WO2017098481A1

WO2017098481A1 - Effervescent compositions of metformin and processes for preparation thereof

Info

Publication number: WO2017098481A1
Application number: PCT/IB2016/057530
Authority: WO
Inventors: Indu Bhushan; Vijay KULKARNI; Rakshith SHETTY
Original assignee: Steerlife India Private Limited
Priority date: 2015-12-12
Filing date: 2016-12-12
Publication date: 2017-06-15
Also published as: US20180360737A1; US11219594B2

Abstract

The present invention relates to effervescent compositions of Metformin and optionally other anti-diabetic agents and processes for preparation thereof. More particularly provides an effervescent composition comprising Metformin, an acid and a base such that the composition is free of affirmatively added binders and granulating solvents. The effervescent composition of the present invention has retained carbon dioxide content of at least 90% of the input blend.

Description

EFFERVESCENT COMPOSITIONS OF METFORMIN AND PROCESSES FOR PREPARATION THEREOF

FIELD OF THE INVENTION

The present invention relates to effervescent compositions of Metformin and fixed dose combinations thereof.

BACKGROUND OF THE INVENTION

Approximately an estimated 387 million people worldwide have Type 1 or Type-2 diabetes. Type-2 diabetes is the most common type, accounting for an estimated 90 to 95 percent of all diagnosed adult diabetes cases in the United States.

Metformin in an immediate release form is approved in the USA as Glucophage^® and in the extended release form as Glucophage XR ^® and Glumetza^®. However, treatment with Metformin compositions presents some challenges. Firstly, in the presence of normal renal function, there are no differences between single- or multiple-dose pharmacokinetics of Metformin between patients with Type-2 diabetes and normal subjects, nor is there any accumulation of Metformin in either group at usual clinical doses. However, limited data from controlled pharmacokinetic studies of GLUCOPHAGE in healthy elderly subjects suggested that total plasma clearance of Metformin is decreased, the half-life is prolonged, and Cmax is increased, compared to healthy young subjects. From these data, it appears that the change in Metformin pharmacokinetics with aging is primarily accounted for by a change in their renal function. Thus a reduction in dose is necessary for such cases where the renal function is decreased. Secondly, a population of patients suffering from Type-2 diabetes is elderly people, pediatric patients and people with dysphagia. Due to the high dose (500-1000 mg) of Metformin available in the form of tablets having a size of 19mm x 10.5mm; oral administration of Metformin is difficult in these patients. A suitable alternative for such patients is administration of Metformin in the form of a solution. A solution of Metformin is approved as Riomet^®. But such a solution or liquid dosage form has its own disadvantages like, larger bulk of the dosage form and faster loss of potency as compared to solid dosage forms. Moreover, Metformin is a bitter drug and has side effects like abdominal or stomach discomfort. Therefore, there is a necessity to administer Metformin as a taste-masked or tasteless composition with excipients that could act as a buffer and are capable of mediating the pH of a patient's stomach from 15 to 30 minutes up to about 1 hour

Fourthly, it is desirable to provide a Metformin containing composition having low mineral content, particularly that of sodium and potassium. Excess potassium intake can cause dangerous heartbeat irregularities and even sudden death in patients with Type-2 diabetes having a co-morbid cardiovascular disease or in diabetic patients at risk of developing a cardiovascular disease; while a sodium-restricted diet has long been a first line of intervention for people with hypertension and is particularly important in those with Type-2 diabetes. Finally, besides having a high dose, Metformin is hygroscopic and has poor compactibility. Binders are known to improve the flowability and compactability of Metformin granulates. However, binders also increase the disintegration time of solid dosage forms. A Metformin composition free of an affirmatively added binder which would rapidly disintegrate is thus preferred, but would be highly challenging to develop. Studies have shown that many patients with Type-2 diabetes do not achieve optimal glycemic control, and progression of diabetes over time requires more than one pharmacotherapy to achieve the glycemic goal. Following are the approved fixed-dose combinations in USA containing Metformin: Avandamet®, Glucovance®, Actoplus Met®, Metaglip®, Prandimet®, Janumet®, Invokamet®, Jentadueto®, Kazano®, Synjardy®, Kombiglyze® XR, Actoplus Met® XR, Fortamet®, Xigduo® XR, Janumet® XR.

Most of these approved compositions are available only with a Metformin content of 500 mg and 1000 mg and therefore present the same challenges enumerated above for Metformin. Therefore, there is also a need in the art to provide compositions of Metformin alone and in combination with other antidiabetic agents which can overcome the challenges associated with Metformin therapy. At the same time, these compositions should be able to be manufactured easily by a cost-effective process. It is preferable that such a manufacturing process be continuous and result into compositions which maintain their integrity over their shelf life.

It has now been surprisingly found that effervescent compositions of the present invention can overcome the aforementioned challenges of anti-diabetic therapy with Metformin and its combinations.

SUMMARY OF THE INVENTION

According to an aspect of the present invention there is provided an effervescent composition comprising Metformin, an acid, a base and optionally, one or more anti- diabetic agents or one or more pharmaceutically acceptable excipients, wherein the composition has a retained carbon dioxide content of at least 90% of the input blend.

According to another aspect of the present invention there is provided a process of preparing effervescent composition comprising the steps of:

a) Processing an acid and a base through a twin screw processor; or

b) Processing an acid, a base and Metformin or atleast one pharmaceutically acceptable salt thereof, optionally with at least one other anti-diabetic agent through a twin screw processor;

c) Mixing the product of step a) with Metformin or atleast one pharmaceutically acceptable salt thereof, and optionally at least one other anti-diabetic agent, and optionally at least one excipient followed, by compressing into tablets or filling into capsules or sachets; or

d) Compressing the product of step b) into tablets or filling it into capsules or sachets; after optionally mixing with at least one other anti-diabetic agent or at least one excipient;

wherein only a portion of acid is melted in Step (a) or Step (b) to serve as an in-situ granulating agent and the said process being free of affirmatively added binders and granulating solvents.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides effervescent compositions comprising Metformin and optionally atleast one other anti-diabetic agent that quickly dissolve on addition to water to give a sparkling solution with good taste which masks the bitter taste of Metformin and enables administration to children, elderly patients and patients with dysphagia. Being buffered solutions, these compositions also overcome the side effects of abdominal or stomach discomfort associated with Metformin therapy. These effervescent compositions are prepared by a novel process, which results in maximum retention of carbon dioxide after processing.

The effervescent compositions can be provided in unit dosage forms, which are easy to carry, stable over their shelf-life and are also suitable for tailoring of dosing regimen of a patient in need thereof. The present invention is capable of offering a variety of fixed dose combinations of Metformin with the actives of the aforementioned marketed preparations, in the form of effervescent compositions. The Metformin combinations of the present invention are capable of delivering Metformin from 250 mg to 1000 mg to the Type-2 diabetes patients and can be also used by physicians to tailor individualized treatment regimens for Type-2 diabetes patients.

In an aspect of the present invention, there is provided an effervescent composition comprising Metformin from 1 to 100% by weight; preferably 10 to 40% by weight of the composition.

In another aspect of the present invention, there is provided a method for treating Type-2 diabetes, in a patient in need thereof comprising administering to the patient an effervescent Metformin composition. In yet another aspect of the present invention, there is provided use of an effervescent Metformin composition in the treatment of Type-2 diabetes.

In an embodiment, the present invention relates to an effervescent composition comprising Metformin.

In another embodiment, the present invention relates to an effervescent composition comprising Metformin and at least one other anti-diabetic agent. The term "effervescent composition" as used herein refers to any composition which, on contact with water, liberates carbon dioxide and can include, but is not limited to granules, granules filled into sachets, tablets, capsules and the like.

The term "Metformin" as used herein includes Metformin and pharmaceutically acceptable salts, esters or derivatives. Metformin hydrochloride is the preferred salt, which is the reason for describing the invention with reference to Metformin hydrochloride, although it must not be considered to be limited only to the use of Metformin hydrochloride. The term "other anti-diabetic agent" as used herein includes, but is not limited to, sulfonylureas, thiazolidinediones, meglitinides, sodium-glucose co-transporter 2 (SGLT2) inhibitors, alpha-glucosidase inhibitors and DPP-IV inhibitors and pharmaceutically acceptable salts, free base forms, free acid form, esters or derivatives thereof. A few non- limiting examples of these classes of drugs are Rosiglitazone Maleate, Glyburide, Pioglitazone Hydrochloride, Glipizide, Glimepiride, Repaglinide, Sitagliptin Phosphate, Canagliflozin, Linagliptin, Alogliptin Benzoate, Empagliflozin, Saxagliptin Hydrochloride, Vildagliptin, Teneligliptin, Pioglitazone Hydrochloride and Dapagliflozin Propanediol or their derivatives or alternative salts thereof. The term "input blend" or "pre mix" as used herein, means the material that is fed into the twin screw processor for processing. It includes an acid, a base, Metformin and/or one or more other anti-diabetic agents, and optionally other excipients. The terms "acid component" and "acid" are used as alternatives to each other. Similarly, the terms "base component" and "base" are used as alternatives to each other, throughout the specification. In an embodiment, the present invention provides an effervescent composition comprising Metformin, an acid and a base, wherein the composition has retained carbon dioxide content of at least 90% of the input blend.

In an embodiment, the present invention provides an effervescent composition comprising Metformin, at least one other anti-diabetic agent, an acid and a base, wherein the composition has retained carbon dioxide content of at least 90% of the input blend.

The retained carbon dioxide content (%) is a measure of the quality of effervescence that would be exhibited by the effervescent composition. It is a relative measurement of the amount of C(¾ in the finished product compared to the amount of C(¾ present in the input blend. Accordingly, 90% retention of carbon dioxide by the composition means that there has been only a 10% loss of carbon dioxide during the process for preparation of the composition. It suggests that the composition will exhibit a stronger effervescence as compared to a composition with 50% carbon dioxide retention. Measurement of C(¾ retention is more elaborately explained in the examples.

The effervescent compositions of the present invention essentially comprise an acid and a base. In accordance with an embodiment, the acid can be selected from one or more of organic acids in the form of free acid, acid anhydride or its salt form. Specifically, the acid can be selected from but not limited to citric acid, tartaric acid, fumaric acid, malic acid, adipic acid, succinic acid, lactic acid, glycolic acid, alpha hydroxy acid, ascorbic acid, amino acid. For example, in some embodiments, the acid is citric acid.

In accordance with an embodiment of the present invention, the base is a carbon dioxide precursor and can be selected from but not limited to one or more of carbonate -containing compounds, such as carbonate, sesquicarbonate or bicarbonate salts of potassium, lithium, sodium, calcium, or ammonium; L-lysine carbonate; arginine carbonate; sodium glycine carbonate; or sodium amino acid carbonate. Mixtures of one or more bases can also be used. For example, in some embodiments, the base is a mixture of sodium carbonate and sodium bicarbonate or a mixture of sodium carbonate and potassium bicarbonate or a mixture of potassium bicarbonate and potassium carbonate or a mixture of sodium bicarbonate and potassium carbonate.

In accordance with an exemplary embodiment, an anhydrous form of the acid is used. In accordance with an exemplary embodiment, an anhydrous form of the base is used. In yet another embodiment, both an anhydrous acid and an anhydrous base can be used.

The amount of the acid and the base in the effervescent compositions can vary depending on the acid and the base used. The acid and base can be present in a molar ratio ranging from 3: 1 to 1 :5, preferably from 1 :2.5 to 1 :3.5. In exemplary embodiments, the weight ratio of the acid and the base can be selected from 1 : 1.1 - 1 : 1.53. Sodium and / or potassium levels are therefore kept well within the total daily intake recommended for such minerals.

One or more excipients can optionally be included in the effervescent compositions either intragranularly or extragranularly or as a combination. Suitable excipients are selected from a group including, but not limited to, fillers, disintegrants, surfactants, taste modifiers, soluble and insoluble lubricants, flavoring substances, coloring agents, sweeteners or combinations thereof.

Suitable fillers include, but are not limited to, starch, mannitol, sorbitol, lactose, microcrystalline cellulose and combinations or co-agglomerates thereof. The amount of the filler in the composition can be from about 1-30 % w/w, preferably about 2-20% w/w of the composition.

Suitable disintegrants include, but are not limited to, natural, modified or pregelatinized starch, crospovidone, croscarmellose sodium, sodium starch glycolate, low-substituted hydroxypropyl cellulose, crospovidone, calcium silicate and starch or mixtures thereof. The amount of the disintegrant in the composition can be from about 2-10% w/w, preferably 2-7% w/w of the composition.

Suitable surfactants include, but are not limited to, sodium docusate, polyoxyethylene sorbitan fatty acid ester, sodium lauryl sulfate, sorbic acid, sorbitan fatty acid ester, and mixtures thereof. The amount of the surfactant in the composition can be from about 1- 10% w/w, preferably 1-5% w/w of the composition.

Suitable taste modifiers include, but are not limited to, ion exchange resins which are either strong or weak cation or anion exchangers which form a resin complex with the drug, oils, surfactants, polyalcohols, lipids, lecithins, salts of metals (such as sodium chloride, sodium acetate, sodium gluconate), amino acids such as glycine, taurine, alanine, adsorbents (such as magnesium aluminium silicate, zeolite^®, silica, clay). The compositions may also include salivating agents including, but not limited to, micronized polyethylene glycol, sodium chloride or precipitated micronized silica. The amount of the taste modifier in the composition can be from about 1-10% w/w, preferably 1-5% w/w of the composition.

Suitable sweeteners include, but are not limited to acesulfame potassium, aspartame, saccharin, sucralose, neotame, advantame, sucrose and combinations thereof. The amount of the sweetener in the composition can be from about 0.25-10% w/w, preferably 0.25-5% w/w of the composition.

Suitable soluble lubricants include, but are not limited to, polyethylene glycols (PEG), for example- PEG 4000, PEG 6000 and PEG 8000, polyoxyethylene stearate and sodium or magnesium lauryl sulphate, sodium benzoate, potassium sorbate, L-leucine and the like and combinations thereof. Insoluble lubricants can include, but are not limited to, magnesium stearate, stearic acid, glyceryl palmitostearate, sodium stearyl fumarate and the like and combinations thereof. The amount of the lubricant in the composition can be from 0.1% to 5% w/w, preferably from 1.5% to 4.5% w/w of the composition.

Suitable flavoring substances include, but are not limited to, natural flavors such as natural oils, extracts from plants, leaves, flowers, fruits and so forth and artificial flavors such as synthetic flavor oils and flavoring aromatics and so forth and combinations thereof. These may include but are not limited to cinnamon oil, oil of wintergreen, peppermint oil, clove oil, bay oil, anise oil, eucalyptus, thyme oil, cedar leaf oil, oil of nutmeg, oil of sage, oil of bitter almonds, cassia oil and the like. Also useful as flavors are vanilla, citrus oil, including lemon, orange, grape, lime and grapefruit, and fruit essences, including apple pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot and so forth. Flavors which have been found to be particularly useful include but are not limited to commercially available orange, lemon, grape, cherry and bubble gum flavors and mixtures thereof. The amount of flavoring may depend on a number of factors, including the organoleptic effect desired. The amount of the flavoring substance in the composition can be from about 0.01% to 10% w/w, preferably from 0.01% to 5% w/w of the composition.

Useful coloring agents include but are not limited to food, drug and cosmetic (FD&C) colors, for example- dyes, pigments, lakes, natural colorants and derived colorants. Useful lakes include dyes adsorbed on aluminum hydroxide and other suitable carriers. Examples of suitable colors include FD&C Red No. 3, FD&C Red No. 40, FD&C Blue No. 1, FD&C Blue No. 2, FD&C Yellow No. 5, FD&C Yellow No. 6, FD&C Green No. 3 and combinations thereof. The amount of coloring agent depends on the aesthetic appearance desired and is well known to those skilled in the art.

In an embodiment, the present invention provides a taste-masked effervescent composition comprising Metformin, at least one sweetener or flavor, an acid, a base and optionally, at least one other anti-diabetic agent; wherein the composition has retained carbon dioxide content of at least 90% of the input blend.

In an embodiment, the present invention provides a taste-masked effervescent composition comprising Metformin, optionally, at least one other anti-diabetic agent, an acid and a base, wherein the composition has retained carbon dioxide content of at least 90% of the input blend and is stable over its shelf life.

In an embodiment, the present invention provides an effervescent Metformin composition comprising:

i. Metformin or at least one pharmaceutically acceptable salt thereof;

ii. An anhydrous acid component comprising a combination of a portion of the acid that has been melted and a portion of the acid that has not been melted;

iii. An anhydrous base component comprising a carbonate functional group, wherein the base component is capable of reacting with the acid component to form carbon dioxide; and

iv. Optionally at least one other anti-diabetic agent;

Wherein the anhydrous acid component and the anhydrous base component are present in a weight ratio ranging from 3: 1 to 1 :5 and the composition is free of affirmatively added binders and granulating solvents.

In an embodiment, the present invention provides an effervescent composition comprising Metformin, an acid and a base, wherein the composition has retained carbon dioxide content of at least 90% of the input blend, and wherein the process for preparation of the composition involves the use of a twin screw processor.

In an embodiment, the present invention provides an effervescent composition comprising Metformin, at least one other anti-diabetic agent, an acid and a base, wherein the composition has retained carbon dioxide content of at least 90% of the input blend, and wherein the process for preparation of the composition involves the use of a twin screw processor. The co-rotating twin-screw processor has two co-rotating screws inside a processor barrel. These screws are open length wise, and closed cross wise. The co-rotating twin screw processor has a modular design for barrels and screws. Segmented screws convey and shear the materials in channels bounded by screw flights and barrel walls, with short mass transfer distances. Each individual screw section is designed to perform specific functions such as conveying, mixing, shearing, or pressure building, thus allowing precise control of conditions along the screw length. The screw elements differ in pitch, pitch direction, length, and angle of offset. Pitch, length, and location of such screw elements on the shaft define a screw profile that influences the product characteristics. Due to variable screw configuration, twin screw processor provides greater flexibility of operations to control characteristics of product by monitoring and regulating residence time, product temperature, pressure, and shear. The processing aspects and parameters related to processing of granulating blend in a twin screw processor are elaborately explained in the examples. Also, the co-pending Indian patent application 4527/CHE/2014 which discloses methods and systems for processing granulation blend in a twin screw processor is incorporated herein by reference. In the twin screw processor, there is melting of only a portion of the acid. This leads to formation of solid bridges with particles of co-processed materials. These bridges lead to binding of the particles, in close proximity, to form deformable, irregular shaped, porous granules that have improved compressibility. As little or no reaction takes place between the acid and the base during processing in the twin screw processor, negligible or no carbon dioxide is lost during the process. Therefore, the granules retain substantially all of the carbon dioxide content of the input blend that is fed into the twin screw processor. This leads to improved effervescence when exposed to water.

Further, as the acid and base are in close proximity, the granules formed according to the present invention exhibit improved mechanical strength. As would be evident from the examples, the tablets formed from granules exhibit improved hardness. The formation of porous effervescent compositions having porosity at least 50% greater than the porosity of the input blend that is fed into the twin screw processor, using an in-situ granulating agent in the form of a meltable acid, results in avoiding the use of aqueous or nonaqueous solvents or affirmatively added binders. This in-situ granulation process therefore successfully eliminates the requirement of adding moisture for processing of input blend fed into the processor and the temperature of the barrels of the twin screw processor leads to evaporation of the moisture that may be generated during granulation. Therefore, the moisture content of the granules can be as low as below 1%. Granules comprising acid and base are prepared using the twin screw processor and Metformin and optionally, the other anti-diabetic agent are subsequently mixed homogenously with the granules i.e. extragranularly or alternatively, Metformin and optionally the other anti-diabetic agent are processed in the twin screw processor along with the acid and base to incorporate them within the effervescent granules i.e. intragranularly. Another variant of the process is to co-process Metformin and the other anti-diabetic agent, separately with the acid and the base through the twin screw processor to obtain two separate set of granules that is mixed in suitable proportions, to form a blend that is compressed into tablets or filled into capsules or sachets.

In an embodiment, the present invention provides a process for preparation of placebo effervescent granules having compressibility index between 20-30% and retained carbon dioxide content of at least 90% of the input blend comprising the step of granulating a mixture comprising an acid and a base in a twin screw processor, in the absence of aqueous and non-aqueous solvents and an affirmatively added binder to obtain granules.

In an embodiment, the present invention provides a process for preparation of effervescent granules comprising Metformin and optionally at least one other antidiabetic agent; having compressibility index between 20-30% and retained carbon dioxide content of at least 90% of the input blend comprising the step of granulating a mixture comprising an acid, a base, Metformin and optionally at least one other anti-diabetic agent, in a twin screw processor, in the absence of aqueous and non-aqueous solvents and an affirmatively added binder, to obtain granules. In an embodiment, the present invention provides effervescent granules comprising Metformin, an acid and a base and optionally at least one other anti-diabetic agent, wherein the effervescent granules have retained carbon dioxide content of at least 90% of the input blend, and wherein the granules do not contain an affirmatively added binder. In an embodiment, the present invention provides an effervescent composition comprising Metformin, an acid and a base and optionally at least one other anti-diabetic agent, wherein the effervescent composition has retained carbon dioxide content of at least 90% of the input blend, and wherein the composition does not contain an affirmatively added binder.

In an embodiment, the present invention provides effervescent granules comprising Metformin, an acid and a base and optionally at least one other anti-diabetic agent, wherein the effervescent granules have retained carbon dioxide content of at least 90% of the input blend, do not contain an affirmatively added binder and have a porosity at least 50% greater than the porosity of input blend. In an embodiment, the present invention provides a process for preparation of an effervescent Metformin composition comprising the steps of:

a) Processing an acid and a base through a twin screw processor; or

In accordance with an embodiment, the effervescent tablet compositions of the present invention exhibit a disintegration time of less than 3 minutes, preferably less than 60 seconds (sees) in water at room temperature of about 25 °C ± 5 °C. In an embodiment, the present invention provides an effervescent composition comprising Metformin, an acid and a base, wherein the composition has retained carbon dioxide content of at least 90% of the input blend, wherein the composition has a disintegration time of less than 3 minutes in water, and wherein the process for preparation of the composition involves the use of a twin screw processor and does not involve the use of aqueous solvents, non-aqueous solvents and an affirmatively added binder.

In an embodiment, the present invention provides an effervescent composition comprising Metformin, at least one other anti-diabetic agent, an acid and a base, wherein the composition has retained carbon dioxide content of at least 90% of the input blend, wherein the composition has a disintegration time of less than 3 minutes in water at room temperature, and wherein the process for preparation of the composition involves the use of a twin screw processor and does not involve the use of aqueous solvents, non-aqueous solvents and an affirmatively added binder.

Any conventional compression techniques well known to the person skilled in the art may be used to prepare the effervescent tablets of the present invention.

In accordance with an embodiment, the tablet compositions of the present invention have a hardness of at least 2 kp (kilopond). In accordance with an exemplary embodiment, the tablets have a hardness of 2 to 25 kp.

The following brands which include Metformin or Metformin combinations with other anti-diabetic agents are indicated for the treatment of Type-2 diabetes:

Table 1: Brands which include Metformin or Metformin combinations with other anti-diabetic agents

Source of label information (Retrieved from the

Brand Internet: 11/18/2015)

http://www.accessdata.fda.gOv/drugsatfda_docs/label/2

ACTOPLUS MET^® 014/021842s0191bl.pdf

http://www.accessdata.fda.gOv/drugsatfda_docs/label/2

ACTOPLUS MET^® XR 013/022024s0011bl.pdf

http://www.accessdata.fda.gOv/drugsatfda_docs/label/2

AVANDAMET ^® 014/021410s036s037s0381bl.pdf http://www.accessdata.fda.gOv/drugsatfda_docs/label/2

FORTAMET^® 008/021574s0101bl.pdf

GLUCOPHAGE^® and http://www.accessdata.fda.gOv/drugsatfda_docs/label/2 GLUCOPHAGE^® XR 008/020357s031 ,021202s0161bl.pdf

http://www.accessdata.fda.gOv/drugsatfda_docs/label/2

GLUCOVANCE^® 013/021178s0151bl.pdf

http://www.accessdata.fda.gOv/drugsatfda_docs/label/2

GLUMETZA^® 011/021748s0101bl.pdf

http://www.accessdata.fda.gOv/drugsatfda_docs/label/2

INVOKAMET^® 015/204353s0031bl.pdf

http://www.accessdata.fda.gOv/drugsatfda_docs/label/2

JANUMET^® 015/022044s0351bl.pdf

http://www.accessdata.fda.gOv/drugsatfda_docs/label/2

JANUMET^® XR 015/202270s0101bl.pdf

http://www.accessdata.fda.gOv/drugsatfda_docs/label/2

JENTADUETO^® 015/201281s0101bl.pdf

http://www.accessdata.fda.gOv/drugsatfda_docs/label/2

KAZANO ^® 015/203414s0051bl.pdf

http://www.accessdata.fda.gOv/drugsatfda_docs/label/2

KOMB IGLYZE^® XR 015/200678 sO 161bledt.pdf

http://www.accessdata.fda.gOv/drugsatfda_docs/label/2

METAGLIP^® 013/021460s0101bl.pdf

http://www.accessdata.fda.gOv/drugsatfda_docs/label/2

PRANDIMET^® 012/022386s0001bl.pdf

http://www.accessdata.fda.gOv/drugsatfda_docs/label/2

RIOMET^® 014/021591s0081bl.pdf

http://www.accessdata.fda.gOv/drugsatfda_docs/label/2

SYNJARDY^® 015/206 llllbl.pdf

http://www.accessdata.fda.gOv/drugsatfda_docs/label/2

XIGDUO^® XR 014/205649s0001bl.pdf

The information from labels available on the URLs mentioned in the table 1 above, in particular, information such as, dosage regimen and indications, is incorporated herein, by reference.

As per present invention, any of the above embodiments can be used in the treatment of Type-2 diabetes mellitus.

In an embodiment, the present invention provides a method for treating Type-2 diabetes, in a patient in need thereof comprising administering to the patient an effervescent composition, as per any of the embodiments mentioned above.

In another embodiment, the present invention provides use of an effervescent composition, as per any of the embodiments mentioned above, in the treatment of Type-2 diabetes.

The present invention is exemplified by the following non-limiting examples. EXAMPLES

Described herein are exemplary processes for determining the moisture content (also referred to as Loss on Drying or LOD), retained CO₂ content, compressibility, hardness, bulk density and tap density of the compositions formed in accordance with embodiments of the present disclosure.

Determination of Moisture Content (LOD): The input blend or pre mix fed into the twin screw processor, and the granules were analyzed by an infrared moisture balance analyzer, Sartorius MA150, at 75°C for 5 minutes. Loss in weight was recorded as percent (%) moisture content with respect to their initial weight.

Determination of Retained CO₂ Content: 5.0 g of input blend or pre mix fed into the twin screw processor, or granules or 5 tablets were added into separate 100 ml 2N sulfuric acid solutions. The loss in weight of the input blend or granules or tablets due to liberation of C(¾ as a result of the reaction between sulfuric acid and bicarbonate or carbonate present in the input blend or granules or the tablets was recorded as observed weight of carbon dioxide. The difference between the weight of the input blend and granules after reaction and the initial weight of input blend and granules respectively was also calculated to measure the retained C(¾ content (g) in the blend or granules or the tablet. The percent (%) retained C(¾ content in the granules or the tablet was then calculated using the formula below:

Retained C(¾ content (%) = (Observed Weight (g) of C(¾ in granules or tablets x 100) / Observed Weight (g) of C(¾ in input blend

Determination of Hardness and Thickness of the Tablet: The hardness was calculated as the average of the hardness measured using Inweka TBH 125 hardness tester (Germany) for each of five tablets (number of units tested, n=5). The thickness was calculated as the average of the thickness measured using vernier callipers for each of 5 tablets (number of units tested, n =5).

Measurement of Bulk and Tap Density: A known amount (m) of the input blend and the granules were added into two separate dry graduated 100 ml cylinders. The contents of the two cylinders were leveled without compacting; and the unsettled apparent bulk volume (Vo) to the nearest graduated unit was read.

The bulk density (g/ml) was calculated using formula:

Bulk Density = Mass (m) / Bulk Volume (V₀)

To calculate the tap density, the contents of the two cylinders were tapped mechanically up to a maximum of 1250 taps and the apparent tapped volume (V_t ) to the nearest graduated unit was read. The tap density was calculated using formula: Tap Density = Mass (m) / Tapped Volume (V_t)

Measurement of porosity: Porosity was measured in terms of percentage relative bulk porosity and percentage relative tap porosity.

Percentage relative bulk porosity can be calculated considering 1 g specific (Sp) volume using formula:

% Relative Bulk Porosity = ((Bulk Sp. volume of 1 g granule - Bulk Sp.volume of 1 g input blend) X 100)/ Bulk Sp. volume of 1 g input blend

Where, Bulk Sp. volume of 1 g granule = 1 / Bulk density of granules; and

Bulk Sp. volume of 1 g input blend = 1 / Bulk density of input blend

Percentage relative tap porosity was calculated considering 1 g specific (Sp) volume using formula:

% Relative Tap Porosity = ((Tap Sp. volume of 1 g granule - Tap Sp. volume of 1 g input blend) X 100)) / Tap Sp. volume of 1 g input blend

Where, Tap Sp. volume of 1 g granule = 1 / Tap density of granules Tap Sp. volume of 1 g input blend = 1 / Tap density of input blend

Measurement of Compressibility: Compressibility was measured in terms of Hausner ratio and Compressibility Index, as provided in Hausner, H.H., Int. J. Powd. Metall, Vol 3, pg 7, 1967 and Carr, R.L.,Chem. Eng.,Vol 72,, Issue 1, pg 163 and Issue 2, pg 69, 1965, respectively. Both the citations are incorporated herein by reference.

The invention is further illustrated by the following examples which are provided to exemplify the invention, and do not limit the scope of the invention. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art, and are intended to be included within the scope of the present invention.

Example 1: Metformin hydrochloride effervescent granules

Table 2- Quantitative composition of Metformin hydrochloride effervescent granules

Manufacturing process:

Metformin hydrochloride was dried at 45 °C for 1 hour and passed through #60 mesh. Citric acid anhydrous, sodium bicarbonate and sodium carbonate were deagglomerated and dried at 45 °C for 3 hours and then weighed accurately as per the formula. Metformin hydrochloride, citric acid anhydrous, sodium bicarbonate and sodium carbonate were blended and immediately processed in a co-rotating twin screw processor (Machine: Omega 20, LVD: 30) at processing area relative humidity (RH) of 20 % ± 5%RH and at a processing area temperature of 30°C ± 2°C. The process was performed at screw speed of 600 rpm and feed rate of 186 g/min. Table 3- Screw configuration for Example 1

List of Abbreviations for Elements

RSE Right Handed Screw Element

RFV Regular Flight Shovel Element

RFN Regular Flight Shovel Element to Normal

NRF Normal to RFV (transition element)

Table 4- Barrel temperature profile (°C) for Example 1

Table 5- Parameters for pre mix and granules of Example 1

Note: Retained Carbon dioxide content (%) of granules is reported m comparison to pre mix.

Table 6- Quantitative compositions of Metformin for Examples 2-4

Ingredients Ex 2 Ex 3 Ex 4

Metformin HCL Metformin HCL Metformin HCL

500 mg 500 mg + 500 mg +

Sitagliptin 50mg Saxagliptin 5mg

% w/w mg tablet % mg/tablet % w/w mg/tablet w/w

Metformin HCL 97.42 4000 95.96 4000 97.27 4000 granules

Sitagliptin Phosphate 1.5 62.53

Saxagliptin HCL 0.15 6.14 monohydrate

Strawberry flavour 0.05 2 0.05 2 0.05 2 Sucralose 0.58 24 0.57 24 0.58 24

Sodium benzoate 1.95 80 1.92 80 1.94 80

Total 100 4106 100 4168 100 4112

Example 2: Metformin hydrochloride 500 mg tablet

Manufacturing process:

Metformin hydrochloride granules (as per Example 1) were passed through #16 mesh sieve, mixed with sucralose and strawberry flavour that were passed through #60 mesh sieve, and then finally lubricated with sodium benzoate passed through #100 mesh sieve. This mixture was compressed using a rotary tablet compression machine (Machine: Riddi Pharma rotary press) using 25 mm round flat face beveled edge tooling. Example 3: Effervescent tablets of Metformin hydrochloride 500 mg and Sitagliptin 50 mg

Manufacturing process:

Metformin hydrochloride granules (as per Example 1), were passed through #16 mesh sieve, mixed with Sitagliptin phosphate, sucralose and strawberry flavour that were all passed through #60 mesh sieve, and then finally lubricated with sodium benzoate passed through #100 mesh sieve. This mixture was compressed using a rotary tablet compression machine (Machine: Riddi Pharma rotary press) using 25 mm round flat face beveled edge tooling. Example 4: Effervescent tablets of Metformin hydrochloride 500 mg and Saxagliptin 5 mg

Manufacturing process:

Metformin hydrochloride granules (as per Example 1), were passed through #16 mesh sieve, mixed with Saxagliptin hydrochloride monohydrate, sucralose and strawberry flavour that were all passed through #60 mesh sieve, and then finally lubricated with sodium benzoate passed through #100 mesh sieve. This mixture was compressed using a rotary tablet compression machine (Machine: Riddi Pharma rotary press) using 25 mm round flat face beveled edge tooling. Example 5: Metformin hydrochloride 500 mg and Sitagliptin 50 mg granules:

Table 7- Quantitative compositions of Metformin for Examples 5-6

Manufacturing process:

Metformin hydrochloride and Sitagliptin phosphate were dried at 45 °C for 1 hour and passed through #60 mesh sieve and weighed accurately as per the formula. Citric acid anhydrous, sodium bicarbonate and sodium carbonate were deagglomerated and dried at 45 °C for 3 hours and then weighed accurately as per the formula. Metformin hydrochloride, Sitagliptin phosphate, citric acid anhydrous, sodium bicarbonate and sodium carbonate were blended and immediately processed in a co-rotating twin screw processor (Machine: Omega 20, L/D: 30) at processing area relative humidity of 20 % ± 5%RH and temperature of 30°C ± 2°C. The process was performed at screw speed of 600 rpm and feed rate of 347.46 g/min.

Table 8- Screw configuration for Example 5

Elements RSE NRF RFV RFN RSE RSE RSE RSE

15/15 40/20 40/40 40/20 30/15 15/30 15/15 20/20

No's 1 1 4 1 1 8 7 1 Table 9- Barrel temperature profile (°C) for Example 5

Table 10- Parameters for pre mix and granules of Example 5

Note: Retained Carbon dioxide content (%) of granules is reported in comparison to pre mix.

Example 6: Metformin hydrochloride 500 mg and Sitagliptin 50 mg tablets

Manufacturing process:

Metformin Hydrochloride & Sitagliptin effervescent granules (as per Example 5), were passed through #16 mesh sieve, mixed with sucralose and strawberry flavour that were passed through #60 mesh sieve, and then finally lubricated with sodium benzoate passed through #100 mesh sieve. This mixture was compressed using a rotary tablet compression machine (Machine: Riddi Pharma rotary press) using 25 mm round flat face beveled edge tooling.

Example 7: Placebo effervescent granules using potassium bicarbonate

Table 11- Quantitative composition of placebo potassium bicarbonate granules

Manufacturing process:

Citric acid anhydrous and potassium bicarbonate were deagglomerated and dried individually at 45 °C for 3 hours and then weighed accurately as per the formula. Citric acid anhydrous and potassium bicarbonate were blended and immediately processed in a co-rotating twin screw processor (Machine: Omega 20, L/D: 30)

at a screw speed of 600 rpm and a feed rate of 228 g/min at processing area relative humidity of 20 % ± 5%RH and processing area temperature of 30°C ± 2°C.

Table 12- Screw configuration for Example 7

Table 13- Barrel temperature profile (°C) for Example 7

Table 14- Parameters for pre mix and granules of Example 7

Note: Retained Carbon dioxide content (%) of granules is reported in comparison to the pre mix.

Table 15- Quantitative compositions of Metformin for Examples 8-10

Ingredients Ex 8 Ex 9 Ex 10

Metformin HCL Metformin HCL Metformin HCL

500 mg 500 mg + 500 mg +

Sitagliptin 50mg Saxagliptin 5mg

% w/w mg/tablet % w/w mg/tablet % w/w mg/tablet

Metformin HCL 12.55 502.01 12.55 502.01 12.55 502.01

Sitagliptin Phosphate 1.56 62.53 - -

Saxagliptin HCL - - - - 0.15 6.14 monohydrate

Placebo potassium 84.79 3391.99 83.23 3329.46 84.65 3385.85 bicarbonate granules

Strawberry flavour 0.05 2 0.05 2 0.05 2

Acesulfame 0.6 24 0.6 24 0.6 24 potassium

Sodium benzoate 2 80 2 80 2 80

Total 100 4000 100 4000 100 4000

Example 8: Metformin hydrochloride 500 mg tablets

Manufacturing process:

Placebo potassium bicarbonate effervescent granules (as per Example 7), were passed through #20 mesh sieve and mixed with Metformin hydrochloride, acesulfame potassium and strawberry flavor that were all passed through #60 mesh sieve, and sodium benzoate (passed through #100 mesh sieve). This mixture was compressed using a rotary tablet compression machine (Machine: Riddi Pharma rotary press) using 25 mm round flat face beveled edge tooling.

Example 9: Metformin hydrochloride 500 mg and Sitagliptin 50 mg tablets:

Manufacturing process:

Placebo potassium bicarbonate effervescent granules (as per Example 7), were passed through #20 mesh sieve and mixed with Metformin hydrochloride, Sitagliptin phosphate, acesulfame potassium and strawberry flavor that were all passed through #60 mesh sieve, and sodium benzoate (passed through #100 mesh sieve). This mixture was compressed using a rotary tablet compression machine (Machine: Riddi Pharma rotary press) using 25 mm round flat face beveled edge tooling. Example 10: Metformin hydrochloride 500 mg and Saxagliptin 5 mg tablets:

Manufacturing process:

Placebo potassium bicarbonate effervescent granules (as per Example 7), were passed through #20 mesh sieve and mixed with Metformin hydrochloride, Saxagliptin hydrochloride monohydrate, acesulfame potassium and strawberry flavor that were all passed through #60 mesh sieve, and sodium benzoate (passed through #100 mesh sieve). This mixture was compressed using a rotary tablet compression machine (Machine: Riddi Pharma rotary press) using 25 mm round flat face beveled edge tooling.

Example 11: Placebo sodium bicarbonate effervescent granules

Table 16- Quantitative composition of placebo sodium bicarbonate effervescent granules

Manufacturing process:

Citric acid anhydrous, sodium bicarbonate and sodium carbonate were deagglomerated and dried individually at 45 °C for 3 hours, and were blended and immediately processed in a co-rotating twin screw processor (Machine: Omega 20, L/D: 30) at a screw speed of 600 rpm and a feed rate of 300 g/min at processing area relative humidity of 20 % ± 5%RH % and temperature of 30°C ± 2°C.

Table 17- Screw configuration for Example 11

Table 18- Barrel temperature profile (°C) for Example 11

Table 19- Parameters for pre mix and granules of Example 11

Parameters Pre mix Granules

Loss on drying (%) (75 °C for 5 minutes) 0.15

Retained Carbon dioxide content (%) 97.90

Bulk density (g/cc) 0.976 0.698

Tapped density (g/cc) 1.460 0.953

Compressibility index (%) 33.33 26.76 Hausner's ratio 1.50 1.36

Median diameter (microns) 280 330

Note: Retained Carbon dioxide content (%) of granules is reported in comparison to the pre mix

Table 20- Quantitative compositions of Metformin for Examples 12-14

Example 12: Metformin hydrochloride 500 mg tablets

Manufacturing process:

Placebo sodium bicarbonate effervescent granules (as per Example 11), were passed through #20 mesh sieve and mixed with Metformin hydrochloride, acesulfame potassium and strawberry flavor that were all passed through #60 mesh sieve and sodium benzoate (passed through #100 mesh sieve). This mixture was compressed using a rotary tablet compression machine (Machine: Riddi Pharma rotary press) using 25 mm round flat face beveled edge tooling. Example 13: Metformin hydrochloride 500 mg and Sitagliptin 50 mg tablets

Manufacturing process:

Placebo sodium bicarbonate effervescent granules (as per Example 11), were passed through #20 mesh sieve and mixed with Metformin Hydrochloride, Sitagliptin phosphate, acesulfame potassium and strawberry flavor that were all passed through #60 mesh sieve, and sodium benzoate (passed through #100 mesh sieve). This mixture was compressed using a rotary tablet compression machine (Machine: Riddi Pharma rotary press) using 25 mm round flat face beveled edge tooling.

Example 14: Metformin hydrochloride 500 mg and Saxagliptin 5 mg tablets

Manufacturing process:

Placebo sodium bicarbonate effervescent granules (as per Example 11), were passed through #20 mesh sieve and mixed with Metformin Hydrochloride, Saxagliptin Hydrochloride monohydrate, acesulfame potassium and strawberry flavor that were all passed through #60 mesh sieve, and sodium benzoate (passed through #100 mesh sieve). This mixture was compressed using a rotary tablet compression machine (Machine: Riddi Pharma rotary press) using 25 mm round flat face beveled edge tooling.

Table 21- Quantitative compositions of Metformin for Examples 15-17

Example 15: Metformin hydrochloride 500 mg Tablets

Manufacturing process:

Placebo sodium bicarbonate effervescent granules (as per Example 11) and placebo potassium bicarbonate effervescent granules (as per Example 7), were passed through #20 mesh sieve and mixed with Metformin Hydrochloride, acesulfame potassium and strawberry flavor that were all passed through #60 mesh sieve, and sodium benzoate (passed through #100 mesh sieve). This mixture was compressed using a rotary tablet compression machine (Machine: Riddi Pharma rotary press) using 25 mm round flat face beveled edge tooling.

Example 16: Metformin hydrochloride 500 mg and Sitagliptin 50 mg tablets

Manufacturing process:

Placebo sodium bicarbonate effervescent granules (as per Example 11) and placebo potassium bicarbonate effervescent granules (as per Example 7), were passed through #20 mesh sieve and mixed with Metformin Hydrochloride, Sitagliptin phosphate, acesulfame potassium and strawberry flavor that were all passed through #60 mesh sieve, and sodium benzoate (passed through #100 mesh sieve). This mixture was compressed using a rotary tablet compression machine (Machine: Riddi Pharma rotary press) using 25 mm round flat face beveled edge tooling.

Example 17: Metformin hydrochloride 500 mg and Saxagliptin 5 mg tablets

Manufacturing process:

Placebo sodium bicarbonate effervescent granules (as per Example 11) and placebo potassium bicarbonate effervescent granules (as per Example 7) were passed through #20 mesh sieve and mixed with Metformin Hydrochloride, Saxagliptin hydrochloride monohydrate, acesulfame potassium and strawberry flavor that were passed through #60 mesh sieve, and sodium benzoate (passed through #100 mesh sieve). This mixture was compressed using a rotary tablet compression machine (Machine: Riddi Pharma rotary press) using 25 mm round flat face beveled edge tooling.

Below are the tablet parameters of the examples mentioned herein.

Table 22- Tablet parameters for examples mentioned herein

Tablet Ex Ex Ex Ex Ex Ex

Ex 2 Ex 3 Ex 4 Ex 6 Ex 8 Ex 9 Ex 17 parameters 10 12 13 14 15 16

Table 23- Quantitative compositions of Metformin for Examples 18-19

Example 18: Metformin hydrochloride 250 mg & Sitagliptin 50 mg tablets

Manufacturing process:

Metformin hydrochloride effervescent granules (as per Example 1) were passed through #16 mesh sieve and mixed with sitagliptin phosphate, sucralose, strawberry flavor which were all passed through #60 mesh sieve, and sodium benzoate which was passed through #100 mesh sieve. This mixture was compressed using a rotary tablet compression machine (Machine: Riddi Pharma rotary press) using 20 mm round flat face beveled edge tooling. Example 19: Metformin hydrochloride 1000 mg & Sitagliptin 50 mg tablets

Manufacturing process:

Placebo sodium bicarbonate effervescent granules (as per Example 11), were passed through #20 mesh sieve and mixed with Metformin hydrochloride, Sitagliptin phosphate, sucralose, strawberry flavor which were all passed through #60 mesh sieve, and sodium benzoate which was passed through #100 mesh sieve. This mixture was compressed using a rotary tablet compression machine (Machine: Riddi Pharma rotary press) using 25 mm round flat face beveled edge tooling.

Table 24- Tablet parameters for examples 18 and 19

Tablet parameters Example 18 Example 19

Average Thickness (mm) (n=5) 4.458 5.954

Average Hardness (kp) (n=5) 26.92 5.7

Average Disintegration time (sees) (n=3) 85 78

Claims

1. An effervescent composition comprising Metformin, an acid, a base and optionally, one or more anti-diabetic agents or one or more pharmaceutically acceptable excipients, wherein the composition has a retained carbon dioxide content of at least 90% of the input blend.

2. The effervescent composition according to claim 1, wherein the composition is free of affirmatively added binders and granulating solvents.

3. The effervescent composition according to claim 1, wherein the process for preparation of the composition involves the use of a twin screw processor.

4. The effervescent composition according to claim 1 wherein the acid is selected from citric acid, tartaric acid, fumaric acid, malic acid, adipic acid, succinic acid, lactic acid, glycolic acid, alpha hydroxy acid, ascorbic acid, amino acid or mixtures thereof.

5. The effervescent composition according to claim 1 wherein the base is selected from carbonate, sesquicarbonate or bicarbonate salts of potassium, lithium, sodium, calcium, or ammonium; L-lysine carbonate; arginine carbonate; sodium glycine carbonate; or sodium amino acid carbonate or mixtures thereof.

6. The effervescent composition according to claim 1 wherein the pharmaceutically acceptable excipient is selected from fillers, disintegrants, surfactants, taste modifiers, soluble or insoluble lubricants, flavoring substances, coloring agents, sweeteners or mixtures thereof.

7. The effervescent composition according to claim 1, wherein the acid and base are present in a weight ratio ranging from 3:1 to 1 :5.

8. The effervescent composition according to claim 1 or 2, wherein the acid and base are anhydrous.

9. The effervescent composition according to claim 1 or 2, wherein the anti-diabetic agent is selected from Rosiglitazone Maleate, Glyburide, Pioglitazone Hydrochloride, Glipizide, Glimepiride, Repaglinide, Sitagliptin Phosphate, Canagliflozin, Linagliptin, Alogliptin Benzoate, Empagliflozin, Saxagliptin Hydrochloride, Vildagliptin, Teneligliptin, Pioglitazone Hydrochloride and Dapagliflozin Propanediol or their derivatives or alternative salts thereof.

10. The effervescent composition according to claim 2, wherein the composition has a disintegration time of less than 3 minutes.

11. The effervescent composition according to claim 2, wherein the composition has a disintegration time of less than 2 minutes.

12. A process for preparation of an effervescent Metformin composition comprising the steps of:

a) Processing an acid and a base through a twin screw processor; or

d) Compressing the product of step b) into tablets or filling it into capsules or sachets; after optionally mixing with at least one other anti-diabetic agent or at least one excipient; wherein only a portion of acid is melted in Step (a) or Step (b) to serve as an in-situ granulating agent and the said process being free of affirmatively added binders and granulating solvents.

13. The process according to claim 12, wherein the acid is selected from citric acid, tartaric acid, fumaric acid, malic acid, adipic acid, succinic acid, lactic acid, glycolic acid, alpha hydroxy acid, ascorbic acid, amino acid or mixtures thereof; and the base is selected from carbonate, sesquicarbonate or bicarbonate salts of potassium, lithium, sodium, calcium, or ammonium; L- lysine carbonate; arginine carbonate; sodium glycine carbonate; or sodium amino acid carbonate or mixtures thereof; and wherein the effervescent Metformin composition has a retained carbon dioxide content of at least 90% of the input blend.

14. A method for treatment of Type-2 diabetes in a patient, comprising administering orally to the patient, the effervescent composition according to any one of the claims 1 toll.

15. The effervescent composition according to any one of the claims 1 to 11, for use in the treatment of Type-2 diabetes.