A nanosuspension composition comprising canagliflozin

Abstract

The present invention relates to a nanosuspension composition comprising a) Canagliflozin or its pharmaceutically acceptable salts, b) hydroxypropyl methylcellulose, c) sodium lauryl sulphate, and d) at least one more surfactant. The said nanosuspension composition has a desirable pharmacokinetic characteristic and better dissolution properties. The invention further relates to a process for the preparation of said nanosuspension composition and use thereof for the preparation of medicament, which is useful in the treatment of type 2 diabetes mellitus.

Description

[0001] A NANOSUSPENSION COMPOSITION COMPRISING CANAGLIFLOZIN

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to a nanosuspension composition comprising a) Canagliflozin or its pharmaceutically acceptable salts, b) hydroxypropyl methylcellulose, c) sodium lauryl sulphate, and d) at least one more surfactant. The said nanosuspension composition has a desirable pharmacokinetic characteristic and better dissolution properties. The invention further relates to a process for the preparation of said nanosuspension composition and use thereof for the preparation of medicament, which is useful in the treatment of type 2 diabetes mellitus.

[0004] BACKGROUND OF THE INVENTION

[0005] Canagliflozin is chemically known as (2S,3R,4R,5S,6R)-2-(3-{[5-(4- fluorophenyl)thiophen-2-yl]methyl}-4-methylphenyl)-6-(hydroxymethyl)oxane-3,4,5-triol, having the following formula (I),

[0006] (I).

[0007] Canagliflozin is an inhibitor of sodium-glucose co-transporter 2 (SGLT2), the transporter responsible for reabsorbing the majority of glucose filtered by the kidney. Sodium-glucose co-transporter 2 (SGLT2), expressed in the proximal renal tubules, is responsible for the majority of the reabsorption of filtered glucose from the tubular lumen. By inhibiting SGLT2, canagliflozin reduces reabsorption of filtered glucose and lowers the renal threshold for glucose (RTG), and thereby increases urinary glucose excretion.

[0008] Canagliflozin is marketed under the brand name of Invokana® as a tablet in 100 mg and 300 mg strengths in Europe since 2013.

[0009] Canagliflozin tablet marketed under the brand name of Invokana® is indicated for the treatment of adults with insufficiently controlled type 2 diabetes mellitus as an adjunct to diet and exercise:

[0010] • as monotherapy when metformin is considered inappropriate due to intolerance or contraindications

[0011] • in addition to other medicinal products for the treatment of diabetes.

[0012] Canagliflozin is also marketed in combination with Metformin in 50 mg / 850 mg, 50 mg / 1000 mg, 150 mg / 850 mg, 150 mg / 1000 mg strengths under the brand name of Vokanamet® in EU since 2014. Vokanamet® is indicated in adults with type 2 diabetes mellitus as an adjunct to diet and exercise:

[0013] • in patients insufficiently controlled on their maximally tolerated doses of metformin alone

[0014] • in combination with other medicinal products for the treatment of diabetes, in patients insufficiently controlled with metformin and these medicinal products

[0015] • in patients already being treated with the combination of canagliflozin and metformin as separate tablets.

[0016] Invokana® contains Canagliflozin hemihydrate as active substance and lactose, microcrystalline cellulose, hydroxypropylcellulose, croscarmellose sodium, magnesium stearate as excipient. The film coating of Invokana® contains poly(vinyl alcohol), titanium dioxide (E171 ), macrogol 3350, talc, iron oxide yellow (E172).

[0017] US 7943788 B2 discloses canagliflozin or salts thereof and the process for its preparation. US 7943582 and US 8513202 discloses crystalline form of 1-(P-D-glucopyranosyl)-4- methyl -3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene hemihydrate and process for preparation thereof. The US’ 582 and US’ 202 further discloses that preparation of the crystalline form of hemi-hydrate Canagliflozin typically involves dissolving in a good solvent (e.g. ketones or esters) crude or amorphous compound prepared in accordance with the procedures described in WO 2005 / 012326 pamphlet and adding water and a poor solvent (e.g. alkanes or ethers) to the resulting solution, followed by filtration.

[0018] CN 103655539 A discloses an oral solid preparation of Canagliflozin, which comprises amorphous Canagliflozin, a filler, a disintegrant and a surfactant, wherein the average particle size of the Canagliflozin is limited to 2.5-30 pm at the same time.

[0019] CN 105769803 A discloses a pharmaceutical composition for treating type 2 diabetes and a preparation method thereof, wherein the composition comprises active ingredient Canagliflozin and pharmaceutic adjuvants such as water-soluble solid dispersion carriers, disintegrants, lubricants and the like.

[0020] CN 107744512 A discloses a Canagliflozin composition, which also aims to solve the problem of low dissolution of Canagliflozin.

[0021] CN 110946840 B discloses Canagliflozin composition comprising the additive comprises at least one of glucomannan and carboxymethyl glucomannan and at least one of glyceryl behenate and ethyl cellulose.

[0022] According to EPAR (European Public Assessment Report) of Canagliflozin (Invokana®) & FDA’s Clinical Pharmacology and Biopharmaceutics Review(s) of Canagliflozin and Metformin (Invokamet®), Canagliflozin is practically insoluble in aqueous media throughout the entire physiologic pH range but soluble in most organic solvents. Solubility of canagliflozin improved in simulated intestinal fluids (FaSSIF, FeSSIF) compared to SIF and SGF; even in these media, the highest solubility observed in FeSSIF could only be defined as “slightly soluble’. Absolute bioavailability of Canagliflozin was approximately 65%, indicative of poor to moderate permeability of the gastrointestinal tract. Caco-2 cell experiments showed that the drug molecule has intermediate permeability. In conclusion, Canagliflozin has low solubility and low permeability i.e. BCS Class IV drug.

[0023] Canagliflozin being class IV drug, various attempts have been made in the art to improve solubility and ultimately its bioavailability. To improve low solubility and low bioavailability of these kind of active ingredients, many approaches are known in the art such as micronization, using of absorption enhancers or cosolvents, using salt of active ingredients, preparation of solid dispersions and micelles, preparation of inclusion complexes using cyclodextrins, liposome, emulsion, microemulsion. Apart from that a different approach like nanosuspension has also become popular in pharmaceutical industry to improve the issue of low solubility of active ingredients.

[0024] Nanosuspensions presents I provides many advantages such as improved solubility, easy scale-up, increased surface area of the particles however, there are critical points while preparing nanosuspension such as being thermodynamically unstable, agglomeration, physical instability, dispersibility etc. have also been taken into the consideration.

[0025] There still exist a need for a nanosuspension composition of Canagliflozin, which having improved solubility and improved bioavailability, being physically and chemically stable and easy to scale up.

[0026] The inventors of the present invention have surprisingly developed a nanosuspension composition comprising Canagliflozin or its pharmaceutically acceptable salts, hydroxypropyl methylcellulose, sodium lauryl sulphate, and at least one more surfactant which has improved solubility with desired physical and chemical stability. The composition of the present invention is not only stable but also exhibits a better dissolution profile when compared to the reference product Invokana® tablet. OBJECT OF THE INVENTION

[0027] An object of the present invention is to provide a nanosuspension composition comprising Canagliflozin or its pharmaceutically acceptable salts having better / superior in-vitro dissolution profile as compared to the reference product i.e. Invokana® tablet.

[0028] Another object of the present invention is to provide a nanosuspension composition comprising Canagliflozin or its pharmaceutically acceptable salts, hydroxypropyl methylcellulose, sodium lauryl sulphate, and at least one more surfactant.

[0029] Yet another object of the present invention is to provide a nanosuspension composition comprising Canagliflozin or its pharmaceutically acceptable salts, hydroxypropyl methylcellulose, sodium lauryl sulphate, polyethylene sorbitan monooleate and poloxamer.

[0030] Yet another object of the present invention is to provide a nanosuspension composition of Canagliflozin, which is redispersible.

[0031] Yet another object of the present invention is to provide a nanosuspension composition of Canagliflozin, which remains physical and chemical stable.

[0032] Yet another object of the present invention is to provide a nanosuspension composition of Canagliflozin, which overcomes the problems of the prior art.

[0033] Yet another object of the present invention is to provide a nanosuspension composition as mentioned herein above is useful in the treatment of type 2 diabetes mellitus.

[0034] Yet another object of the present invention is to provide a pharmaceutical composition comprising a nanosuspension composition of Canagliflozin and one or more additional therapeutic agent. SUMMARY OF THE INVENTION

[0035] In one aspect, the present invention provides a nanosuspension composition comprising: a) Canagliflozin or its pharmaceutically acceptable salts, b) Hydroxypropyl methylcellulose, c) Sodium lauryl sulphate, and d) at least one more surfactant.

[0036] In another aspect, the present invention provides a nanosuspension composition comprising: a) Canagliflozin or its pharmaceutically acceptable salts, b) Hydroxypropyl methylcellulose, c) Sodium lauryl sulphate, and d) at least one more surfactant wherein Canagliflozin is present in amount of about from 60 % to 80 % (w / w) with respect to the total weight of the nanosuspension composition.

[0037] In another aspect, the present invention provides a nanosuspension composition comprising: a) Canagliflozin or its pharmaceutically acceptable salts, b) Hydroxypropyl methylcellulose, c) Sodium lauryl sulphate, and d) at least one more surfactant wherein hydroxypropyl methylcellulose is present in amount of about from 10 % to 30 % (w / w) with respect to the total weight of the nanosuspension composition.

[0038] In another aspect, the present invention provides a nanosuspension composition comprising: a) Canagliflozin or its pharmaceutically acceptable salts, b) Hydroxypropyl methylcellulose, c) Sodium lauryl sulphate, and d) at least one more surfactant wherein sodium lauryl sulphate is present in amount of about from 0.1 % to 1 % (w / w) with respect to the total weight of the nanosuspension composition.

[0039] In another aspect, the present invention provides a nanosuspension composition comprising: a) Canagliflozin or its pharmaceutically acceptable salts, b) Hydroxypropyl methylcellulose, c) Sodium lauryl sulphate, and d) at least one more surfactant wherein at least one more surfactant is selected from polyethylene sorbitan monooleate, poloxamer and Soluplus®.

[0040] In another aspect, the present invention provides a nanosuspension composition comprising: a) Canagliflozin or its pharmaceutically acceptable salts, b) Hydroxypropyl methylcellulose, c) Sodium lauryl sulphate, and d) at least one more surfactant wherein Canagliflozin is present in amount of about from 60 % to 80 % (w / w) and hydroxypropyl methylcellulose is present in amount of about from 10 % to 30 % (w / w) with respect to the total weight of the nanosuspension composition.

[0041] In another aspect, the present invention provides a nanosuspension composition comprising: a) Canagliflozin or its pharmaceutically acceptable salts, b) Hydroxypropyl methylcellulose, c) Sodium lauryl sulphate, and d) at least one more surfactant wherein Canagliflozin is present in amount of about from 60 % to 80 % (w / w) and sodium lauryl sulphate is present in amount of about from 0.1 % to 1 % (w / w) with respect to the total weight of the nanosuspension composition.

[0042] In another aspect, the present invention provides a nanosuspension composition comprising: a) Canagliflozin or its pharmaceutically acceptable salts, b) Hydroxypropyl methylcellulose, c) Sodium lauryl sulphate, and d) at least one more surfactant wherein hydroxypropyl methylcellulose is present in amount of about from 10 % to 30 % (w / w) and sodium lauryl sulphate is present in amount of about from 0.1 % to 1 % (w / w) with respect to the total weight of the nanosuspension composition.

[0043] In another aspect, the present invention provides a nanosuspension composition comprising: a) 60 % to 80 % (w / w) of Canagliflozin or its pharmaceutically acceptable salts, b) 10 % to 30 % (w / w) of hydroxypropyl methylcellulose, c) 0.1 % to 1 % (w / w) of sodium lauryl sulphate, d) 0.5 % to 2 % (w / w) of polyethylene sorbitan monooleate, e) 5 % to 10 % (w / w) of poloxamer, with respect to the total weight of the nanosuspension composition.

[0044] In another aspect, the present invention provides a preparation of nanosuspension composition comprising: a) hydroxypropyl methylcellulose is dissolved in water, b) Poloxamer, polyethylene sorbitan monooleate and sodium lauryl sulphate are added to the solution obtained in step a), c) Canagliflozin or its pharmaceutically acceptable salt is added to the solution obtained in step b), d) solution obtained in step c) is subjected to wet milling to obtain nanosuspension, and e) mannitol is optionally added to nanosuspension of step d) and spray dried to obtain a solid form of nanosuspension.

[0045] In another aspect, the present invention provides a pharmaceutical composition comprising a nanosuspension composition of Canagliflozin and one or more additional therapeutic agent.

[0046] In another aspect, the present invention provides use of such nanosuspension composition for the preparation of medicament in the treatment of Type 2 diabetes mellitus.

[0047] The details of one or more embodiments of the present invention are set forth in the description below. Other features, objects and advantages of the invention will be apparent from the description.

[0048] DETAILED DESCRIPTION OF THE PRESENT INVENTION

[0049] The present invention will now be more specifically illustrated as hereunder.

[0050] The term % used in this specification means the percentage by weight unless otherwise stipulated.

[0051] The term "about" can indicate a difference of 10 percent of the value specified. Numerical ranges as used herein are meant to include every number and subset of numbers enclosed within that range, whether particularly disclosed or not. Further, these numerical ranges should be construed as providing support for a claim directed to any number or subset of numbers in that range. The term “nanosuspension” refers to submicron colloidal dispersions of nanoparticles and stabilized with the addition of stabilizers, co-surfactants, buffer, osmogents and / or carrier. Nanoparticles have typical dimensions between 100 nm and 1000 nm. Particle size of the nanosuspension of the present invention is between 100 nm to 250 nm, preferably 100 nm to 220 nm, and the average particle size is measured by dynamic light scattering (DLS) using Litesizer 500 (Anton Paar).

[0052] The term ' Canagliflozin ' as used in the present invention includes, but is not limited to, Canagliflozin per se, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, and pharmaceutically acceptable prodrugs thereof, and also its various crystalline and amorphous forms.

[0053] In general embodiment, the present invention provides a nanosuspension composition comprising: a) Canagliflozin or its pharmaceutically acceptable salts, b) Hydroxypropyl methylcellulose, c) Sodium lauryl sulphate, and d) at least one more surfactant.

[0054] In one embodiment, the present invention provides a nanosuspension composition comprising: a) Canagliflozin or its pharmaceutically acceptable salts, b) Hydroxypropyl methylcellulose, c) Sodium lauryl sulphate, and d) at least one more surfactant wherein at least one more surfactant is selected from polyethylene sorbitan monooleate, poloxamer and Soluplus®. In one embodiment, a nanosuspension composition comprises: a) 60 % to 80 % (w / w) of Canagliflozin or its pharmaceutically acceptable salts, b) 10 % to 30 % (w / w) of hydroxypropyl methyl cellulose; c) 0.1 % to 1 % (w / w) of sodium lauryl sulphate, and d) 0.5 % to 2 % (w / w) of polyethylene sorbitan monooleate, and e) 5 % to 10 % (w / w) of poloxamer with respect to the total weight of the nanosuspension composition.

[0055] In one embodiment, the present invention provides a preparation of nanosuspension composition comprising: a) hydroxypropyl methylcellulose is dissolved in water, b) Poloxamer, polyethylene sorbitan monooleate and sodium lauryl sulphate are added to the solution obtained in step a), c) Canagliflozin or its pharmaceutically acceptable salt is added to the solution obtained in step b), d) solution obtained in step c) is subjected to wet milling to obtain nanosuspension, and e) mannitol is optionally added to nanosuspension of step d) and spray dried to obtain a solid form of nanosuspension.

[0056] In another aspect, the present invention provides a pharmaceutical composition comprising a nanosuspension composition of Canagliflozin and one or more additional therapeutic agent.

[0057] In another embodiment, a nanosuspension composition of the present invention further comprises one or more pharmaceutically acceptable excipients. The excipients to be used in accordance with the present invention are well known and are those excipients which are conventionally used by the person skilled in the art. Depending on the dosage form chosen for the pharmaceutical composition, the person skilled in the art will be able to select suitable pharmaceutically acceptable excipients. The pharmaceutically acceptable excipient can be selected from stabilizers, co-surfactants, buffer, osmogents and optionally carrier.

[0058] The ratio of stabilizer to active ingredient is from about 3: 1 to about 1 :50.

[0059] Stabilizers includes, but are not limited to, poloxamers, lecithin, polysorbates, cellulosic derivatives, polyvinyl pyrrolidone (PVP), and mixtures thereof.

[0060] The amount of the co-surfactant used in the present invention is from about 0.1 wt% to about 6 wt% based on the total weight of the composition.

[0061] Co-surfactant includes, but are not limited to, bile acids, dipotassium glycyrrhizinate, transcutol, glycofurol, and mixtures thereof.

[0062] The ratio of the active ingredient to buffer used in the present invention is from about 1 : 1 to about 1 :3 wt%.

[0063] Buffer includes, but are not limited to, carbonates, bicarbonates, hydrogen phosphates, formic acid, fumaric acid, sulfamic acid and mixtures thereof.

[0064] The amount of the osmogents used in the present invention is from about 0.01 wt% to about 3 wt% based on the total weight of the composition.

[0065] Osmogents includes, but are not limited to, glycerol, lactulose, sorbitol, polyethylene glycol, sodium chloride and mixtures thereof.

[0066] Carrier is optionally used in the nanosuspension of Canagliflozin to obtain a solid form of nanosuspension. Obtained solid form of nanosuspension can be used one of the following methods spray drying, freeze-drying, wet granulation. The ratio of the carrier to active ingredient is about 1 .5: 1 to about 2.5: 1 . Carrier includes, but are not limited to, lactose, mannitol, sucrose, trehalose and maltodextrin.

[0067] The invention further relates to use of said nano composition for the preparation of medicament, which is useful in the treatment of type 2 diabetes mellitus.

[0068] Moreover, the pharmaceutical composition of the present invention is very suitable for production on commercial scale making use of equipment and techniques commonly used in industry.

[0069] The following examples are intended to illustrate the scope of the present invention but not to limit it thereto.

[0070] Examples:

[0071] Example 1 : Preparation of a nanosuspension composition of Canagliflozin

[0072] Table-1

[0073] Process for the Preparation:

[0074] 1. Deionized water was heated till 65°C and HPMC E15 was added into the water and then was mixed with mechanical mixer with crushing tip till having clear solution. 2. Poloxamer 407, SLS (sodium lauryl sulphate), Tween® 80 respectively were added into the container of Step-1 and mixed.

[0075] 3. Canagliflozin or its pharmaceutically acceptable salts was added into the container of Step-2 and mixed.

[0076] 4. The suspension prepared at Step-3 was loaded into DynoMill (wet milling) and milled to obtain nanosuspension.

[0077] Example 2: Preparation of a nanosuspension composition of Canagliflozin

[0078] Table-2

[0079] Process for the Preparation:

[0080] 1. Deionized water was heated till 65°C and HPMC E15 was added into the water and then was mixed with mechanical mixer with crushing tip till having clear solution.

[0081] 2. SLS (Sodium Lauryl Sulphate) were added into the container of Step-1 and mixed.

[0082] 3. Canagliflozin or its pharmaceutically acceptable salts was added into the container of Step-2 and mixed.

[0083] 4. The suspension prepared at Step-3 was loaded into DynoMill (wet milling) and milled to obtain nanosuspension. Example 3: Dissolution Data of Canagliflozin (API), reference product i.e.

[0084] Invokana®, Example 1 and Example 2

[0085] Table-3- pH 6.8 Phosphate Buffer

[0086] Table-4- pH 4.5 Acetate Buffer Dissolution of test products of Example-1 & Example-2, Canagliflozin (API) and reference product Invokana® 100 mg were performed using standard USP apparatus II, pedal, at 75 rpm in 600 ml at pH 6.8 phosphate buffer and pH 4.5 acetate buffer. The drug release was determined by using an HPLC method. From the above dissolution data given in table-3 & table-4, it is observed that Example-1 shows better dissolution results compared to canagliflozin (API), reference product and Example-2.

Claims

Claims1. A nanosuspension composition comprising, a) Canagiifiozin or its pharmaceutically acceptable salts, b) Hydroxypropyl methylcellulose, c) Sodium lauryl sulphate, and d) at least one more surfactant.

2. A nanosuspension composition according to claim 1 , wherein Canagliflozin or its pharmaceutically acceptable salt is present in an amount from 60 % to 80 % (w / w) with respect to the total weight of the nanosuspension composition.

3. A nanosuspension composition according to claim 1 , wherein hydroxypropyl methylcellulose is present in an amount from 10 % to 30 % (w / w) with respect to the total weight of the nanosuspension composition.

4. A nanosuspension composition according to claim 1 , wherein sodium lauryl sulphate is present in an amount from 0. 1 % to 1 % (w / w) with respect to the total weight of the nanosuspension composition.

5. A nanosuspension composition according to claim 1 , wherein at least one more surfactant is selected from polyethylene sorbitan monooleate, poloxamer and Soluplus®.

6. A nanosuspension composition according to claim 1 or claim 5, wherein the surfactant is mixture of polyethylene monooleate and poloxamer.

7. A nanosuspension composition according to claim 6, wherein the surfactant is mixture of: i) 0.5 % to 2 % (w / w) of polyethylene sorbitan monooleate, and ii) 5 % to 10 % (w / w) of poloxamer,with respect to the total weight of the nanosuspension composition.

8. A nanosuspension composition according to any of the preceding claims comprising: a) 60 % to 80 % of (w / w) Canagliflozin and its pharmaceutically acceptable salts, b) 10 % to 30 % (w / w) of hydroxypropyl methylcellulose, c) 0. 1 % to 1 % (w / w) of sodium lauryl sulphate, d) 0.5 % to 2 % (w / w) of polyethylene sorbitan monooleate, and e) 5 % to 10 % (w / w) of poloxamer, with respect to the total weight of the nanosuspension composition.

9. A nanosuspension composition according to claim 1 , wherein the nanosuspension composition optionally comprising one or more pharmaceutically acceptable excipients, which are selected from stabilizers, co-surfactants, buffer and osmogents.

10. A nanosuspension composition according to any of the preceding claims, wherein the nanosuspension composition optionally comprising one or more carrier, which is selected from lactose, mannitol, sucrose, trehalose and maltodextrin.

11. A nanosuspension composition according to any of the preceding claims is obtained by: a) hydroxypropyl methylcellulose is dissolved in water, b) Poloxamer, polyethylene sorbitan monooleate and sodium lauryl sulphate are added to the solution obtained in step a), c) Canagliflozin or its pharmaceutically acceptable salt is added to the solution obtained in step b), d) solution obtained in step c) is subjected to wet milling to obtain nanosuspension, and e) mannitol is optionally added to nanosuspension of step d) and spray dried to obtain a solid form of nanosuspension.

12. A nanosuspension composition according to any of the preceding claims is useful for the treatment of type 2 diabetes mellitus.

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