JP2001501222A - Liquid alendronate preparation - Google Patents

Abstract

  (57) [Summary] A liquid formulation of alendronic acid or a pharmaceutically acceptable salt has a pH of 4-7.5 of this formulation, and 15 ml of this formulation has a pH of 50 ml of 0.1 N HCl of 1 to at least 3, preferably Has enough buffer to raise it to 4.

Description

BACKGROUND OF THE INVENTION Field of the liquid alendronate formulations INVENTION The present invention, alendronic acid or a pharmaceutically acceptable liquid pharmaceutical formulation of the salt with a (pharmaceutical formulatios), may particularly control the pH of gastric buffer And an agent. BACKGROUND OF THE INVENTION Alendronate, sodium (4-amino-1-hydroxy-butylidene-1,1-bisphosphonic acid monosodium salt trihydrate), is postmenopausal by various regulatory agencies, including the US Food and Drug Administration. Has been approved as an oral treatment for osteoporosis in women. The currently marketed formulation is a tablet, and patients are instructed to take the tablet with a glass of water at least 30 minutes before eating and drinking in the morning. Many people suffer from heartburn due to reflux of stomach acid into the esophagus. This can cause a burning sensation. There is an overlap between the population requiring alendronate treatment and the population of patients suffering from heartburn or similar symptoms. It would therefore be desirable to develop a formulation in which a bisphosphonate, such as alendronate sodium, would be taken orally, with the added benefit of alleviating heartburn symptoms. DETAILED DESCRIPTION OF THE INVENTION The present invention relates to the following: Alendronic acid or a pharmaceutically acceptable salt as an active ingredient; A) the pH of this formulation is about 3.5 to about 7.5; B) A sufficient amount of a buffer to allow 15 ml of this formulation to raise the pH (about pH 1) of 50 ml of 0.1 N HCl to at least pH 3.0; and optionally preservatives, flavors, colorings And one or more additional drugs, including those selected from the group consisting of sweeteners. Another aspect of the invention is a pharmaceutical formulation made by mixing the active ingredient, a buffer, and one or more optional agents. The type of buffer that can be used in this formulation is not critical as long as its buffer capacity is as follows: That is, the pH of the acidic solution can be sufficiently increased even with a relatively small amount. Examples of buffer systems include those selected from the group consisting of citrate, tartrate, fumarate, phosphate, acetate, and mixtures thereof. Typically, 0.2-3 g of salt or free acid and base will be used to make a combination of buffer salts (per 15 ml dose). Generally, a 15 ml dose of a formulation of the invention will contain from 0.2 to 3 g of at least one of the following: That is, disodium phosphate, trisodium citrate dihydrate, disodium tartrate dihydrate, or disodium formate. For example, useful buffer systems are citric anhydride and citrate buffers, including trisodium citrate dihydrate, both of which are about 1: 1 to 350, preferably about 1:50 to 150, more preferably about 1 It is present in a molar ratio of 1:81. In addition to the buffering agents, various bases, such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, etc., can be used to further adjust the buffer system. Another aspect of the invention is the use of an alendronate active ingredient such that it is not exposed to a pH of less than about 3.0, preferably about 3.5, more preferably less than about 4.0 while in vivo. In order to provide a buffered environment. Accordingly, the present invention also provides for inhibiting bone resorption comprising administering to a patient a pharmaceutical formulation comprising alendronic acid and a buffer such that alendronic acid is not exposed to the gastrointestinal environment at a pH of about 3.0 or less. Also includes methods. It is believed that the bioavailability of the active ingredient is enhanced at a pH above about 3.0. Another aspect of the invention is that prior to mixing, the following: Alendronic acid or a pharmaceutically acceptable salt as an active ingredient; A) The pH of the formulation is from about 3.5 to about 7.5. And B) 15 ml of this formulation can raise the pH of 50 ml of 0.1N HCl to at least pH3, and a sufficient amount of a buffer; and optionally preservatives, flavors, colorings, and An aqueous liquid pharmaceutical formulation comprising one or more additional agents selected from the group consisting of sweeteners. Another aspect of the invention is the following: alendronic acid or a pharmaceutically acceptable salt as an active ingredient; A) the pH of the formulation is from about 3.5 to about 7.5; B) 15 ml of this formulation consist of sufficient buffer to raise the pH of 50 ml of 0.1 N HCl to at least pH3; and optionally, preservatives, flavors, colors and sweeteners An aqueous liquid pharmaceutical formulation, prepared by combining one or more additional agents selected from the group: Another aspect of the invention is that alendronic acid or a pharmaceutically acceptable salt as an active ingredient; A) the pH of the formulation is from about 3.5 to about 7.5; and B) the formulation. 15 ml is sufficient to increase the pH of 50 ml of 0.1 N HCl to at least pH3, a buffer sufficient to: and optionally selected from the group consisting of preservatives, flavoring, coloring and sweetening agents A method of preparing an aqueous liquid pharmaceutical composition, comprising the step of combining one or more additional agents. As used throughout this specification and the claims, the term "alendronic acid" includes the related bisphosphonic acid form, pharmaceutically acceptable salt forms, and equilibrium mixtures thereof. This includes crystals, hydrated crystals, and amorphous forms of alendronic acid and pharmaceutically acceptable salts thereof. This includes in particular alendronate sodium and its hydrates, also known as alendronate monosodium trihydrate. "Pharmaceutically acceptable salt form" refers to forms commonly used in pharmaceutical preparations, such as alkali metals (Na ⁺ , Ca ²⁺ , K ⁺ , and Mg ²⁺ ), organic bases (eg, N-methylglucamine ), And salts containing amino acids (eg, lysine). Methods 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 U.S. Patent Nos. 4,922,007, 5,019,651, and 5,510,517. Each of these patents is incorporated herein by reference. The concentration of alendronic acid or alendronate sodium or other alendronate salt in this formulation is about 0.05 mg / ml to 2 mg / ml based on alendronic acid, preferably about 0,1 mg / ml based on alendronic acid. Will be 1 mg / ml to 0.9 mg / ml. Particularly useful concentrations are about 0.13, 0.33, and 0.67 mg / ml based on alendronic acid. One table spoonful (about 15 ml) of such a solution would correspond to doses of about 2 mg, 5 mg and 10 mg, respectively, based on alendronic acid. This is mixed with water (about 60 to 200 ml) and ingested. Alternatively, if a higher daily dose, for example 20 mg based on alendronic acid, is considered desirable, the patient may mix two tablespoons (about 30 ml) of this solution with water. This gives a dose of 10 mg per tablespoon based on alendronic acid. This dilute solution will be administered once a day, but may provide additional doses if desired. Alternatively, a full dose may be given once a day. In another mode of administration, the formulation, which may include water, is not diluted prior to ingestion by the patient. In this embodiment, the patient drinks only a small amount (about 15 ml) of liquid. The formulations of the present invention have many different advantages. Preferred formulations are supplied as concentrates. This is convenient for manufacturers and pharmacists. For example, a month's supply (eg containing a dose of 31 tablespoons) is only about 1 pint of liquid (473 ml). This facilitates handling and storage. It can be easily diluted by the patient before ingestion. In addition, liquid formulations are advantageous in the following respects. That is, alendronate sodium is often prescribed to older patients, who may have difficulty swallowing tablets and capsules, but liquid formulations are easier to swallow. The liquid dosage form can also contain flavors to make it easier for the patient to drink. Furthermore, the bioavailability of the active ingredient appears to be improved in this formulation when compared to the prior art tablet form. The buffer also eliminates the need for the patient to take various additional antacids to address acid reflux, heartburn, or other gastric problems. The inclusion of relatively large amounts of buffer is an important feature of the present invention. The amount of buffering agent is such that A) the pH of the formulation is about 3.5 to about 5, preferably about 4 to about 7, more preferably about 4 to about 5.5; It should be sufficient to raise the pH of 50 ml of 0.1N HCl (pH about 1) to at least pH 3.5, preferably about 4. The pH of the formulation itself is important because at pH 3.5-5.5, boosting to the stomach may be minimized. It is important that this formulation can buffer about 50 ml of strong acid. This is because they have the ability to buffer gastric acid. Reflux of gastric acid into the esophagus can cause irritation and even erosion of the esophagus. Typically, a person has about 50 ml of gastric juice at a pH of about 1 in the stomach. When ingesting the alendronate formulation of the present invention, stomach acid is buffered to at least 3.5, preferably to about 4. In an animal model according to the invention, it was found that a mixture of alendronate sodium and stomach acid did not irritate esophageal tissue at least at pH 3.5. Thus, even if the patient has reflux, esophageal irritation will not occur. Preservatives that can be used to provide multiple dosages can be any of the known pharmaceutically acceptable preservatives. These preservatives have a pH of 3.5-7. No. 5 is active in the liquid and does not interact adversely with the active ingredient. These may be used at normal concentrations. Preferred preservatives include sodium benzoate, potassium sorbate, benzyl alcohol, butylparaben, ethylparaben, methylparaben, propylparaben, and the like, and mixtures thereof. In an exemplary embodiment, sodium benzoate is used at a concentration of 1.0 to 2.0 mg / ml. It may be desirable to include taste enhancers, such as sweeteners and colorings. However, including them in the formulation is entirely optional. 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, which is about 0.1-1.0 mg / ml, preferably about 0.5-0. It can be used at a concentration of 7 mg / ml. Combinations of one or more sweeteners can also be used. An additional optional ingredient is a flavor. Flavors which have been found to be suitable (in terms of formulation clarity) include orange # 782 (Virginia Dare), Tutti Fruity (Fermenich / 51.880-CE) ), Artificial Berry # 491 (Pharmenic), and Artificial Strawberry (Pharmenic / 5.883-C). Other flavors include, but are not limited to, all natural and artificial oranges, strawberries, citrus flavors, tomatoes, apples, and tutti fruity. Typical concentrations are between 10 and 50 mg / ml, especially about 10 mg / ml. The following non-limiting examples are provided to better illustrate the invention. EXAMPLES Example 1 Alendronate Monosodium Trihydrate 0.87 ^* mg Sodium Benzoate 1.3mg Orange Flavor (Virginia Dare # 792) 10mg Sodium Citrate Dihydrate 100mg Citric Anhydride 0.45mg Xylitol 250 mg purified water qs1 ml Total citrate (M) is 0.50M. The pH of this 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 alendronic acid 0.67 mg / ml. Example 2 alendronate monosodium trihydrate 0.87 ^* mg sodium benzoate 1.3mg potassium sorbate 1.3mg xylitol 400mg sodium citrate dihydrate 100mg anhydrous citric acid 0.45mg flavoring 10mg purified water qs1ml ^* Corresponds to alendronic acid 0.67 mg / ml. Example 3 alendronate monosodium trihydrate 0.87 ^* mg potassium sorbate 1.3mg xylitol 400mg sodium citrate dihydrate 100mg citric anhydride 0.45mg purified water qs1ml ^* is alendronic acid 0. This corresponds to 67 mg / ml. Example 4 alendronate-sodium trihydrate 0.87 ^* mg sodium citrate dihydrate 100mg anhydrous citric acid 0.45mg xylitol 400mg purified water qs1ml ^* corresponds to alendronic acid 0.67mg / ml . Example 5 alendronate monosodium trihydrate 0.87 ^* mg tartaric acid, NF 75 mg sodium hydroxide pellets, NF 38.5 mg xylitol 400 mg sodium benzoate NF 1.3 mg flavor N & A # 782 orange 10 mg purified water qs1 ml ^* , 0.67 mg / ml of alendronic acid. Example 6 alendronate monosodium trihydrate 0.87 ^* mg tartaric acid, NF 70 mg sodium hydroxide pellets, NF 36 mg xylitol 400 mg sodium benzoate, NF 1.3 mg flavor N & A # 782 orange 10.0 mg purified water qs1 ml ^* Corresponds to alendronic acid 0.67 mg / 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 methylparaben 1.3mg flavor N & A # 782 orange 10.0mg purified water qs1ml ^* Corresponds to alendronic acid 0.67 mg / ml. Example 8 Alendronate Sodium 0.87 ^* mg Citric Acid 70.59mg Sodium Citrate 0.57mg Xylitol 50mg Sodium Saccharin 0.5mg Flavor N & A # 782 Orange 10.0mg Purified Water qs1ml ^* is 0.1% alendronic acid This corresponds to 67 mg / ml. Example 9 alendronate sodium 0.87 ^* mg tartaric acid, NF 75mg sodium hydroxide pellets, NF 38.5mg sodium saccharin 0.7mg sodium methylparaben 1.3mg flavor N & A # 782 orange 10.0mg purified water qs1ml ^* This corresponds to 0.67 mg / ml of alendronic acid.

────────────────────────────────────────────────── ─── Continuation of front page    (31) Priority claim number 60 / 036,002 (32) Priority date January 22, 1997 (22 January 1997) (33) Priority country United States (US) (81) Designated countries EP (AT, BE, CH, DE, DK, ES, FI, FR, GB, GR, IE, IT, L U, MC, NL, PT, SE), OA (BF, BJ, CF) , CG, CI, CM, GA, GN, ML, MR, NE, SN, TD, TG), AP (GH, KE, LS, MW, S D, SZ, UG, ZW), EA (AM, AZ, BY, KG) , KZ, MD, RU, TJ, TM), AL, AM, AU , AZ, BA, BB, BG, BR, BY, CA, CN, CU, CZ, EE, GE, HU, ID, IL, IS, J P, KG, KR, KZ, LC, LK, LR, LT, LV , MD, MG, MK, MN, MX, NO, NZ, PL, RO, RU, SG, SI, SK, SL, TJ, TM, T R, TT, UA, US, UZ, VN, YU (72) Hanke, William A. Inventors             New Jersey, United States             07065, Lowway, East Linker             N Avenue 126 (72) Inventor Ostovsk, Drazen             New Jersey, United States             07065, Lowway, East Linker             N Avenue 126

Claims (1)

[Claims] 1. Alendronic acid or a pharmaceutically acceptable salt as an active ingredient;   A) the pH of the formulation is about 3.5 to about 7.5; and   B) 15 ml of this formulation have a pH of 50 ml 0.1 N HCl at least p Can be raised to H3,   A sufficient amount of a buffer;   Optionally one or a member selected from the group consisting of preservatives, flavors, colorings, and sweeteners Further additional drugs,   An aqueous liquid pharmaceutical formulation comprising: 2. If the buffer is citric acid / sodium citrate or tartaric acid / sodium tal The formulation according to claim 1, which is a torate buffer system. 3. Alendronate-sodium trihydrate concentration based on alendronic acid The formulation according to claim 2, which is 0.1 to 0.9 mg / ml. 4. Alendronate-sodium trihydrate concentration based on alendronic acid At 0.133 or 0.67 mg / ml 4. The formulation of claim 3, wherein the formulation. 5. The concentration of citric acid and sodium citrate is 0.06-0.65M; The pH of the formulation is 3.5-7.5 and 50 ml when 15 ml of the formulation are added The formulation of claim 2, wherein the pH of the 0.1N HCl is above pH 3. 6. Expressed in mg / ml,   Alendronate-sodium trihydrate 0.2-0.9   (Based on alendronic acid)   Sodium benzoate 1.0-2.0   Sodium citrate dihydrate 75-125   Citric anhydride 0.3-40   Xylitol 100-640   An aqueous liquid pharmaceutical formulation comprising:   The citric acid and sodium citrate present in the present invention are between 0.06 and 0.65 M, the pH of the formulation is 3.5-7.5, and when 15 ml of the formulation is added A formulation wherein the pH of 50 ml of 0.1 N HCl is above pH 3. 7. Expressed in mg / ml,   Alendronate-sodium trihydrate 0.1-0.9   (Based on alendronic acid)   Sodium benzoate 1.0-2.0   Potassium sorbate 1.0-2.0   Xylitol 400   Artificial flavor 5-50   Sodium citrate dihydrate 75-125   Citric anhydride 0.3-40   The liquid pharmaceutical formulation of claim 6, comprising: 8. Alendronate-sodium trihydrate is based on alendronic acid 7. The pharmaceutical formulation according to claim 6, wherein the formulation is present at 0.33-0.67 mg / ml. 9. Expressed in mg / ml,   Alendronate-sodium trihydrate 0.1-0.9   (Based on alendronic acid)   Tartaric acid, NF 70-140   Sodium hydroxide pellets, NF 36-72   Xylitol 100-640   Sodium benzoate NF 0-3   Flavoring N & A # 782 Orange 0-100   An aqueous liquid pharmaceutical formulation comprising: 10. Alendronate monosodium trihydrate is based on alendronic acid Pharmaceutical formulation according to claim 9, which is present at a concentration of from 0.13 to 0.67 mg / ml. . 11. The total amount of citric acid and sodium citrate present in the formulation should be at least 3. The pharmaceutical formulation according to claim 2, wherein the is also about 50 mg / ml. 12. The total amount of citric acid and sodium citrate present in the formulation should be at least 9. The pharmaceutical formulation according to claim 8, wherein is also about 75 mg / ml. 13. The total amount of citric acid and sodium citrate present in the formulation should be at least 9. The pharmaceutical formulation according to claim 8, wherein is also about 100 mg / ml. 14． To prevent exposure of aledronic acid to the gastrointestinal environment at a pH below about 3.5, Administering an aqueous liquid formulation of dronic acid or a pharmaceutically acceptable salt and a buffer. And a method for inhibiting bone resorption. 15. Before mixing   Alendronic acid or a pharmaceutically acceptable salt as an active ingredient;   A) the pH of the formulation is about 3.5 to about 7.5; and   B) 15 ml of this formulation have a pH of 50 ml 0.1 N HCl at least p Can be raised to H3,   A sufficient amount of a buffer;   Optionally one or a member selected from the group consisting of preservatives, flavors, colorings, and sweeteners Further additional drugs,   An aqueous liquid pharmaceutical formulation comprising: 16. Alendronic acid or a pharmaceutically acceptable salt as an active ingredient;   A) the pH of the formulation is about 3.5 to about 7.5; and   B) 15 ml of this formulation have a pH of 50 ml 0.1 N HCl at least p Can be raised to H3,   A sufficient amount of a buffer;   Optionally one or a member selected from the group consisting of preservatives, flavors, colorings, and sweeteners Further additional drugs,   Aqueous liquid pharmaceutical preparations prepared by combining 17． Alendronic acid or a pharmaceutically acceptable salt as an active ingredient;   A) the pH of the formulation is about 3.5 to about 7.5; and   B) 15 ml of this formulation have a pH of 50 ml 0.1 N HCl at least p Can be raised to H3,   A sufficient amount of a buffer;   One or optionally selected from the group consisting of preservatives, flavors, colorants, and sweeteners Further additional drugs,   A method for preparing an aqueous liquid pharmaceutical formulation, comprising the step of combining