A nanosuspension composition comprising azilsartan

Abstract

The present invention relates to a nanosuspension composition comprising i) Azilsartan medoxomil and / or pharmaceutically acceptable salts, ii) copovidone iii) at least one surfactant and iv) at least one pharmaceutically acceptable excipient. The said nanosuspension composition has a desirable pharmacokinetic characteristic properties and stability. The invention further relates to a process for the preparation of said nanocomposition and use thereof for the preparation of medicament, which is useful in the treatment of hypertension.

Description

[0001] A NANOSUSPENSION COMPOSITION COMPRISING AZILSARTAN

[0002] DESCRIPTION

[0003] FIELD OF THE INVENTION

[0004] The present invention relates to a nanosuspension composition comprising i) Azilsartan medoxomil and / or pharmaceutically acceptable salts, ii) copovidone iii) at least one surfactant and iv) at least one pharmaceutically acceptable excipient. The said nanosuspension composition has a desirable pharmacokinetic characteristic properties and stability. The invention further relates to a process for the preparation of said nanocomposition and use thereof for the preparation of medicament, which is useful in the treatment of hypertension.

[0005] BACKGROUND OF THE INVENTION

[0006] Azilsartan medoxomil is chemically known as 1 H-Benzimidazole-7-carboxylic acid, 1 - [[2’-(2,5-dihydro-5-oxo-1 ,2,4-oxadiazol-3-yl)[1 ,T-biphenyl]-4-yl]methyl]-2-ethoxy-,(5- methyl-2-oxo-1 ,3-dioxol-4-yl)methyl ester , having the following formula (I),

[0007] (I).

[0008] Azilsartan medoxomil is highly selective angiotensin II type 1 receptor (AT1 ) antagonist. They achieve their antihypertensive effects by selectively blocking the binding of angiotensin II to the AT1 receptor, which results in a reduction of blood pressure by antagonizing the vasoconstrictive actions of angiotensin II. Azilsartan medoxomil is marketed by Takeda Pharmaceuticals under the brand name of Edarbi ® as a tablet in 20 mg, 40 mg and 80 mg strengths in Europe since 2011 .

[0009] Azilsartan medoxomil tablet marketed under the brand name of Edarbi ® is indicated for the treatment of essential hypertension in adults.

[0010] Azilsartan medoxomil is also marketed in combination with Chlorthalidone in 40mg / 12.5mg and 40mg / 25mg under the brand name of Edarbyclor® in USA since 2011. Edarbyclor® is indicated for the treatment of hypertension, to lower blood pressure:

[0011] • In patients not adequately controlled with monotherapy

[0012] • As initial therapy in patients likely to need multiple drugs to help achieve blood pressure goals.

[0013] Edarbi® contains Azilsartan medoxomil potassium salt as active substance, mannitol, fumaric acid, sodium hydroxide, hydroxypropylcellulose, croscarmellose sodium, microcrystalline cellulose, and magnesium stearate.

[0014] US7157584 B2 discloses azilsartan medoxomil or potassium salt.

[0015] US7572920 B2 discloses pharmaceutical formulations of azilsartan medoxomil and the process of preparation azilsartan medoxomil.

[0016] EP 2124903 B1 discloses solid formulations comprising azilsartan medoxomil and monosodium fumarate or a combination of fumaric acid and sodium hydroxide to adjust a pH range of 2 to 5. W02022003643 A1 discloses a pharmaceutical composition for treating hypertension and a preparation method thereof, wherein the composition comprises Azilsartan kamedoxomil and one or more pharmaceutically acceptable excipients such as fillers, diluents, binders, disintegrants, coating agents, glidants, surfactants, pH modifiers or pH adjusting agents, lubricants, vehicle, and polymer or coating system.

[0017] CN1 11617046 A discloses a dispersible tablet, wherein the composition comprises micronized azilsartan having a particle size distribution of D90 less than 40 pm, pharmaceutically acceptable excipients such as disintegrants, fillers, binders, stabilizers, and lubricants.

[0018] According to the European Public Assessment Report (EPAR) of Azilsartan medoxomil (Edarbi®), absolute bioavailability of Azilsartan was approximately 60% and azilsartan medoxomil potassium salt is practically insoluble in water. Namely, Azilsartan has poor aqueous solubility and low bioavailability i.e. BCS Class II medicament and according to FDA Edarbi New Drug Application Chemistry Review, Azilsartan medoxomil potassium salt belongs to Biopharmaceutical Classification System (BCS) class IV i.e.: low solubility and low permeability which can present challenges for effective absorption in the gastrointestinal tract

[0019] Due to the biopharmaceutical class of azilsartan and azilsartan medoxomil various attempts have been made in the art to improve low solubility and low bioavailability of these kind of active ingredients, 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.

[0020] Drug nanocrystals are nanoparticle structures with sizes in the nanometer range. The drug carrier systems prepared by dispersing drug nanocrystals in a liquid medium are called "nanosuspensions." 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.

[0021] There still exists a need for a nanosuspension composition of Azilsartan medoxomil, which having improved solubility and improved bioavailability, being physically and chemically stable and easy to scale up.

[0022] The inventors of the present invention have surprisingly developed a nanosuspension composition comprising Azilsartan medoxomil and / or pharmaceutically acceptable salts, copovidone, at least one surfactant, and at least one pharmaceutically acceptable excipient 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 Edarbi® tablet.

[0023] OBJECT OF THE INVENTION

[0024] An object of the present invention is to provide a nanosuspension composition comprising Azilsartan medoxomil or its pharmaceutically acceptable salts having better / superior in-vitro dissolution profile as compared to the reference product i.e. Edarbi® tablet.

[0025] Another object of the present invention is to provide a nanosuspension composition comprising Azilsartan medoxomil or its pharmaceutically acceptable salts, copovidone, at least one surfactant and at least one more pharmaceutically acceptable excipient. Yet another object of the present invention is to provide a nanosuspension composition comprising Azilsartan medoxomil or its pharmaceutically acceptable salts, copovidone, Vitamin E or derivative and fumaric acid.

[0026] Yet another object of the present invention is to provide a nanosuspension composition of Azilsartan medoxomil, which is redispersible.

[0027] Yet another object of the present invention is to provide a nanosuspension composition of Azilsartan medoxomil, which remains physically and chemically stable.

[0028] Yet another object of the present invention is to provide a nanocrystal of Azilsartan medoxomil.

[0029] Yet another object of the present invention is to provide a nanosuspension composition of Azilsartan medoxomil, which overcomes the problems of the prior art.

[0030] Yet another object of the present invention is to provide a nanocomposition as mentioned herein above is useful in the treatment of hypertension.

[0031] SUMMARY OF THE INVENTION

[0032] In one aspect, the present invention provides a nanosuspension composition comprising: a) Azilsartan medoxomil and / or pharmaceutically acceptable salts, b) Copovidone, c) at least one surfactant and d) at least one pharmaceutically acceptable excipient. In another aspect, the present invention provides a nanosuspension composition comprising: a) Azilsartan medoxomil and / or pharmaceutically acceptable salts, b) Copovidone, c) at least one surfactant d) at least one pharmaceutically acceptable excipient wherein Azilsartan medoxomil is present in amount of about from 1 % to 10 % (w / w) with respect to the total weight of the nanosuspension.

[0033] In another aspect, the present invention provides a nanosuspension composition comprising: a) Azilsartan medoxomil and / or pharmaceutically acceptable salts, b) Copovidone, c) at least one surfactant d) at least one pharmaceutically excipient wherein copovidone is present in amount of about from 1 % to 20 % (w / w) with respect to the total weight of the nanosuspension.

[0034] In another aspect, the present invention provides a nanosuspension composition comprising: a) Azilsartan medoxomil and / or pharmaceutically acceptable salts, b) Copovidone, c) at least one surfactant d) at least one pharmaceutically acceptable excipient wherein surfactant is selected from Tween 80, sodium lauryl sulfate, Vitamin E or derivatives, poloxamer 188 and Soluplus®. In another aspect, the present invention provides a nanosuspension composition comprising: a) Azilsartan medoxomil and / or pharmaceutically acceptable salts, b) Copovidone, c) at least one surfactant d) at least one pharmaceutically acceptable excipient wherein pharmaceutically acceptable excipient is pH adjusting agent which selected from citric acid and fumaric acid.

[0035] In another aspect, the present invention provides a nanosuspension composition comprising: a) Azilsartan medoxomil and / or pharmaceutically acceptable salts, b) Copovidone, c) at least one surfactant d) at least one pharmaceutically acceptable excipient wherein Azilsartan medoxomil is present in amount of about from 1 % to 10 % (w / w) and copovidone is present in amount of about from 1 % to 20 % (w / w) with respect to the total weight of the nanosuspension composition.

[0036] In another aspect, the present invention provides a nanosuspension composition comprising: a) Azilsartan medoxomil and / or pharmaceutically acceptable salts b) copovidone, c) Vitamin E or derivative d) fumaric acid. In another aspect, the present invention provides a nanosuspension composition comprising: a) Azilsartan medoxomil and / or pharmaceutically acceptable salts, b) copovidone, c) Vitamin E tocopherol polyethylene glycol succinate (TPGS), d) fumaric acid.

[0037] In another aspect, the present invention provides a nanosuspension composition comprising: a) 1 % to 10 % of (w / w) Azilsartan medoxomil and / or pharmaceutically acceptable salts, b) 1 % to 20 % (w / w) of copovidone, c) 0.1 % to 5 % (w / w) of Vitamin E TPGS d) 0.1 % to 0.5 % (w / w) of fumaric acid, with respect to the total weight of the nanosuspension composition.

[0038] In another aspect, particle size of the nanosuspension of the present invention is between 100 nm to 500 nm, preferably 200 nm to 400 nm and stable at pH between 3.0 and 5.0.

[0039] In another aspect, the present invention provides a preparation of nanosuspension composition comprising the steps of: a) Fumaric acid is dissolved in water, b) Copovidone is added to the solution obtained in step a), c) Vitamin E TPGS is added to the solution obtained in step b), d) Azilsartan medoxomil and / or pharmaceutically acceptable salts is added to the solution obtained in step c), e) suspension obtained in step d) is subjected to wet milling to obtain nanosuspension, and f) optionally nanosuspension obtained in step e) is sprayed onto mannitol in a fluidized bed device to obtain a solid form of nanocrystals.

[0040] In one embodiment, the present invention provides nanocrystals comprising a) 5-40 % (w / w) of nanosuspension comprising Azilsartan Medoxomil or its pharmaceutically acceptable salts, b) 60-95 % (w / w) Mannitol

[0041] In another aspect, particle size of the nanocrsytals of the present invention is between 100 nm to 500 nm, preferably 200 nm to 400 nm.

[0042] In another aspect, the present invention provides a pharmaceutical composition comprising a nanocomposition of Azilsartan medoxomil and one or more additional therapeutic agent.

[0043] In another aspect, the present invention provides use of such nanocomposition for the preparation of medicament in the treatment of hypertension.

[0044] 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. DETAILED DESCRIPTION OF THE PRESENT INVENTION

[0045] The present invention will now be more specifically illustrated as hereunder.

[0046] The term % used in this specification means the percentage by weight unless otherwise stipulated.

[0047] The term "about" can indicate a difference of 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.

[0048] The term "nanocrystal" as used herein, refers to semiconductor crystals with dimensions in the nanometer range (i.e., less than about 1000 nm) in length, width, or height. Nanocrystals of the invention may include various shapes such as nanoscale dots, rods, bars, nanofibers, nanowires, sheets, and similar structures. Particle size of the nanocrsytal of the present invention is between 100 nm to 500 nm, preferably 200 nm to 400 nm, and the average particle size is measured by dynamic light scattering (DLS).

[0049] Nanocrystals can be obtained by using one of the following methods bottom-up method or top-down method, preferably top-down method. Top-down method includes, but not limited to, wet milling, high pressure homogenization or combination technology. In the present invention, preferably wet milling is used.

[0050] 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 500 nm, preferably 200 nm to 400 nm, and the average particle size is measured by dynamic light scattering (DLS) using Litesizer 500 (Anton Paar).

[0051] The term “Nano composition” refers to nano suspension or nanocrystals interchangeably.

[0052] The term “Azilsartan medoxomil” as used in the present invention includes, but is not limited to, Azilsartan medoxomil 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] The salt of Azilsartan medoxomil of the present invention includes, but not limited to, sodium salt, monopotassium salt and potassium salt. Preferably, it is Azilsartan medoxomil potassium salt i.e.: azilsartan kamedoxomil.

[0054] In nanosuspension formulation development, neutral forms of active ingredients are typically preferred. It has been demonstrated that salt forms are less suitable candidates for grinding methods due to the risk of disproportionation and aggregation when exposed to pH variations. However, the present invention provides a nanosuspension formulation comprising azilsartan medoxomil potassium salt, which is shown to remain stable for a period of 3 months when stored under refrigerated conditions (5°C ± 3°C) at pH between 3.0 and 5.0.

[0055] In general embodiment, the present invention provides a nanosuspension composition comprising: a) Azilsartan medoxomil and / or pharmaceutically acceptable salts, b) Copovidone, c) at least one surfactant. c) at least one pharmaceutically acceptable excipient.

[0056] In one embodiment, the present invention provides a nanosuspension composition comprising: a) Azilsartan medoxomil and / or pharmaceutically acceptable salts, b) Copovidone, c) at least one surfactant d) at least one pharmaceutically acceptable excipient wherein surfactant is selected from Tween 80, sodium lauryl sulfate, Vitamin E, poloxamer 188 and Soluplus®.

[0057] In one embodiment, the present invention provides a nanosuspension composition comprising: a) Azilsartan medoxomil and / or pharmaceutically acceptable salts, b) Copovidone, c) at least one surfactant d) at least one pharmaceutically acceptable excipient wherein pharmaceutically acceptable excipient is pH adjusting agent which is selected from citric acid and fumaric acid.

[0058] In one embodiment, a nanosuspension composition comprises: a) 1 % to 10 % of (w / w) Azilsartan medoxomil and / or pharmaceutically acceptable salts, b)1 % to 20 % (w / w) of copovidone, c) 0.1 % to 5 % (w / w) of Vitamin E TPGS d) 0.1 % to 0.5 % (w / w) of fumaric acid, with respect to the total weight of the nanosuspension composition.

[0059] In one embodiment, the present invention provides a preparation of nanosuspension composition comprising the steps of: a) Fumaric acid is dissolved in water, b) Copovidone is added to the solution obtained in step a), c) Vitamin E TPGS is added to the solution obtained in step b), d) Azilsartan medoxomil and / or pharmaceutically acceptable salts is added to the solution obtained in step c), e) suspension obtained in step d) is subjected to wet milling to obtain nanosuspension, and f) optionally nanosuspension obtained in step e) is sprayed onto mannitol in a fluidized bed device to obtain a solid form of nanocrystals.

[0060] Surfactant includes, but is not limited to, Tween 80, sodium lauryl sulfate, Vitamin E or derivatives, poloxamer 188 and Soluplus® and mixtures thereof.

[0061] Pharmaceutical acceptable excipient includes, but not limited to, pH adjusting agentand pH adjusting agent includes, but are not limited to, citric acid, fumaric acid and mixtures thereof.

[0062] 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 carrier.

[0063] Carrier is used in the nanosuspension of Azilsartan medoxomil 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. Carrier includes, but are not limited to, lactose, mannitol, sucrose, trehalose and maltodextrin. Preferably, it is mannitol.

[0064] In one embodiment, the present invention provides nanocrystals comprising a) 5-40 % (w / w) of nanosuspension comprising Azilsartan Medoxomil or its pharmaceutically acceptable salts, b) 60-95 % (v / v) Mannitol

[0065] The invention further relates to use of said nano composition for the preparation of medicament, which is useful in the treatment of hypertension.

[0066] 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.

[0067] The following examples are intended to illustrate the scope of the present invention but not to limit it thereto. Examples

[0068] Example 1 : Preparation of a nanosuspension composition of Azilsartan

[0069] Medoxomil

[0070] Table-1

[0071] Process for the Preparation a) Fumaric acid is dissolved in water, b) Copovidon is added to the solution obtained in step a), c) Vitamin E TPGS is added to the solution obtained in step b), d) Azilsartan medoxomil and / or pharmaceutically acceptable salts is added to the solution obtained in step c), e) suspension obtained in step d) is subjected to wet milling (DynoMill) to obtain nanosuspension.

[0072] Example 2: Stability data of Azilsartan Medoxomil nanosuspension at 5°C±3°C.

[0073] Table 2

[0074] PDI:Polydispersity index During the stability, it was observed that there is no significant change in particle size, PDI, Zeta Potential, Assay results and pH and all values are in defined range. It is shown that nanosuspesion remains stable for a period of 3 months when stored under refrigerated conditions (5°C ± 3°C). Example-3 Dissolution Data of Azilsartan Medoxamil Potassium Salt (API), reference product i.e. Edarbi®, Example 1.

[0075] Table-3 pH 6.8 Phosphate Buffer

[0076] Table-40.1 N HCI

[0077] Dissolution of test product of Example 1 (Nanosuspension containing 40 mg of active ingredient), Azilsartan Medoxomil Potassium Salt (API, equivalent to 40 mg Azilsartan Medoxomil) and reference product Edarbi® 40 mg were performed using standard USP apparatus II. pedal, at 50 rpm in 900 ml at pH 6.8 phosphate buffer and 0.1 N HCI. The drug release was determined by using UV spectroscopy. From the above dissolution data given in table-3 & table-4., it is observed that Example 1 shows better dissolution results compared to API and reference product.

[0078] Example-4 Preparation of a nanocrystals Table-5

[0079] Process for the Preparation a) Fumaric acid is dissolved in water, b) Copovidon is added to the solution obtained in step a), c) Vitamin E TPGS is added to the solution obtained in step b), d) Azilsartan medoxomil and / or pharmaceutically acceptable salts is added to the solution obtained in step c), e) suspension obtained in step d) is subjected to wet milling (DynoMill) to obtain nanosuspension. f) nanosuspension obtained in step e) is sprayed onto mannitol in a fluidized bed device to obtain a solid form of nanocrystals.

[0080] Example 5 - Comparison of nanosuspension and nanocrystals

[0081] Table-6

[0082] PDI:Polydispersity index

[0083] It is observed that there is no significant change in particle size, PDI, Zeta Potential results of nanosuspension and nanocrystals and all values are in defined range.

Claims

Claims1 . A nanosuspension composition comprising, a. Azilsartan medoxomil and / or pharmaceutically acceptable salts, b. Copovidone c. at least one surfactant and d. at least one pharmaceutically acceptable excipient.

2. A nanosuspension composition according to claim 1 , wherein nanosuspension comprises Azilsartan medoxomil salt.

3. A nanosuspension composition according to claim 1 or claim 2, salt is potassium salt.

4. A nanosuspension composition according to claim 1 , wherein the particle size of the nanosuspension is between 200 nm to 400 nm.

5. A nanosuspension composition according to claim 1 , at least one surfactant is selected from Tween 80, sodium lauryl sulfate, Vitamin E or its derivative, poloxamer 188 and Soluplus®.

6. A nanosuspension composition according to claim 1 or claim 5, surfactant is vitamin E TPGS.

7. A nanosuspension composition according to claim 1 , at least one pharmaceutically acceptable excipient is pH adjusting agent.

8. A nanosuspension composition according to claim 1 or claim 7, pH adjusting agent is selected from citric acid and fumaric acid.

9. A nanosuspension composition according to claim 8, pH adjusting agent is fumaric acid.

10. A nanosuspension composition according to claim 1 , wherein the said nanosuspension is stable at pH between 3.0 and 5.0.

11. A nanosuspension composition according to any of the preceding claims comprising: a) 1 % to 10 % of (w / w) Azilsartan medoxomil and / or pharmaceutically acceptable salts, b) 1 % to 20 % (w / w) of copovidone, c) 0.1 % to 5 % (w / w) of Vitamin E TPGS d) 0.1 % to 0.5 % (w / w) of fumaric acid, with respect to the total weight of the nanosuspension composition.

12. A nanosuspension composition according to any of the preceding claims comprises the steps of: a. Fumaric acid is dissolved in water, b. Copovidon is added to the solution obtained in step a), c. Vitamin E TPGS is added to the solution obtained in step b), d. Azilsartan medoxomil and / or pharmaceutically acceptable salts is added to the solution obtained in step c), e. suspension obtained in step d) is subjected to wet milling to obtain nanosuspension, and f. optionally nanosuspension obtained in step e) is sprayed onto mannitol in a fluidized bed device to obtain a solid form of nanocrsytals .

13. Nanocrystals according to claim 12 comprises, a) 5-40 % (w / w) of nanosuspension comprising Azilsartan Medoxomil or its pharmaceutically acceptable salts, b) 60-95 % (w / w) Mannitol14. A nanocomposition composition according to any of the preceding claims is used for the treatment of hypertension.

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