ν & Α # 782 orange 10 mg Purified water Up to 1 ml * Corresponds to 0.67 mg / ml alendron acids. EXAMPLE 6 Monone Alendronate Trihydrate - triya 0.87 * mg Tartaric acid, ΝΓ 70 mg Sodium hydroxide granules. ΝΓ 36 mg Xylitol 400 mg Sodium benzoate, ΝΕ 1.3 mg Flavor Ν & Α # 782 Apel- blue 10 mg Purified water Up to 1 ml * Corresponds to 0.67 mg / ml alendron acids. EXAMPLE 7 Alendronate Sodium 0.87 * mg Tartaric acid, ΝΓ 75 mg Sodium hydroxide granules, ΝΕ 38.5 mg Xylitol 50 mg Saccharin sodium 0.7 mg Methylparaben Sodium 1.3 mg Flavor Ν & Α # 782 Apel- blue 10 mg Purified water Up to 1 ml * Corresponds to 0.67 mg / ml alendron acids. EXAMPLE 8 Alendronate Sodium 0.87 * mg Lemon acid 70.59 mg Sodium citrate 0.57 mg Xylitol 50 mg Saccharin sodium 0.5 mg Flavor Ν & Α # 782 Apel- blue 10.0 mg Purified water Up to 1 ml * Corresponds to 0.67 mg / ml alendron acids. EXAMPLE 9 Αlendronate sodium 0.87 * mg Tartaric acid, ΝΕ 75 mg G sodium hydroxide granules, ΝΕ 38.5 mg Saccharin sodium 0.7 mg Methylparaben Sodium 1.3 mg Flavor Ν & Α # 782 Apel- blue 10.0 mg Purified water Up to 1 ml

* Corresponds to 0.67 mg / ml alendronic acid.

Claims (17)

1. An aqueous liquid pharmaceutical composition comprising: alendronic acid or a pharmaceutically acceptable salt as an active ingredient; enough buffer so that A) the pH of the composition is between about 3.5 and about 7.5; and B) 15 ml of the composition can increase the pH of 50 ml of 0.1 n HCl to a pH of at least 3; and optionally one or more additional reagents selected from the group consisting of preservatives, flavors, colorants and sweeteners. 2. The composition according to claim 1, where the buffer is a buffer system of citric acid / sodium citrate or tartaric acid / sodium tartrate. 3. The composition according to claim 2, where the concentration of monosodium alendronate trihydrate is 0.10.9 mg / ml alendronic acid. 4. The composition according to claim 3, where the concentration of monosodium alendronate trihydrate is 0.133 or 0.67 mg / ml for alendronic acid. 5. The composition according to claim 2, where the concentration of citric acid and sodium citrate present is 0.06-0.65 M, the pH of the formulation is 3.5-7.5, and the pH is 50 ml 0.1 n HC1 when 15 ml is added formulations exceeding pH 3. 6. Aqueous liquid pharmaceutical composition, including, mg / ml: Monosodium alendronate trihydrate (for alendronic acid) 0.2-0.9 Sodium benzoate 1.0-2.0 Dihydrated Sodium Citrate 75-125 Anhydrous citric acid 0.3-40 Xylitol 100-640 where the concentration of citric acid and sodium citrate present in the present invention is 0.06-0.65 M, the pH of the composition is 3.5-7.5 and the pH is 50 ml 0.1 n HCl is more than pH 3 when 15 ml of this formulation is added. 7. The aqueous liquid pharmaceutical composition according to claim 6, including, mg / ml: Mono- Alendronate Trihydrate sodium (on alendronova- slot) 0.1 -0.9 Sodium benzoate 1.0-2.0 Potassium sorbate 1.0-2.0 Xylitol 400 Artificial Flavor 5-50 Dihydrated citrate sodium 75-125 Anhydrous citric acid 0.3-40 8. The pharmaceutical composition according to claim 6, in which monosodium alendronate trihydrate is present in an amount of from 0.33 to 0.67 mg / ml by alendronic acid. 9. Aqueous liquid pharmaceutical formulation, including, mg / ml: Monosodium Alendronate Trihydrate (for alendronic acid) 0.1-0.9 Tartaric acid, ΝΓ 70-140 Sodium hydroxide granules. ΝΓ36-72 Xylitol 100-640 Sodium Benzoate, ΝΓ0-3 Flavor Ν & Α # 782 orange 0-100 10. The pharmaceutical composition according to claim 9, where monosodium alendronate trihydrate is present in a concentration of from 0.13 to 0.67 mg / ml alendronic acid. 11. The pharmaceutical composition according to claim 2, where the total total amount of citric acid and sodium citrate present in the composition is at least about 50 mg / ml. 12. The pharmaceutical composition of claim 8, where the total total amount of citric acid and sodium citrate present in the composition is at least about 75 mg / ml. 13. The pharmaceutical composition of claim 8, where the total total amount of citric acid and sodium citrate present in the composition is at least about 100 mg / ml. 14. A method of inhibiting bone resorption, comprising administering an aqueous liquid composition of alendronic acid or a pharmaceutically acceptable salt and buffer so that alendronic acid is not exposed to the gastrointestinal environment, which has a pH below about 3.5. 15. An aqueous liquid pharmaceutical composition before mixing, comprising: alendronic acid or a pharmaceutically acceptable salt as an active ingredient; enough buffer so that A) the pH of the composition is between about 3.5 and about 7.5; and B) 15 ml of the composition can increase the pH of 50 ml of 0.1 n HCl to a pH of at least 3; and optionally one or more additional reagents selected from the group consisting of preservatives, flavors, colorants and sweeteners. 16. An aqueous liquid pharmaceutical composition prepared by the compound of alendronic acid or a pharmaceutically acceptable salt as an active ingredient; enough buffer so that A) the pH of the composition is between about 3.5 and about 7.5; and B) 15 ml of the composition can increase the pH of 50 ml of 0.1 n HCl to a pH of at least 3; and optionally one or more additional substances selected from the group consisting of preservatives, flavors, colorants and sweeteners. 17. A method of preparing an aqueous liquid pharmaceutical composition, comprising the step of combining alendronic acid or a pharmaceutically acceptable salt as an active ingredient; and enough buffer so that A) the pH of the composition is between about 3.5 and about 7.5; and B) 15 ml of the composition can increase the pH of 50 ml of 0.1 n HCl to a pH of at least 3; and optionally one or more additional substances selected from the group consisting of preservatives, flavors, colorants and sweeteners.