KR20000048829A - Liquid alendronate formulations - Google Patents

Abstract

PURPOSE: Provided are liquid pharmaceutical formulations of alendronic acid or a pharmaceutically acceptable salt thereof, and in particular, those containing a buffer which can control gastric pH. CONSTITUTION: Provided is a liquid pharmaceutical formulation comprising: alendronic acid or a pharmaceutically acceptable salt as an active ingredient; a sufficient amount of 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 of 0.1 N HCl (pH approximately 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, colorants, and sweeteners. Another aspect of this invention is a pharmaceutical formulation made by mixing the aforementioned active ingredients, buffer and optional agent(s). Buffering systems include those selected from the group consisting of citrate, tartrate, fumarate, phosphate, acetate, and mixtures thereof. Typically, 0.2 to 3 g of a salt or free acid and base will be used to make a buffer salt combination (per 15 ml dose). Generally, a 15 ml dose of the formulation of this invention will contain between 0.2 to 3 g of at least one of the following: disodium phosphate, trisodium citrate dihydrate, disodium tartrate dihydrate, or di sodium formate. For example a useful buffering system is a citrate buffer comprising anhydrous citric acid and trisodium citrate dihydrate, present in a molar ratio of about 1:1-350, preferably about 1:50-150, and more preferably about 1:81.

Description

Liquid alendronate formulations

Reference to related patent applications

The present invention relates to U.S. Provisional Patent Application Serial No. 60 / 026,765, filed Oct. 4, 1996, and No. 60 / 036,002, filed Jan. 22, 1997, the contents of which are incorporated herein by reference. Is cited.

Alendronate, Sodium (4-amino-1-hydroxy-butylidene-1,1-bisphosphonic acid monosodium salt trihydrate) is a U.S. Food and Drug Administration as a therapeutic agent for oral osteoporosis in postmenopausal women. It has been approved by several agencies, including. A widely available formulation is a tablet and the patient is instructed to take the tablet with a glass of water in the morning, at least 30 minutes before eating or drinking.

Many people often suffer from heartburn due to the reflux of stomach acid into the esophagus. This can cause burning sensation. There is an overlap between the population in need of the Alendronate therapy and the population of patients suffering from heartburn or similar symptoms.

Therefore, it would be desirable to develop formulations that allow the oral use of bisphosphonates, such as alendronate sodium, and have the added benefit of alleviating heartburn symptoms.

The present invention relates to liquid pharmaceutical formulations of alendronic acid or pharmaceutically acceptable salts thereof, in particular pharmaceutical formulations containing a buffer capable of adjusting the pH of the stomach.

The present invention provides an alendronic acid or a pharmaceutically acceptable salt thereof as an active ingredient; A) the pH of the formulation is about 3.5 to about 7.5; B) 15 ml of the formulation to raise the pH of 50 ml of 0.1 N HCl (pH approximately 1) above pH 3.0 Sufficient amount of buffer; And optionally one or more additives including those selected from the group consisting of preservatives, flavors, colorants and sweeteners. Another aspect of the present invention is a pharmaceutical formulation prepared by mixing the active ingredients, buffers and optional agents mentioned above.

The type of buffer that can be used in such formulations is not critical, as long as its buffering capacity is sufficient to raise the pH of the acidic solution to a relatively small volume. Exemplary buffer systems include those selected from the group consisting of citrate, tartrate, fumarate, phosphate, acetate, and mixtures thereof. Typically, a buffer salt mixture (per 15 ml dose) can be prepared using 0.2 to 3 g of salt or free acid and base. In general, a 15 ml dose of a formulation of the present invention may contain 0.2 to 3 g of one or more of the following ingredients: disodium phosphate, trisodium citrate dihydrate, disodium tartrate dihydrate or disodium formate. For example, useful buffer systems include anhydrous citric acid and trisodium citrate dihydrate, present in a molar ratio of about 1: 1-350, preferably about 1: 50-150, more preferably about 1:81. Citrate buffer.

In addition to the buffers described above, the buffer system can be further adjusted using various bases such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, and the like.

Another aspect of the present invention provides a buffered environment for the active ingredient such that the alendronic acid active ingredient is not exposed to a pH in vivo of less than about 3.0, preferably about 3.5, more preferably less than about 4.0. will be. Accordingly, the present invention also provides a method of inhibiting bone resorption, comprising administering to a patient a pharmaceutical formulation comprising alendronic acid and a buffer that prevents it from being exposed to a gastrointestinal environment having a pH of less than about 3.0. It includes. Bioavailability of the active ingredient is considered to be elevated at a pH of about 3.0 or higher.

Another aspect of the present invention is an alendronic acid or a pharmaceutically acceptable salt thereof as an active ingredient; A) the pH of the formulation is about 3.5 to about 7.5; B) an amount of buffer sufficient to allow 15 ml of the formulation to raise the pH of 50 ml of 0.1N HCl above pH 3; And optionally one or more additives including one or more additives including those selected from the group consisting of preservatives, flavors, colorants and sweeteners.

Another aspect of the present invention is an alendronic acid or a pharmaceutically acceptable salt thereof as an active ingredient; A) the pH of the formulation is about 3.5 to about 7.5; B) an amount of buffer sufficient to allow 15 ml of the formulation to raise the pH of 50 ml of 0.1N HCl above pH 3; And optionally, an aqueous liquid pharmaceutical formulation prepared by admixing one or more additives including those selected from the group consisting of preservatives, flavors, colorants and sweeteners.

Another aspect of the present invention is an alendronic acid or a pharmaceutically acceptable salt thereof as an active ingredient; A) the pH of the formulation is about 3.5 to about 7.5; B) an amount of buffer sufficient to allow 15 ml of the formulation to raise the pH of 50 ml of 0.1N HCl above pH 3; And optionally, mixing at least one additive comprising those selected from the group consisting of preservatives, flavors, colorants and sweeteners.

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

“Pharmaceutically acceptable salt form” means alkali metals (Na ⁺ , Ca ²⁺ , K ⁺ and Mg ²⁺ ), organic bases (eg N-methylglucamine) and amino acids (eg lysine) By a form conventionally used in pharmaceutical formulations, such as salts of the family.

Processes for preparing alendronic acid and alendronate sodium salt trihydrate are known. In particular, methods for preparing alendronic acid and pharmaceutically acceptable salts thereof can be found in US Pat. Nos. 4,922,007, 5,019,651 and 5,510,517, which are incorporated herein by reference. have.

The concentration of the alendronic acid or the alendronate sodium or other alendronate salt in the formulation is in the range of about 0.05 to 2 mg / ml on the basis of the alendronic acid, preferably about 0.1 to 0.9 mg / ml on the basis of the alendronic acid. Particularly useful concentrations are 0.13, 0.33 and 0.67 mg / ml on the basis of alendronic acid, where 1 tablespoon (approximately 15 ml) of this solution corresponds to dosages of approximately 2, 5 and 10 mg, respectively, on the basis of alendronic acid. It can be consumed by mixing in water (approximately 60-200 ml). In addition, if a higher daily dose, e.g. 20 mg, is considered preferred on the basis of the alendronic acid, the patient may mix 2 tablespoons of the solution (approximately 30 ml) with water and 10 mg on the basis of the alendronic acid per tablespoon. Dosage may be provided. Dilutions can be administered once a day, but if necessary, additional doses can be provided; It is also contemplated that it may provide a dosage of less than once a day.

In another method of administration, formulations which may contain water are not diluted before the patient takes them. In this embodiment, the patient swallows only a small amount of liquid (approximately 15 ml).

The formulations of the present invention have a number of significant advantages. Preferred formulations are supplied as concentrates to provide convenience to manufacturers and pharmacists. For example, a one-month supply (such as containing 31 tablespoons dose) is only approximately one pint liquid (473 ml). This facilitates handling and storage. It can be easily diluted before the patient takes it.

Liquid formulations are also advantageous in that sodium alendronate is often prescribed to elderly patients who may experience difficulty swallowing tablets or capsules, but who may swallow liquid formulations more easily. Liquid dosage forms can also include flavoring agents that can improve patient tolerance. In addition, the bioavailability of the active ingredient appears to be enhanced in the formulation as compared to the tablet forms of the prior art.

In addition, with the use of buffers, the patient does not need to take various additional antacids to solve acid reflux, heartburn or other stomach problems.

The inclusion of a relatively large amount of buffer is a major feature of the present invention. The amount of buffer is A) such that the pH of the formulation is about 3.5 to about 7.5, preferably about 4 to about 7, more preferably about 4 to about 5.5; B) 15 ml of the formulation should be sufficient to be able to raise the pH of 50 ml of 0.1 N HCl (pH approximately 1) to a pH above 3.5, preferably about 4. The pH of the formulation itself is important because there is minimal potential for further gastric irritation at pH 3.5 to 5.5.

Since the formulation has the ability to buffer gastric acid, its ability to buffer about 50 ml of strong acid is important. Reflux of stomach acid into the esophagus can cause irritation and even erosion of the esophagus. Typically, a person has about 50 ml of gastric juice with a pH of approximately 1 in the stomach. When ingesting the alendronate formulation of the present invention, gastric acid is buffered to at least 3.5, preferably about 4. In the animal model according to the invention, it has been found that the mixture of alendronate sodium and gastric acid at a pH of 3.5 or higher does not irritate esophageal tissue. Thus, even when the patient experiences reflux, esophageal irritation does not occur.

Preservatives that can be used to provide multiple doses can be one of the known pharmaceutically acceptable preservatives that are active in liquids of pH 3.5 to 7.5 that do not adversely interact with the active ingredient. They should be used at their usual concentrations. Preferred preservatives include sodium benzoate, potassium sorbate, benzyl alcohol, butylparaben, ethylparaben, methylparaben, propylparaben and others, and mixtures thereof. In a typical embodiment, sodium benzoate is used at a concentration of 1.0 to 2.0 mg / ml.

Although the inclusion in the formulation is strictly optional, it may be desirable to include taste enhancers such as sweeteners and colorants. Suitable sweeteners include various sugars, sorbitol, xylitol, sucrose and the like. Useful concentrations of sorbitol or xylitol are about 100-700 mg / ml, preferably about 200-500 mg / ml. Sodium saccharin is another useful sweetener and may be used at a concentration of about 0.1-1.0 mg / ml, preferably about 0.5-0.7 mg / ml. Mixtures of one or more sweeteners may also be used.

Further optional ingredients are flavoring agents. Flavors found to be suitable (in terms of formulation transparency) include Orange # 782 (Virginia Dare), Tumen-Fruti (Fermenich / 51.880-CE), Artistic Berry # 491 (Fermenich) and Artistic Strawberry (Fermenich / 57.883-C). Other flavoring agents include, but are not limited to, natural and artificial oranges, strawberries, all citrus flavors, tomatoes, apples, and tuty-fruity. Typical concentrations are 10 to 50 mg / ml, in particular about 10 mg / ml.

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

Example 1

Alendronate Monosodium Trihydrate 0.87 ^* mg

1.3 mg sodium benzoate

Orange Flavor (Virginia Dare # 792) 10mg

Sodium Citrate Dihydrate 100mg

Citric acid anhydride 0.45mg

Xylitol 250mg

1 ml of purified water

Total citrate (M) is 0.50M. The pH of the formulation is 4.8. When 15 ml of formulation is added to 50 ml of 0.1N HCl, the pH is 4.04.

^* Equivalent to Alendronic Acid 0.67mg / ml.

Example 2

Alendronate Monosodium Trihydrate 0.87 ^* mg

1.3 mg sodium benzoate

Potassium Sorbate 1.3mg

Xylitol 400mg

Sodium Citrate Dihydrate 100mg

Citric acid anhydride 0.45mg

Flavor 10mg

1 ml of purified water

^* Equivalent to Alendronic Acid 0.67mg / ml.

Example 3

Alendronate Monosodium Trihydrate 0.87 ^* mg

Potassium Sorbate 1.3mg

Xylitol 400mg

Sodium Citrate Dihydrate 100mg

Citric acid anhydride 0.45mg

1 ml of purified water

^* Equivalent to Alendronic Acid 0.67mg / ml.

Example 4

Alendronate Monosodium Trihydrate 0.87 ^* mg

Sodium Citrate Dihydrate 100mg

Citric acid anhydride 0.45mg

Xylitol 400mg

1 ml of purified water

^* Equivalent to Alendronic Acid 0.67mg / ml.

Example 5

Alendronate Monosodium Trihydrate 0.87 ^* mg

Tartaric Acid, NF 75mg

Sodium Hydroxide Pellets, NF 38.5mg

Xylitol 400mg

Sodium benzoate, NF 1.3 mg

Flavor N & A # 782 Orange 10mg

1 ml of purified water

^* Equivalent to Alendronic Acid 0.67mg / ml.

Example 6

Alendronate Monosodium Trihydrate 0.87 ^* mg

Tartaric Acid, NF 70mg

Sodium Hydroxide Pellets, NF 36mg

Xylitol 400mg

Sodium benzoate, NF 1.3 mg

Flavor N & A # 782 Orange 10.0mg

1 ml of purified water

^* Equivalent to Alendronic Acid 0.67mg / ml.

Example 7

Alendronate Sodium 0.87 ^* mg

Tartaric Acid, NF 75mg

Sodium Hydroxide Pellets, NF 38.5mg

Xylitol 50mg

Sodium saccharin 0.7mg

Sodium methyl paraben 1.3mg

Flavor N & A # 782 Orange 10.0mg

1 ml of purified water

^* Equivalent to Alendronic Acid 0.67mg / ml.

Example 8

Alendronate Sodium 0.87 ^* mg

Citric Acid 70.59mg

Sodium citrate0.57mg

Xylitol 50mg

Sodium Saccharin 0.5mg

Flavor N & A # 782 Orange 10.0mg

1 ml of purified water

^* Equivalent to Alendronic Acid 0.67mg / ml.

Example 9

Alendronate Sodium 0.87 ^* mg

Tartaric Acid, NF 75mg

Sodium Hydroxide Pellets, NF 38.5mg

Sodium saccharin 0.7mg

Sodium methyl paraben 1.3mg

Flavor N & A # 782 Orange 10.0mg

1 ml of purified water

^* Equivalent to Alendronic Acid 0.67mg / ml.

Claims (17)

Alendronic acid or a pharmaceutically acceptable salt thereof as the active ingredient; A) the pH of the formulation is about 3.5 to about 7.5; B) 15 ml of formulation to raise the pH of 50 ml of 0.1N HCl to above pH 3 Sufficient amount of buffer; And optionally one or more additives selected from the group consisting of preservatives, flavors, colorants and sweeteners. The formulation of claim 1, wherein the buffer is a citric acid / sodium citrate or tartaric acid / sodium tartrate buffer system. The formulation of claim 2, wherein the concentration of the alendronate monosodium trihydrate is from 0.1 to 0.9 mg / ml based on the alendronic acid. The formulation of claim 3, wherein the concentration of the alendronate monosodium trihydrate is 0.133 or 0.67 mg / ml on the basis of the alendronic acid. The formulation of claim 2 wherein the concentration of citric acid and sodium citrate present is from 0.06 to 0.65 M, the pH of the formulation is from 3.5 to 7.5 and the pH of 50 ml of 0.1 N HCl is above pH 3 when 15 ml of the formulation is added. Alendronate monosodium trihydrate (based on alendronic acid) 0.2 to 0.9 mg / ml, sodium benzoate 1.0 to 2.0 mg / ml, sodium citrate dihydrate 75 to 125 mg / ml, citrate anhydride 0.3 to 40 mg / ml and xylitol 100 To 640 mg / ml, wherein the concentrations of citric acid and sodium citrate present in the present invention are 0.06 to 0.65 M, the pH of the formulation is 3.5 to 7.5 and the pH of 50 ml of 0.1 N HCl is added when 15 ml of the formulation is added. Liquid pharmaceutical formulations above pH 3. 7. Alendronate monosodium trihydrate (based on alendronic acid), 0.1 to 0.9 mg / ml, sodium benzoate 1.0 to 2.0 mg / ml, potassium sorbate 1.0 to 2.0 mg / ml, xylitol 400 mg / ml , Liquid pharmaceutical formulation comprising 5 to 50 mg / ml artificial flavor, 75 to 125 mg / ml sodium citrate dihydrate and 0.3 to 40 mg / ml citric anhydride. The pharmaceutical formulation of claim 6, wherein the alendronate monosodium trihydrate is present at 0.33 to 0.67 mg / ml on the basis of the alendronic acid. Alendronate monosodium trihydrate (based on alendronic acid) 0.1 to 0.9 mg / ml, tartaric acid, NF 70 to 140 mg / ml, sodium hydroxide pellets, NF 36 to 72 mg / ml, xylitol 100 to 640 mg / ml, sodium benzoate , Aqueous liquid pharmaceutical formulation comprising 0-3 mg / ml NF and 0-100 mg / ml flavor N & A # 782 orange. The pharmaceutical formulation according to claim 9, wherein the alendronate monosodium trihydrate is present at 0.13 to 0.67 mg / ml on the basis of the alendronic acid. The pharmaceutical formulation of claim 2, wherein the total amount of citric acid and sodium citrate present in the formulation is at least about 50 mg / ml. The pharmaceutical formulation of claim 8, wherein the total amount of citric acid and sodium citrate present in the formulation is at least about 75 mg / ml. The pharmaceutical formulation of claim 8, wherein the total amount of citric acid and sodium citrate present in the formulation is at least about 100 mg / ml. A method of inhibiting bone resorption, comprising administering to a patient an aqueous liquid formulation of alendronic acid or a pharmaceutically acceptable salt and a buffer that prevents the alendronic acid from being exposed to a gastrointestinal environment having a pH of less than about 3.5 . Alendronic acid or a pharmaceutically acceptable salt thereof as the active ingredient; A) the pH of the formulation is about 3.5 to about 7.5; B) an amount of buffer sufficient to allow 15 ml of the formulation to raise the pH of 50 ml of 0.1N HCl above pH 3; And optionally one or more additives selected from the group consisting of preservatives, flavors, colorants and sweeteners. Alendronic acid or a pharmaceutically acceptable salt thereof as the active ingredient; A) the pH of the formulation is about 3.5 to about 7.5; B) an amount of buffer sufficient to allow 15 ml of the formulation to raise the pH of 50 ml of 0.1N HCl above pH 3; And optionally an aqueous liquid pharmaceutical formulation prepared by mixing one or more additives selected from the group consisting of preservatives, flavors, colorants and sweeteners. Alendronic acid or a pharmaceutically acceptable salt thereof as the active ingredient; A) the pH of the formulation is about 3.5 to about 7.5; B) an amount of buffer sufficient to allow 15 ml of the formulation to raise the pH of 50 ml of 0.1N HCl above pH 3; And optionally, mixing at least one additive selected from the group consisting of preservatives, flavors, colorants, and sweeteners.