Description:Alendronate Sodium Effervescent Formulation

Field of the Invention:
This invention relates to pharmaceutical compositions, specifically an effervescent composition containing alendronate sodium designed for oral solution. The formulation employs fluidized bed granulation technology combined with specific excipients to enhance solubility, stability, and palatability, ensuring improved patient compliance and therapeutic efficacy.

Background of the Invention:
Alendronate Sodium is widely used for the treatment of osteoporosis and other bone-related diseases. Conventional tablets and oral solutions often face issues related to stability, taste, and patient compliance. Existing patents such as US 9,592,195 and US 7,488,496 address some of these issues but have limitations in terms of process efficiency, formulation stability and cost effectiveness. US 9,592,195 discloses a stable effervescent tableted composition, comprising micronized sodium alendronate trihydrate of size distribution X10=2.7 μm, X50=6.2 μm, X90=13 μm, and is free from excipients and tableting lubricants. Tabletting without proper lubrication is always a challenge. Further, micronizing drug particles to a very fine particle size is having its own set of challenges. This invention aims to overcome these limitations by providing an effervescent tablet that rapidly dissolves in water, ensuring ease of administration and improved patient adherence through the use of fluidized bed granulation process.

Summary of the Invention:
The invention provides a pharmaceutical formulation comprising Alendronate Sodium in an effervescent composition form for oral solution. The formulation utilizes fluidized bed granulation technology with specific excipients to enhance the stability, solubility, and bioavailability of Alendronate Sodium. The effervescent tablet dissolves quickly in water, producing a palatable solution that is easy to ingest.

In one aspect of the invention provides a binder free pharmaceutical formulation comprising Alendronate Sodium in an effervescent composition form for oral solution

In one aspect of the invention provides a process of preparation of an effervescent pharmaceutical formulation comprising alendronate sodium comprises the steps:
• Dissolving alendronate sodium in water
• Spraying the alendronate sodium onto acid component
• Drying the acid component drug mixture till moisture content is between 0.1-3%,
• Blend the drug mixture with base component and optionally with colour and flavour,
• Lubricate the total mixture with a lubricating agent,
• Optionally compressing the blend into a tablet.

Detailed Description of the Invention:
The present invention relates to an effervescent formulation designed for oral administration, which contains Alendronate Sodium as the active ingredient. The innovative aspect of this formulation lies in the use of fluidized bed granulation technology combined with specific excipients and process parameters to enhance the solubility, stability, and palatability of Alendronate Sodium. This invention aims to overcome the limitations of conventional tablets and oral solutions by ensuring ease of administration and improved patient adherence.

Some of the major challenges for manufacturing effervescent compositions are particle size of the drug, low porosity, longer disintegration times, granule flow issues, difficulty in compression, low mechanical strength. Effervescent compositions are highly sensitive to moisture, which can initiate premature effervescent reactions. The manufacture of effervescent compositions is complex due to their reactivity in the presence of moisture, which can lead to auto-catalyzed reactions that are difficult to control. These compositions require rapid disintegration times, typically less than 60 seconds, and must also have adequate hardness for packaging and transportation. Therefore, there is a need for effervescent compositions stable, high mechanical strength, and a manufacturing process that is rapid, easily controlled, and preferably continuous.

Alendronate sodium is an inhibitor of bone resorbtion useful for the treatment of diseases such as Paget's disease and osteoporosis. The term "inhibition of bone resorption" as used herein refers to the treatment and prevention of bone loss, particularly by inhibiting the removal of existing bone through direct or indirect alteration of osteoclast formation or activity. The present invention prevents bone loss by the direct or indirect alteration of osteoclast formation or activity and which may increase bone mass in patient treatment populations.

"Alendronate" includes the related bisphosphonic acid and salt forms. It includes crystalline, hydrated crystalline, and amorphous forms of alendronate. It specifically includes alendronate sodium and alendronate monosodium trihydrate.

In one embodiment, alendronate sodium is present in a therapeutically effective amount from about 1 to about 30% by weight of the effervescent composition, preferably from about 2 to about 27% by weight of the effervescent composition.

In one embodiment, the present invention uses alendronate sodium having a particle size of about 15 microns to about 1000 microns, preferably about 50 microns to about 500 microns. In another embodiment, the present invention uses alendronate sodium having a particle size distribution having d90 value from about 15 microns to about 300 microns. In another embodiment, the present invention uses alendronate sodium having a particle size distribution having d90 value from about 25 microns to about 250 microns. In another embodiment, the present invention uses alendronate sodium having a particle size distribution having d90 value from d90 value from about 50 microns to about 200 microns,

The effervescent composition alendronate sodium comprises an effervescent system comprising an acid component and a base component.

The acid component is an acid compound or a mixture of two or more acid compounds capable of reacting with base component to cause the release of carbon dioxide when contacted with sufficient water. Suitable acids include 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 and the like, including mixtures thereof. The preferred acid is citric acid. In an embodiment, the acid component has a particle size of about 420 microns. This larger particle size is necessary to prevent manufacturing problems such as capping.

In one of the embodiments, the acid component has a particle size from about 50 to about 420 microns. A particle size of less than 50 microns promotes excessive static charge and results in processing problems such that the acid will not mix uniformly with the granulation and the mixture will not flow consistently. A particle size of greater than 420 microns causes processing issues and slow disintegration. In a preferred embodiment, the acid component has a particle size of about 50 to about 400 microns and more preferably has a particle size of about 75 to about 400 microns. The acid component is present in an amount from about 25 to about 75% by weight of total weight of the effervescent composition. Acid component content of less than about 25% results in slow disintegration and slow rate of solution of the alendronate sodium. Acid components greater than about 75% results in processing difficulties such as poor flow and mixing as well as capping during tablet manufacture. In a preferred embodiment, the acid component is present in the amount of about 35 to about 70% by weight of total weight of the effervescent composition. In a more preferred embodiment, the acid component is present in the amount of about 50 to about 65% by weight of total weight of the effervescent composition.

In one of the embodiments, the base component is a base compound or a mixture of two or more base compounds capable of reacting with acidic compounds with the release of carbon dioxide when contacted with sufficient water. In particular, the inorganic carbonates, and more particularly the alkali metal and ammonium carbonate materials may be used. Non-limiting examples of base compounds are sodium carbonate, sodium bicarbonate, sodium sesquicarbonate, potassium carbonate, potassium bicarbonate, lithium carbonate, lithium bicarbonate, ammonium carbonate, ammonium bicarbonate, ammonium sesquicarbonate and the like, including mixtures of these. The base component is present in an amount from about 15 to about 60% by weight of the total weight of effervescent composition.

The lubricant used in the present invention can be any pharmaceutically acceptable lubricant which includes metallic stearates, stearic acid, hydrogenated vegetable oils, polyethylene glycols, corn starch, sodium benzoate, sodium acetate, L-leucine, sodium laurel sulfate and PEG and the like or mixtures thereof. Sodium benzoate is the preferred lubricant of the present invention. The lubricant is present in an amount from about 1.5 to about 10% by weight of the total weight of the effervescent composition. In a preferred embodiment, the lubricant is present in the amount of about 2 to about 7.5% by weight of total weight of the effervescent composition. In a more preferred embodiment, the lubricant is present in the amount of about 2.5 to about 6% by weight of total weight of the effervescent composition.

The effervescent composition may additionally contain conventional additives such as, flavoring agents, and sweeteners.

Non-limiting examples of flavoring agents including both natural and artificial flavors, and mints such as peppermint, menthol, artificial vanilla, cinnamon, various fruit flavors, both individual and mixed, and the like are contemplated. The flavoring agents are generally utilized in amounts that will vary depending upon the individual flavor, and may, for example, range in amounts of about 0.5 to about 3% by weight of total weight of the effervescent composition.

The sweeteners includes both natural and artificial sweeteners. Non-limiting examples are sugars such as sucrose, glucose (corn syrup), invert sugar, fructose, and mixtures thereof; saccharin and its various salts such as the sodium or calcium salt; cyclamic acid and its various salts such as the sodium salt; the dipeptide sweeteners such as aspartame; dihydrochalcone; glycyrrhizin; Stevia rebaudiana (Stevioside); and sugar alcohols such as sorbitol, sorbitol syrup, mannitol, xylitol, and the like. The sweeteners are used in amounts of up to about 5% by weight. In general, the amount of sweetener will vary according to the type of sweetener and the desired taste of the final product. Natural sweeteners are generally used in amounts up to about 5% by weight. In contrast, artificial sweeteners are used in amounts up to about 1% by weight of total weight of the effervescent composition.

The effervescent composition may optionally contain conventional additives such as antifoaming agents, colorants, and glidants.

The antifoaming agent optionally used in the present invention can be any pharmaceutically acceptable antifoaming agent which includes simethicone and the like, or mixtures thereof. Simethicone is the preferred antifoaming agent of the present invention. The antifoaming agent is present in an amount from about 0.05 to about 0.22% by weight of total weight of the effervescent composition.

The colorants optionally used in the present invention include but are not limited to food, drug and cosmetic (FD&C) colors, for example the pigments, such as titanium dioxide, that may be incorporated in amounts of up to about 1% by weight, and preferably up to about 0.6% by weight. Also, the colorants may include other dyes suitable for food, drug and cosmetic applications, and known as F.D. & C. dyes and the like. The materials acceptable for the foregoing spectrum of use are preferably water-soluble. Illustrative examples include indigoid dye, known as F.D. & C. Blue No. 2, which is the disodium salt of 5,5'-indigotin disulfonic acid. Similarly, the dye known as F.D. & C. Green No. 1, comprises a triphenylmethane dye and is the monosodium salt of 4-[4-N ethyl-p-sulfobenzylamino)diphenylmethylene][1-(N-ethyl-N-p-sulfoniumbenzyl)-2,5-cyclohexadienimine].

Non-limiting examples of glidants are microfine silicas, corn starch, microcrystalline cellulose, metallic stearates and the like, including mixtures of these that may be incorporated in amounts up to about 2% by weight of total weight of the effervescent composition.

In one of the embodiments, the acid component is present at least an equivalent amount relative to the base component.

In one aspect of this invention the acid component is present in an amount equal or greater than the base component, on a molecular equivalent basis. Thus, when citric acid is the acid component and sodium bicarbonate is the base component, the mole ratio of citric acid/ bicarbonate is at least 3:1. 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 flavor enhancer.
In one aspect of this invention, the mole ratio of citric acid to bicarbonate ranges from 1:1 to 3:1. Analogous ratios can be calculated for any component of acid and carbonate, and of course the carbonate component 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 component to provide an antacid effect to the formulation.

The present invention is further illustrated by the following examples. All parts and percentages in the examples and throughout the specification and claims are by weight of the total effervescent composition.

The manufacture of effervescent compositions is complex due to their reactivity with moisture, which can lead to uncontrolled, auto-catalyzed reactions. These compositions require rapid disintegration times, typically under 60 seconds, which depend on their porosity. Additionally, they must have sufficient hardness for packaging and transport and must effectively release carbon dioxide in water. The present invention provides a process for manufacturing alendronate sodium effervescent compositions having stable and high mechanical strength and which do not require affirmatively adding a binder.

In one aspect of the invention provides a process of preparation of an effervescent pharmaceutical formulation comprising alendronate sodium in absence of a binder. Binders as known as binding agents/excipients are formulated to act as an adhesive to literally “bind together” powders, granules and other dry ingredients to impart to the product the necessary mechanical strength. They can also give volume to low active dose tablets. Commonly used in wet granulation, binders are added to create a more effective and predictable granule formation. Non-limiting examples of binders are gelatin, cellulose, cellulose derivatives, polyvinylpyrrolidone, starch, sucrose, polyethylene glycol, povidone (polyvinylpyrrolidone, PVP), hydroxypropyl cellulose (HPC), polyethylene glycol (PEG), carbomers and sodium carboxymethyl cellulose (NaCMC).

In one aspect of the invention provides a binder free effervescent pharmaceutical formulation comprising alendronate sodium or a pharmaceutically acceptable salt thereof, an acid component, a base component and a lubricant, wherein the composition is prepared by fluidized bed granulation comprises moisture content between 01.-3% (w/w) of the total blend.

In one aspect of the invention provides a process of preparation of an effervescent pharmaceutical formulation comprising alendronate sodium in presence of a comprises the steps:
• Dissolving alendronate sodium in water
• Spraying the alendronate sodium onto acid component
• Drying the acid component drug mixture till moisture content is between 0.1-3% w/w of the total blend,
• Blend the drug mixture with base component and optionally with colour and flavour,
• Lubricate the total mixture with a lubricating agent,
• Optionally compressing the blend into a tablet.

In another embodiment of the invention provides a process of preparation of an effervescent pharmaceutical formulation comprising alendronate sodium, wherein drug mixture till moisture content is between 0.1-3% w/w of the total blend. In another embodiment of the invention provides a process of preparation of an effervescent pharmaceutical formulation comprising alendronate sodium, wherein drug mixture till moisture content is between 0.3-2.5% w/w of the total blend. In another embodiment of the invention provides a process of preparation of an effervescent pharmaceutical formulation comprising alendronate sodium, wherein drug mixture till moisture content is between 0.1-1% w/w of the total blend. In another embodiment of the invention provides a process of preparation of an effervescent pharmaceutical formulation comprising alendronate sodium, wherein drug mixture till moisture content is between 0.1-1 % w/w of the total blend.

In another embodiment of the invention provides a process of preparation of an effervescent pharmaceutical formulation comprising alendronate sodium, wherein the alendronate sodium is dissolved in water at temperature between 40°-70°C.

In one aspect of the invention provides a process of preparation of an effervescent pharmaceutical formulation comprising alendronate sodium in presence of a comprises the steps:
• Dissolving alendronate sodium in hot water at temperature between 40°-70°C
• Spraying the alendronate sodium onto acid component
• Drying the acid component drug mixture till moisture content is between 0.1-3% w/w of the total blend,
• Blend the drug mixture with base component and optionally with colour and flavour,
• Lubricate the total mixture with a lubricating agent,
• Optionally compressing the blend into a tablet.

In one aspect of this invention, a process for preparing the effervescent composition of alendronate sodium comprises:
• Preparing an acid component by mixing two or more acid compounds
• forming alendronate sodium solution in water
• loading the drug onto an acid component
• Drying the drug loaded acid component mixture till moisture content is between 0.1-1% w/w of the total blend,
• sizing the dried granulation;
• admixing a base component with drug-acid component mixture;
• Optionally mixing with a colouring agent, a flavouring agent, a glidant and an antifoaming agent;
• Lubricate the mixture with a lubricant;
• Optionally compressed to a tablet.

More specifically, the process involves dissolving the alendronate sodium in an amount from about 1 to about 30% by weight of the effervescent composition in a solvent, preferably in water to form a solution, granulating the acid component with the drug solution to form a granules using fluidized bed granulation at inlet temperature between about 50 to about 70° C., sizing the dried granulation by grinding and screening to obtain particles having a size of about 500 to about 1200 microns, admixing the base component with the sized granules; optionally mixing the antifoaming agent, the sweetener, colouring agent, and flavouring agent to the drug mixture; lubricating the drug mixture. The final product may be used as is or formed into any desirable shape such as a tablet to render the product suitable for providing the necessary amount of alendronate sodium.

The granules formed by combining the drug solution with acid component is ground and screened such that it has a particle size from about 500 to about 1150 microns. A particle size of less than 50 microns yields a fine material which results in processing problems such as poor mixing and compressibility properties. A particle size of greater than 1200 microns causes a slow rate of solubilization and will leave undissolved alendronate sodium on the bottom of the effervescent solution after disintegration of the effervescent composition. In a preferred embodiment, the granulation has a particle size of about 600 to about 1200 microns and more preferably has a particle size of about 800 to about 1150 microns. In a preferred embodiment, the granulation has a particle size from about 800 to about 1100 microns.

The present invention pertains to an effervescent pharmaceutical formulation, which can be prepared either as a tablet or in powder form. This formulation is designed to be dissolved in a convenient amount of water, resulting in an effervescent liquid that the patient can easily ingest. The effervescent property not only enhances patient compliance, especially for those who have difficulty swallowing conventional tablets, but also potentially improves the bioavailability of the active ingredients. In one embodiment, the tablets weigh between approximately 10 mg and 10,000 mg. In another embodiment, the tablets have a more specific weight range from about 100 mg to 7,500 mg, with a particular focus on weights from 1000 mg to 5,000 mg. This versatile dosage form aims to provide a convenient and effective means of delivering medication, catering to a wide range of therapeutic needs.

In one aspect of the invention provides manufacturing of effervescent compositions comprising alendronate sodium by fluidized bed granulation technology. The fluidized bed granulation process involves suspending particles in an air stream and spraying a liquid on to it and drying the particles. In one aspect of the invention provides manufacturing of effervescent compositions comprising alendronate sodium by fluid-bed top-spray granulation method.

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

In one aspect of the invention provides treatment and prevention of bone loss, especially inhibiting the removal of existing bone, for example through direct or indirect alteration of osteoclast formation or activity by using the present composition. The composition of the present invention uses for treatment and prevention of various diseases including but not limited to Osteoporosis, Osteoarthritis, Paget's Disease, Osteohalisteresis, Osteomalacia, Bone loss from multiple myeloma and other cancers, Bone loss from steroid use, disuse, or rheumatoid-related conditions, age-related loss of bone mass and the like. Methods according to the present invention may have particular utility for the treatment of female patients who are post-menopausal.

The term “treating” or “inhibiting” as used herein with respect to methods of the present invention shall mean providing a patient with an amount of a pharmaceutically acceptable alendronate salt sufficient to act prophylactically or to alleviate or substantially eliminate bone resorption-related diseases.

Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments described herein, certain preferred methods, devices, and materials are now described.

As used herein and in the appended claims, the singular forms "a", "an", and "the" include plural reference unless the context clearly dictates otherwise. Thus, for example, reference to "an excipient" is a reference to one or more excipients and equivalents thereof known to those skilled in the art, and so forth.

The term "about" is used to indicate that a value includes the standard level of error for the device or method being employed to determine the value. The use of the term "or" in the claims is used to mean "and/or" unless explicitly indicated to refer to alternatives only or the alternatives are mutually exclusive, although the disclosure supports a definition that refers to only alternatives and to "and/or." The terms "comprise," "have" and "include" are open-ended linking verbs. Any forms or tenses of one or more of these verbs, such as "comprises," "comprising," "has," "having," "includes" and "including," are also open-ended. For example, any method that "comprises," "has" or "includes" one or more steps is not limited to possessing only those one or more step and also covers other unlisted steps.

While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Examples:
Sr. No. Ingredient % W/W
Dry mix
1 Monosodium citrate (sodium dihydrogen citrate) 51.66
2 Anhydrous citric acid 13.61
Drug Dispersion
3 Alendronate sodium 2.48
4 Purified water q.s.
Blending
4 Sodium bicarbonate (Sodium hydrogen carbonate) 22.57
5 Sodium carbonate 4.62
6 Sucralose 0.82
7 Acesulfame potassium 0.11
8 Strawberry flavour 0.11
Lubrication
9 Sodium benzoate 4.02
Total 100.00

Process:
Step I: Dry mix: Sift Monosodium citrate (sodium dihydrogen citrate) and Anhydrous Citric acid through #20 sieve and load in GPCG 1.1.
Step II: Binder (Drug dispersion): Add Alendronate sodium to Purified water under stirring until a uniform dispersion is seen.
Step III: Granulation and Drying: Spray drug dispersion of step II on dry mix of step I in GPCG 1.1 using top spray to form granules and dry the granules in GPCG 1.1 until LOD of NMT 0.5% is achieved.
Step IV: Blending: Sift Sodium bicarbonate, Sodium carbonate, Sucralose, Acesulfame potassium and Strawberry flavour through #40 sieve and mix the blend in blender for 20 minutes.
Step V: Lubrication: Sift Sodium benzoate through #100 sieve and blend for 5 minutes.
Step VI: Compression: Compress the blend using suitable punches. , Claims:We Claim:
1. An effervescent pharmaceutical formulation comprising alendronate sodium or a pharmaceutically acceptable salt thereof, an acid component, a base component and a lubricant, wherein the composition is prepared by fluidized bed granulation comprises moisture content between 0.1-3% (w/w) of the total blend.
2. The composition as claimed in claim 1, wherein the moisture content is between 0.1-1% (w/w) of the total blend.
3. The composition as claimed in claim 1, wherein the particle size of alendronate sodium is from about 15 microns to about 1000 microns.
4. The composition as claimed in claim 1, wherein the particle size of alendronate sodium is having a d90 value from about 15 microns to about 300 microns.
5. The composition as claimed in claim 1, wherein the composition is prepared by a process comprising the steps:
• Dissolving alendronate sodium in water,
• Spraying the alendronate sodium onto acid component,
• Drying the acid component drug mixture till moisture content is between 0.1-1%
• Blend the drug mixture with base component and optionally with colour and flavour,
• Lubricate the total mixture with a lubricating agent,
• Optionally compressing the blend into a tablet.
6. The composition as claimed in claim 5, wherein alendronate sodium is dissolved in water at temperature between 40°-70° C.
7. The composition as claimed in claim 1, wherein the acid component is a mixture of Monosodium citrate (sodium dihydrogen citrate) and Anhydrous Citric acid.
8. The composition as claimed in claim 1, wherein the base component is a mixture of Sodium bicarbonate and Sodium carbonate.
9. The composition as claimed in claim 1, wherein the lubricating agent is Sodium benzoate.
10. The composition as claimed in claim 1, wherein the composition is binder free composition.
11. The composition as claimed in claim 1, wherein the composition comprises Monosodium citrate (sodium dihydrogen citrate), Anhydrous Citric acid, Sodium bicarbonate and Sodium carbonate and Sodium benzoate.
12. The composition as claimed in claim 1, wherein the composition comprises Monosodium citrate (sodium dihydrogen citrate), Anhydrous Citric acid, Sodium bicarbonate and Sodium carbonate and Sodium benzoate, and wherein the composition comprises moisture content is 0.5-1% (w/w) of the total blend.