AU6315499A - Effervescent bisphosphonate formulation - Google Patents

Description

F,

S&F Ref: 439896D1

AUSTRALIA

PATENTS ACT 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT

ORIGINAL

S. Name and Address of Applicant Actual Inventor(s): Address for Service: Invention Title: Merck Co., Inc.

126 East Lincoln Avenue Rahway New Jersey 07065 United States of America Ashok V Katdare, Kenneth A Kramer and Colin R Gardner Spruson Ferguson St Martins Tower 31 Market Street Sydney NSW 2000 Effervescent Bisphosphonate Formulation The following statement is a full description of this invention, including the best method of performing it known to me/us:- 5845c Effervescent Bisphosphonate Formulation Field of the Invention This invention relates to pharmaceutical effervescent formulations of bisphosphonates, especially alendronate, and in particular, tablets and powders which effervesce when added to water.

Background of the Invention There are numerous bisphosphonates which have been identified as having utility as pharmaceutical agents which inhibit bone resorption. These include: alendronate--(4-amino-1-hydroxy-butylidene)bis-phosphonate; cimadronate--[(cycloheptylamino)methylene]bis-phosphonate; clodronate--(dichloromethylene)-bis-phosphonate; EB-1053-[1-hydroxy-3-(1-pyrrolidinyl)-propylidene]bis-phosphonate; etidronate--(1 -hydroxyethylidene)-bis-phosphonate; ibandronate--[1 -hydroxy-3-(methylpentylamino)propylidene]bis-phosphonate; neridronate--(6-amino-1 -hydroxyhexylidene)bis-phosphonate; olpadronate--[3-(dimethylamino)- -hydroxy-propylidene]bis-phosphonate; pamidronate--(3-amino-1-hydroxypropylidene)bis-phosphonate; risedronate--[1 -hydroxy-2-(3-pyridinyl)-ethylidene]bis-phosphonate; tiludronate--[[(4-chlorophenyl)thio]methylene]bis-phosphonate; YH 529--[1-hydroxy-2-imidazo-(1,2a)pyridin-3-ylethylidene]bis-phosphonate; and zoledronate-[1-hydroxy-2-(1H-imidazol-1-yl)ethylidene]bis-phosphonate.

Alendronate has been approved by various regulatory agencies, including the Food and Drug Administration in the United States as an oral osteoporosis treatment in post menopausal women.

The currently marketed formulation is a tablet, and the patient is instructed to take the tablet with a full :'::'glass of water in the morning, at least a half hour prior to eating or drinking. However, certain side effects, including esophageal irritation and erosion have been reported if the tablet was not taken with enough water, or if the patient did not remain in an upright position for approximately one-half hour after taking the medication.

It would be desirable to develop a formulation which allows a bisphosphonate to be taken orally, yet avoids problems associated with prolonged contact between the medication and the oesophagus.

Detailed Description of the Invention The present invention is directed to an effervescent pharmaceutical formulation comprising, as an active ingredient, a bisphosphonate selected from the group consisting of: alendronate, cimadronate, clodronate, EB-1053, etidronate, ibandronate, neridronate, olpadronate, pamidronate, [R:\LIBAA]07742.doc:tab r risedronate, tiludronate, YH 529, zoledronate, pharmaceutically acceptable salts and esters of the foregoing, and mixtures of the foregoing; an acid source selected from the group consisting of: citric acid, tartaric acid, malic acid, fumaric acid, adipic acid, succinic acid; an anhydride of said acids; an acid salt selected from the group consisting of sodium dihydrogen phosphate, disodium dihydrogen pyrophosphate and sodium acid sulfite; and mixtures of the acids, anhydrides and acid salts; a carbonate source selected from the group consisting of: sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, sodium sesquicarbonate, sodium glycine carbonate, and mixtures thereof; a binder selected from the group consisting of a non-reducing sugar such as mannitol, lactose, dextrose or sorbitol; polyvinyl pyrrolidone, or, sodium chloride, sodium benzoate and sodium sulfate; a lubricant selected from the group consisting of stearic acid salts, powdered sodium benzoate, L-leucine, sodium laurel sulfate and polyethylene glycol (PEG); and optionally, one or more additional agents selected from the group consisting of flavouring 15 agents (such as orange and cherry) colorants, and sweeteners (including xylitol, aspartame or acesulfame K).

The present invention is also directed to an effervescent pharmaceutical formulation comprising alendronate or a pharmaceutically acceptable salt thereof as an active ingredient and an acid source selected from the group consisting of: citric acid, tartaric acid, malic acid, 20 fumaric acid, adipic acid, succinic acid; an anhydride of said acids; an acid salt selected from the group consisting of sodium dihydrogen phosphate, disodium dihydrogen pyrophosphate and sodium acid sulfite; and mixtures of the acids, anhydrides and acid salts; a carbonate source selected from the group consisting of: sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, sodium sesquicarbonate, sodium glycine 25 carbonate, and mixtures thereof; wherein the acid source is present in at least an equivalent amount relative to the source of carbonate; a binder selected from the group consisting of mannitol, sorbitol, polyvinyl pyrrolidone, lactose, sodium chloride sodium benzoate and sodium sulfate; a lubricant selected from the group consist of stearic acid salts, powdered sodium benzoate, L-leucine, sodium laurel sulfate, powdered sodium bicarbonate and polyethylene glycol (PEG); and optionally, one or more additional agents selected from the group consisting of flavouring agents, particularly orange and cherry colorants, and sweeteners selected from the group consisting of xylitol, aspartame and acesulfame K.

[R:\LIBAA]07742.doc:tab r The effervescent pharmaceutical formulation of the present invention may be either a tablet or a powder. To use the formulation, the tablet or powders are placed in a convenient amount of water to produce an effervescent liquid, and the patient drinks the effervescent liquid.

Particularly disclosed herein are the following formulations comprising (in mg): A formulation comprising (in mg): Alendronate sodium (in mg alendronic acid) 5 to citric acid 600 to 750 sodium bicarbonate 300 to 500 sodium carbonate 20 to sodium benzoate 5 to water 0 to A formulation comprising (in mg): Alendronate sodium (in mg alendronic acid) 5 citric acid 450 to 650 15 sodium bicarbonate (total) 800 to 1150.

A formulation comprising (in mg): Alendronate sodium (in mg alendronic acid) 2.5 to citric acid 400 to 800 sodium bicarbonate 1000 to 2000 20 sodium carbonate 20 to sodium benzoate 25 to 175 xylitol 100 to 300.

A formulation made by the process of combining: Alendronate sodium (in mg alendronic acid) 2.5 to 25 citric acid 400 to 800 sodium bicarbonate 1000 to 2000 sodium carbonate 20 to sodium benzoate 25 to 175 xylitol 100 to 300.

In one embodiment the formulation is a tablet, wherein in one class the total weight of the tablet ranges from about 100 to about 50,000 mg. In another embodiment, the tablet weight ranges from about 1500 to about 32,500 mg and more particularly from 20,800 to about 30,150 mg.

As used throughout this specification and claims, the term "bisphosphonate" is intended to include the related bisphosphonic acids and salts, and various crystalline and amorphous forms.

"Alendronate" includes the related bisphosphonic acid, and salt forms. It includes crystalline, hydrated [R:LIBAA]07742.doc:tab r crystalline, and amorphous forms of alendronate. It specifically includes alendronate sodium and alendronate monosodium trihydrate.

Methods for the preparation of bisphosphonates are well known in the art. Methods for the preparation of alendronate and alendronate sodium salt trihydrate are known. In particular, methods for the preparation of alendronate may be found in US patents 4,922,007, 5,019,651 and 5,510,517, each of which is hereby incorporated by reference. The amount of active in the formulation based on a weight of alendronate will range from 1 to 80 mg, particularly 5-40 mg and more particularly 5-15 mg. Exemplary amounts of alendronate are 5, 10 and 40 mg.

The formulations of this invention have many distinct advantages. First of all, the patients drinks an effervescent liquid, which limits the amount of time in which the bisphosphonate is in contact with the esophageal tissue, thus minimising the risk of irritation. Secondly, the bioavailability of at least some of the bisphosphonates, including alendronate is increased as a consequence of an excipient acting as a sequestering agent. Thirdly, the alendronate formulations are particularly advantageous in that alendronate is often prescribed to elderly patients who may experience difficulty 15 in swallowing pills, but can more easily swallow a liquid formulation.

In preferred embodiments of the invention the acid source is chosen from acid sources which are also sequestering agents. This is an important consideration because bisphosphonates, particularly alendronate, can be a potent sequestering agent of divalent cations, especially Ca 2 and Mg 2 If either of these cations are present, the alendronate will sequester them, rendering the S 20 alendronate less bioavailable. Preferred acid sources which also act as a sequestering agent include citric acid and tartaric acid, and mixtures thereof. The excess citric acid or tartaric acid in the formulation binds the ions in issue and prevents their complexation with alendronate.

The carbonate source should be chosen so that it does not contain divalent cations which could be sequestered by the bisphosphonate. Suitable carbonate sources are sodium bicarbonate, sodium 25 carbonate, potassium bicarbonate, potassium carbonate and sodium glycine carbonate. Preferred carbonate sources are sodium bicarbonate, sodium carbonate, and mixtures thereof.

In one aspect of this invention the acid source is present in an amount equal or greater than the carbonate source, on a molecular equivalent basis. Thus, when citric acid is the acid source and sodium bicarbonate is the carbonate source, the mole ratio of citric acid/bicarbonate is at least 1:3. In a particular class of this aspect there is an excess of citric acid, as this not only helps to efficiently generate the effervescence, but also acts to sequester any ions which might otherwise complex with alendronate and the excess also acts as a flavour enhancer. In an illustration of the excess acid source, the mole ratio of citric acid to bicarbonate ranges from 1:1 to 3:1. Where sodium carbonate is used as the source of carbonate an equal equivalent with citric acid will require a mole ratio of 2 moles citric acid to 3 moles carbonate. Analogous ratios can be calculated for any source of acid and [R:\LIBAA]07742.doc:tab carbonate, and of course the carbonate source may be present as a mixture of bicarbonate and carbonate.

For patients who exhibit gastric irritation another aspect of this invention is to employ excess amounts of the carbonate source to provide an antacid effect to the formulation. Example 2 below demonstrates such a formulation.

The binder may be a non-reducing sugar, such as mannitol, compressible lactose, dextrose or sorbitol. Alternatively, a polymer such as polyvinylpyrrolidone may be used. Other binders can include sodium chloride, sodium benzoate and sodium sulfate. The binder is usually present in approximately 3-10% of the tablet, and preferably about 5% (based on wtlwt), e.g. if the tablet weighs 1000 mg, the binder will be from about 30-100 mg, more preferably about 50 mg. If, however, a direct compression process is used to make the tablets, then a higher amount of binder is employed, preferably about 300-400 mg.

The tablet should also contain a lubricant, which typically comprises about 0.5 to about 5% of the tablet on a wt/wt basis, and preferably about Preferred lubricants include powdered sodium benzoate, micronised polyethylene glycol 6000 and polyethylene glycol 8000, sodium lauryl sulfate, powdered sodium bicarbonate and L-leucine.

For effervescent powder formulations, the composition of the powder is similar to that of the tablet, except that the lubricant is generally present in a lesser amount (about less than one-half that in the tablet) and the binder should be chosen so that it is a dry binder. In preferred formulations, the S 20 powder is granulated.

Where desired a colorant, flavouring agent such as orange or cherry or sweetener from the group xylitol, aspartame, or acesulfame K may be added to the formulation. Various methodologies for preparing the formulations of the current invention are illustrated in the examples below.

The following formulations and manufacturing procedures can be used for manufacture of 25 effervescent tablets containing alendronate sodium.

CC. It should be understood that one skilled in this art will recognise equivalent formulations which are intended to be included with the scope of this invention.

[R:\LIBAA]07742.doc:tab Example 1 Alendronate sodium (in mg alendronate acid) Citric acid, anhydrous (granular) Sodium bicarbonate (granular) Sodium carbonate, anhydrous Flavouring agent (optional) Colorant (optional) Sodium benzoate to Water 5-10 600-700 300-500 20-60 10-50 0-10 5-15 0-5 10 mg 650 mg 367 mg 40 mg 25 mg 5 mg 7.5 mg 2 mg.

S

Premix sodium benzoate with sodium bicarbonate and alendronate sodium. Mix colour with sodium carbonate. Place citric acid in a bowl of a suitable blender. Add the 2 mg water to the citric acid slowly and mix thoroughly to form a moist blend. Add to the blend, in sequence, while mixing, the sodium bicarbonate mix, and the sodium carbonate-colour mix until 15 uniformly distributed. Compress tablets using suitable size tooling. Cure the tablets, cool and package in aluminium foil.

Example 2 Alendronate sodium (in mg alendronate acid) 5-10 5 mg or 10 mg Citric acid, anhydrous (granular) 450-650 590 mg Sodium bicarbonate (granular) 750-1000 850 mg Sodium carbonate, powder 50-150 87 mg Citrus flavour (optional) 0-50 25 mg Water 0-25 15 mg.

Blend alendronate sodium, citric acid and citrus flavour in a suitable blender. Quickly add all of water and mix until a workable mass is formed. Granulate through a suitable screen using a granulator. Spread evenly on a paper-lined tray or a fluid bed dryer. Please a dried granulation in a suitable blender and add powder sodium bicarbonate. Mix well. Compress tablets using a suitable flat face bevelled edge tooling. Package in aluminium foil or aluminium tubes.

(R:\LIBAA]07742.doc:tab Example 3 Alendronate sodium (in mg alendronate acid) 10 mg Mannitol, direct compression grade 165 mg Sodium bicarbonate 850 mg Citric acid 530 mg Sodium benzoate 15 mg.

Mix alendronate sodium and sodium benzoate in a suitable mixer. Add mannitol and continue mixing till uniform. Add sequentially citric acid and sodium bicarbonate. Roller compact the powder mix followed by granulation using a suitable screen. Compress the granulation using a suitable tooling. Package the tablets in aluminium foil.

Example 4 Alendronate sodium (in mg alendronate acid) 2.5-10 10 mg S 15 Citric acid, anhydrous (granular) 400-800 600 mg Sodium bicarbonate (granular) 1000-2000 1500 mg Sodium carbonate, anhydrous 20-80 40 mg Flavouring agent (optional) 0-50 25 mg Colorant (optional) 0-15 5 mg Sodium benzoate 25-175 150 mg Xylitol 100-300 200 mg Sweetener (aspartame) 1-10 2.5 mg.

Part 1. Blend in a suitable mixer xylitol, alendronate and 400 mg sodium bicarbonate. Roller compact this mixture.

25 Part 2. Blend in a suitable mixer sodium benzoate, citric acid, 900 mg sodium bicarbonate, colour, flavour, and sweetener; then roller compact this mixture.

Part 3. Granulate Parts 1 and 2 through a suitable screen, add remaining powders and mix.

Compress the granulation using a suitable tooling. Package the tablets in aluminium foil.

[R:\LIBAA]07742.doc:tab

Claims (16)

1. An effervescent pharmaceutical formulation comprising as an active ingredient a bisphosphonate selected from the groups consisting of: alendronate, cimadronate, clodronate, EB-1053, etidronate, ibandronate, neridronate, olpadronate, pamidronate, risedronate, tiludronate, YH 529, zoledronate, pharmaceutically acceptable salts and esters of the foregoing, and mixtures of the foregoing; and an acid source selected from the group consisting of: citric acid, tartaric acid, malic acid, fumaric acid, adipic acid, succinic acid; an anhydride of said acids; an acid salt selected from the group consisting of sodium dihydrogen phosphate, disodium dihydrogen pyrophosphate and sodium o1 acid sulfite; and mixtures of the acids, anhydrides and acid salts; a carbonate source selected from the group consisting of: sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, sodium sesquicarbonate, sodium glycine carbonate, and mixtures thereof; a binder selected from the group consisting of a non-reducing sugar, polyvinyl pyrrolidone, sodium chloride, sodium benzoate and sodium sulfate; 15 a lubricant selected from the group consist of stearic acid salts, powdered sodium S" benzoate, L-leucine, sodium laurel sulfate and PEG; and optionally, one or more additional agents selected from the group consisting of flavouring agents, colorants, and sweeteners.

2. An effervescent pharmaceutical formulation according to claim 1 wherein the active 20 ingredient comprises alendronate or a pharmaceutically acceptable salt thereof as an active ingredient and further comprising: San acid source selected from the group consisting of: citric acid, tartaric acid, malic acid, fumaric acid, adipic acid, succinic acid; an anhydride of said acids; an acid salt selected from the Sgroup consisting of sodium dihydrogen phosphate, disodium dihydrogen pyrophosphate and sodium 25 acid sulfite; and mixtures of the acids, anhydrides and acid salts; a carbonate source selected from the group consisting of: sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, sodium sesquicarbonate, sodium glycine carbonate, and mixtures thereof; wherein the acid source is present in an equal or excess amount compared to the carbonate source, based on molecular equivalent amounts; a binder selected from the group consisting of mannitol, sorbitol, polyvinyl pyrrolidone, lactose, sodium chloride, sodium benzoate and sodium sulfate; a lubricant selected from the group consist of stearic acid salts, powdered sodium benzoate, L-leucine, sodium laurel sulfate and PEG; and optionally, one or more additional agents selected from the group consisting of flavouring agents, colorants, and sweeteners. [R:\LIBAA]07742.doc:tab

3. A formulation according to claim 2 wherein the amount of alendronate or salt thereof is from 1 to

4. A formulation according to claim 3 wherein the acid source is citric acid, tartaric acid or mixtures thereof.

5. A formulation according to claim 3 or claim 4 wherein the carbonate source is sodium bicarbonate, sodium carbonate, and mixtures thereof.

6. A formulation according to claim 5 wherein the mole ratio of citric acid to bicarbonate is from 1:1 to 1:3.

7. A formulation according to claim 5 wherein the binder is mannitol, lactose, dextrose or sorbitol.

8. A formulation comprising (in mg): Alendronate sodium (in mg alendronic acid) 5 to citric acid 600 to 750 sodium bicarbonate 300 to 500 15 sodium carbonate 20 to :sodium benzoate 5 to water 0 to

9. A formulation according to claim 8, further comprising a flavouring agent or a colorant.

A formulation comprising (in mg): 20 Alendronate sodium (in mg alendronic acid) 5 citric acid 450 to 650 S: sodium bicarbonate (total) 800 to 1150.

11. A formulation comprising (in mg): Alendronate sodium (in mg alendronic acid) 2.5 to 25 citric acid 400 to 800 sodium bicarbonate 1000 to 2000 sodium carbonate 20 to sodium benzoate 25 to 175 xylitol 100 to 300.

12. A formulation made by the process of combining: Alendronate sodium (in mg alendronic acid) 2.5 to citric acid 400 to 800 sodium bicarbonate 1000 to 2000 sodium carbonate 20 to sodium benzoate 25 to 175 xylitol 100 to 300. [R:\LIBAA]07742.doc:tab

13. An effervescent pharmaceutical formulation, substantially as hereinbefore described with reference to any one of the Examples.

14. An effervescent tablet, substantially as hereinbefore described with reference to any one of the Examples.

15. A method of making an effervescent tablet, substantially as hereinbefore described with reference to any one of the Examples.

16. An effervescent tablet produced by the method according to claim Dated 1 December, 1999 Merck Co., Inc. Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON •0 #b o 6 S* 0 o [R:\L1BAA]07742.doc:tab