Pharmaceutical composition comprising dapagliflozin base in amorphous form

Abstract

The present invention relates to a stable pharmaceutical composition comprising amorphous form of dapagliflozin base presenting proper in vivo and in vitro dissolution profiles.

Description

[0001]DESCRIPTION PHARMACEUTICAL COMPOSITION COMPRISING DAPAGLIFLOZIN BASE IN AMORPHOUS FORM Field Of The Invention The present invention relates to a stable pharmaceutical composition comprising amorphous form of dapagliflozin base presenting proper in vivo and in vitro dissolution profiles. Background Of The Invention Diabetes is a group of metabolic disorder in which is related with high glucose in plasma. Currently, there is three types of diabetes, such as type 1, type 2, and gestational diabetes. However, type 2 diabetes is known to be the most common form of the diabetes in both of the developed and developing counties. Type 2 diabetes (non-insulin dependent diabetes, (NIDDM)) is a condition and is called as insulin resistance where the body produces insulin, but certain mechanisms prevent insulin from moving glucose into cells. Therefore, glucose level rises to the unsafe in the blood and which is called as hyperglycemia. Sustained hyperglycemia leads to worsen insulin resistance contributes to dysfunction in the beta cells of the pancreas. Diabetic microvascular complications and macro-vascular complications is the directly result of the degree of the sustained hyperglycemia. Thus, Type 2 diabetes is characterized by hyperglycemia and an increased risk of microvascular and macro- vascular complications. In normal healthy individuals, glucose in plasma is filtered by glomerulus in the kidney and is actively reabsorbed in the proximal tube. However, Sodium-glucose co-transporter-2 (SGLT2) reabsorbs nearly all glucose at this site. Thus, a selective inhibitor of the SGLT2 in the kidney is essential to help the body retain glucose for its energy requirements. Dapagliflozin is a first-in class compound which is a highly selective and orally active inhibitor of the human sodium-dependent glucose co-transporter 2 (SGLT2), and also is the major transporter responsible for renal glucose reabsorption from the turbula lumen. It inhibits the renal reabsorption of glucose and promotes excretion of excess glucose in the urine, thus it improves glycemic control in patients with Type 2 diabetes and lower glucose level in plasma. The chemical name of Dapagliflozin is (2S,3R,4R,5S,6R)-2-[4-Chloro-3-(4- ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol. The empirical formula of Dapagliflozin is C21H25ClO6 and its relative molecular mass is 408.87 mg / mole as a free base and 502.98 mg / mole as propanediol monohydrate salt. Propane diol salt is the form that reference product Forxiga consisting of. Dapagliflozin is a white to off-white powder, soluble in many polar organic solvents and non- hygroscopic. Dapagliflozin in drug product marketed by Astra Zeneca is rapidly and well absorbed after oral administration. Maximum dapagliflozin plasma concentrations (Cmax) were usually attained within 2 hours after administration in the fasted state. Geometric mean steady-state dapagliflozin Cmax and AUCτ values following once daily 10 mg doses of dapagliflozin were 158 ng / mL and 628 ng h / mL, respectively. The absolute oral bioavailability of dapagliflozin following the administration of a 10 mg dose is 78%. Administration with a high-fat meal decreased dapagliflozin Cmax by up to 50% and prolonged Tmax by approximately 1 hour, but did not alter AUC as compared with the fasted state. Thus, AstraZeneca developed composition comprising Dapagliflozin for the treatment of the Type 2 diabetes, wherein Dapagliflozin is presented in the immediate release formulation. It is currently marketed under the trade name of Forxiga in the strengths of 5 mg and 10 mg per tablet. In the state of art there are many patents / patent applications which are summarized below. EP3024442 relates to an amorphous solid dispersion of at least one polymer such as polyethyleneglycol, polyethylene oxide, hydroxypropyl cellulose, hydroxypropyl cellulose, and dapagliflozin in its free form. The adsorbate comprising dapagliflozin adsorbed onto the surface of a substrate wherein dapagliflozin is substantially amorphous. Finally, a pharmaceutical composition comprising amorphous dapagliflozin, is formed by mixing with pharmaceutically acceptable excipients. WO2015104658 relates to a pharmaceutical composition comprising amorphous dapagliflozin, is formed by adding pharmaceutically acceptable excipients. In the manufacturing process, an amorphous solid dispersion is formed with a pre-treatment and other pharmaceutically acceptable excipients are mixed subsequently. WO2016161995 relates to a pharmaceutical composition comprises amorphous dapagliflozin base and a polymer such as hydroxypropyl cellulose, hydroxypropyl methylcellulose, hypromellose acetate succinate, povidone PVP 30, Soluplus™, PEG 6000, copovidone VA64, D-(+) glucose, D-(+) saccharose and urea to obtain polymorphic stability. WO2021165316 relates to a pharmaceutical composition comprising amorphous dapagliflozin, mannitol, microcrystalline cellulose, glidant and optionally a lubricant. Most of the patents and patent applications are related with the preparation of dapagliflozin base in amorphous form and / or the drug products comprise it with a pre-treatment of dapagliflozin base in amorphous form with a polymer as to form an adsorbate due to stability issues. However, there is a need for a manufacturing process to obtain a stable pharmaceutical composition in immediate release dosage form comprising dapagliflozin base in amorphous form and at least one pharmaceutically acceptable excipient with excellent correlation of in- vitro and in-vivo release attributes without pre-treatment such as to form adsorbate, solid dispersion or co-crystal structure with a polymer that binder functionality. Summary Of The Invention The object of this invention relates to pharmaceutical composition comprising dapagliflozin base in amorphous form and at least one pharmaceutically acceptable excipient. It is an object of the present invention is that dapagliflozin base in amorphous form and at least one pharmaceutically acceptable excipient present in the prepared pharmaceutical composition is used for the treatment of major depressive disorder (MDD) in adults. In a preferred embodiment present invention, the active agent is dapagliflozin base in amorphous form, defined herein as not presenting any peaks in X-ray powder diffraction pattern. Another object of the present invention is to provide a pharmaceutical composition comprising dapagliflozin base in amorphous form and at least one pharmaceutically acceptable excipients manufactured by using direct compression process. Another object of the present invention is to provide a stable pharmaceutical composition comprising dapagliflozin base in amorphous form and at least one pharmaceutically acceptable excipients manufactured by using direct compression process. Another object of the present invention is to provide a stable pharmaceutical composition comprising dapagliflozin base in amorphous form and at least one pharmaceutically acceptable excipient manufactured by using direct compression process which presents homogenous matrix texture as well, without a pre-treatment of active substance along with any excipients presenting binder functionality. Another object of the present invention is to provide a preparation method of a pharmaceutical composition herein disclosed can be manufactured into stable oral solid dosage forms, such as tablets, film-coated tablet, capsule, and sachet. Another object of the present invention is to provide a pharmaceutical composition comprising dapagliflozin base in amorphous manufactured by using direct compression process wherein provided for the manufacture of tablets containing the active ingredient, diluent, disintegrant, glidant and lubricant selected as to be the most suitable ones with respect to the intended form of administration. The composition is also free of binder. As a routine medical approach, the second and further active ingredients to be combined with dapagliflozin are also anti-diabetic drugs, for a combined treatment of diabetes mellitus. Thus, one of the embodiment comprises the second anti-diabetic drug to be combined with dapagliflozin is metformin, or a pharmaceutically acceptable salt thereof, preferably metformin hydrochloride. Another object of the present invention is to provide a stable pharmaceutical composition comprising dapagliflozin base in amorphous and at least one pharmaceutically acceptable excipient manufactured by using direct compression process with proper bioavailability and in- vitro dissolution profile. Brief Description Of Figures And Analysis Methods Dapagliflozin base in amorphous form was characterized by X-ray powder diffraction (XRPD). The X-ray powder diffraction (XRPD) spectra shown in figure 1 was collected under the following operating conditions: CuKα radiation (λ = 1.54 Å), scanning with a 2θ angle range of 2-50° with a step size of 0.019° for 23.8 sec. Dapagliflozin base in amorphous form does not include any solvent to be identified as solvate form. This form is non-solvated and 100% amorphous. Figure 1: XRPD (X-ray powder diffraction) of the dapagliflozin base in amorphous form obtained. The x-axis shows the angle °2θ, and the y-axis the intensity in counts. Figure 2: A comparative XRPD (X-ray powder diffraction) of the pharmaceutical composition comprising dapagliflozin base in amorphous form, and the composition only comprising the pharmaceutically acceptable excipients (not includes dapagliflozin), obtained in the embodiment of the invention. The x-axis shows the angle °2θ, and the y-axis the intensity in counts. No any extra °2θ peak is arised except originated from the excipients, which means the polymorphic form of dapaglifozin base is not changed, remained as amorphous. Detailed Description Of The Invention The present invention provides a stable pharmaceutical composition comprising dapagliflozin base in amorphous form and at least one pharmaceutically acceptable excipient in the immediate release dosage form except binder, manufactured by using direct compression process. The term "dapagliflozin base in amorphous form” as used herein includes the polymorphic form of amorphous. Polymorphism is the phenomenon wherein forms have different arrangements and / or conformations of the molecules in the structure lattice. The differences in chemical and physical properties cause to obtain large variations between drug substances due to affecting quality, safety, and efficacy of the drug product as a whole. Therefore, characterization of the polymorphs of a drug substance is very important and should be done to obtain the appropriate drug product with bioavailability and bioequivalence. An amorphous structure has no dedicated or definite molecule organization. Also, there is only a glass transition temperature instead of an accurate melting point (temperature). Thus, it is understood that the decomposition begins at low temperatures that could be challenging during manufacturing, particularly in tablet compression and coating processes. X-ray diffraction (XRD) or X-ray powder diffraction (XRPD) analysis is a rapid analytical technique that provides a unique and highly effective method of determining the crystallinity of materials based on their diffraction pattern and can provide information on unit cell dimensions. XRPD analysis is a key quality control tool in regulatory purposes or during drug development due to detecting polymorphic changes occurring during storage or manufacturing process where temperature and time variations or process steps such as compaction or milling can trigger to change the morphology of active pharmaceutical ingredients (APIs) or excipients. Therefore, detailed insights into polymorphic forms are highly relevant to control final product quality. In a preferred embodiment of the present invention is related to a pharmaceutical composition comprising dapagliflozin in amorphous form can be characterized by not showing an X-ray powder diffraction containing characteristic peaks at any 2-theta angles by using Cu-Kα radiation (^ = 1.54). Based on the performed XRPD spectra of Figure 1. Dapagliflozin is available in different particle sizes. Particle size of dapagliflozin base in amorphous form is used in the invention is between 10 micrometers to 60 micrometers. The use of micronized dapagliflozin can be challenging during direct compression manufacturing process. Direct compression method is an effective manufacturing method to obtain solid dosage forms. However, the qualitative and quantitative compositions should significantly be considered to get homogenous and processable matrix textures. The preferred embodiment comprises dapagliflozin base is in amorphous form and very low amount between 4-6% by weight of the composition. Based on EPAR document belongs to Forxiga reference product, dapagliflozin has poor flow, cohesiveand sticky nature. These are the major obstacles to avoid the inventors to use direct compression method. On the other hand, the targeted dose is very low. However, dapagliflozin has the affinity to present oxidative degradation in the presence of excipients and moisture. These are the main reasons to use propandiol salt of dapagliflozin by the originator company. Thus, challenging issues may most probably be seen while using direct compression process to get stable drug product with dapagliflozin base in amorphous form. Therefore, excipients and their use are the key materials to overcome all of them get a stable drug product. In another preferred embodiment of the present invention also comprises at least one pharmaceutically acceptable excipient presented in the prepared pharmaceutical composition wherein the composition is manufactured by using direct compression process to get solid dosage forms containing the active ingredient, diluent, disintegrant, glidant and lubricant selected as to be the most suitable ones with respect to the intended form of administration. In a preferred embodiment of the present invention, at least two diluents selected from the group comprising compressible sugar, dextrates, dextrin, dextrose, lactose, mannitol, microcrystalline cellulose, powdered cellulose, sorbitol, sucrose, talc, and the like and mixtures thereof. Preferably, diluents are lactose and microcrystalline cellulose. In a preferred embodiment of the present invention, the glidant selected from the group comprising silicon dioxide, colloidal silicon dioxide, magnesium silicate, magnesium trisilicate, talc and other known glidant. Preferably, the glidant is silicon dioxide. In a preferred embodiment of the present invention, the disintegrant selected from the group comprising croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, starch, sodium starch glycolate, carmellose, and the like and mixtures thereof. Preferably, the disintegrant is crospovidone. In a preferred embodiment of the present invention, the lubricant selected from the group comprising magnesium stearate, calcium stearate, stearic acid, talc, polyethylene glycol, sodium lauryl sulphate and magnesium lauryl sulphate and the like and mixtures thereof. Preferably, the lubricant is magnesium stearate. In a preferred embodiment of the present invention is to provide a pharmaceutical composition for oral administration. Suitable solid oral dosage forms are selected from the group comprising tablet, capsule, granule, powder, preferably the solid oral dosage form is tablet. The inventors surprisingly have found that prepared pharmaceutical composition by using direct compression process comprises dapagliflozin in amorphous form and at least one pharmaceutically acceptable excipient exhibit proper correlation between in vitro and in vivo release profiles. The embodiment was designed with adjusted quantitative composition composed of pharmaceutically acceptable ingredients mentioned above by using direct compression process. The embodiment, Example 1 is given in Table 1 below. The proposed embodiment provides an immediate release oral solid pharmaceutical composition wherein the amount ranges in w / w% by weight of the total composition are as stated in the table below. Table 1: Unit Formula of Example 1 Ingredients w / w, % Dapagliflozin base in amorphous form 4-6 Lactose 20-25 Microcrystalline cellulose 65-70 Crospovidone 4-8 Silicone dioxide 0.1-1 Polyethylene glycol 1-5 Core tablet 100.0 The detailed manufacturing steps are presented below: a. Dapagliflozin base in amorphous form, Lactose, Silicon dioxide, Polyethylene glycol and Crospovidone are screened through a proper sieve and stirred, b. Polyethylene glycol is screened through a proper sieve and added to the powder mixture prepared in Step (a) and stirred to obtain a uniform final blend, c. Tablets are compressed with the final blend in Step (b) and optionally coated. Nevertheless, sticking problem was observed during the manufacturing process. No further actions were able to be performed. Another embodiment was designed by changing the type of lubricant. The embodiment, Example 2 is given in Table 2 below. The proposed embodiment provides an immediate release oral solid pharmaceutical composition wherein the amount ranges in w / w% by weight of the total composition are as stated in the table below. Table 2: Unit Formula of Example 2 Ingredients w / w, % Dapagliflozin base in amorphous form 4-6 Lactose 20-25 Microcrystalline cellulose 65-70 Crospovidone 4-8 Silicone dioxide 0.1-1 Magnesium stearate 0.1-1 Core tablet 100.0 The detailed manufacturing steps are presented below: a. Dapagliflozin base in amorphous form, Lactose, Microcrystalline cellulose, Silicon dioxide and Crospovidone are screened through a proper sieve and stirred, b. Magnesium stearate is screened through a proper sieve and added to the powder mixture prepared in Step (a) and stirred to obtain a uniform final blend, The obtained final blend does not present a uniform blend texture and not able to be compressed for tableting. Therefore, another embodiment was proposed to over this problem. Since the sticking problem was solved, type of excipients and their quantities were not changed. Instead, processability was re-designed. The embodiment, Example 3 is given in Table 3 below. The proposed embodiment provides an immediate release pharmaceutical composition in accordance with the present invention wherein the amount ranges in w / w% by weight of the total composition are as stated in the table below. Table 3: Unit Formula of Example 3 Ingredients w / w, % Dapagliflozin base in amorphous form 4-6 Lactose 20-25 Microcrystalline cellulose 65-70 Crospovidone 4-8 Silicone dioxide 0.1-1 Ingredients w / w, % Magnesium stearate 0.1-1 Core tablet 100.0 The detailed manufacturing steps are presented below: a. Dapagliflozin base in amorphous form, Lactose, half amount of Microcrystalline cellulose quantity, Silicon dioxide and Crospovidone are screened through a proper sieve and stirred, b. The rest of Microcrystalline cellulose amount is added to the powder mixture obtained in Step (a). c. Magnesium stearate is screened through a proper sieve and added to the powder mixture prepared in Step (b) and stirred to obtain a uniform final blend, d. Tablets are compressed with the final blend presenting homogeneous texture in Step (c) and optionally coated. In this embodiment, total amount of microcrystalline cellulose was used in two equal amounts to carry out dilution process in two steps. Tablets are subjected into in-vitro dissolution study. The conditions of dissolution study are described in international guidelines and identified as 900 mL of dissolution medium, 50 rpm at temperature of 37°C±0.5°C with USP apparatus is II (Paddle) in three different physiological media to stimulate the behavior of drug product during gastrointestinal tract. The physiological media are 0.1N HCI, pH 4.5 acetate buffer and pH 6.8 phosphate buffer. Table 4: The results of dissolution study for Example 3 in 0.1N HCI Results, % Time, min Example 1 Reference drug product (FORXIGA®) 10 101 100 15 101 100 20 101 100 30 101 99 45 101 99 60 100 98 Table 5: The results of dissolution study for Example 3 in pH 4.5 acetate buffer Results, % Time, min Example 1 Reference drug product (FORXIGA®) 10 101 101 15 101 101 20 101 101 30 101 100 45 100 100 60 100 99 Table 6: The results of dissolution study of Example 3 in pH 6.8 phosphate buffer Results, % Time, min Example 1 Reference drug product (FORXIGA®) 10 104 102 15 104 102 20 104 101 30 104 101 45 103 100 60 103 100 The similarity is clearly observed for the product bioequivalency between example and reference drug product due to differences in formulation design, manufacturing process and the polymorphic form of active substance. In the present invention, the similarity between Example-3 and the reference product in each medium is obviously very high. It is understood that dapagliflozin base in amorphous form presented in the prepared pharmaceutical composition exhibits proper in vitro dissolution characteristics. After the evaluation of the in-vitro dissolution results, the prepared tablets were subjected to bioequivalence study. According to “Guideline on the Investigation on Bioequivalence” published by EMA, to establish bioequivalence of the test product with that of reference product. The assessment of bioequivalence is based upon 90% Confidence Intervals (CI) for the ratio of Test / Reference products and that, CI should be contained within the acceptance interval of 80.00-125.00%. Table 7: In-vivo Bioequivalence study results Pharmacokinetic Test / Reference Parameters Ln_Cmax 93.9 Ln-AUC 98.1 PK parameters (AUC and Cmax) are in line with the specifications based on Guideline on the Investigation on Bioequivalence. According to the results of the in-vitro and in-vivo release profile, pharmaceutical composition comprises dapagliflozin base in amorphous form and at least one pharmaceutically acceptable excipient presents convenience with the reference drug product. Example-3 was also examined regarding related substances and genotoxic impurity due to comprising amorphous form of dapagliflozin base that presents degradation attributes in nature. Thus, Example-3 was subjected to cabinets under various stability conditions. The most adversely effective condition is the accelerated stability condition with 40°C±0.5°C, 75%±5% RH for 6-month period. The examination for related substances and genotoxic impurities was performed by using validated analytical methods based on the international guidelines with the Example-3 samples stored under accelerated stability conditions. Table 8: Impurity profile of the Example-3 under accelerated stability conditions at 6thmonth period Nitrosamine impurity, %*Total Related substances, %Example-3 Not detected 0.18 *specified limit is 1.0% In the manufacturing process and the composition of Example 3, amorphous dapagliflozin was demonstrated to be polymorphically stable by having no polymorphic conversion in the amorphous state despite being subjected to several stress factors during manufacturing process including excipients compatibility or during storage. According to all results of the impurity analysis, in the embodiment of the present invention, a stable composition comprising dapagliflozin base in amorphous form and at least one pharmaceutically acceptable excipient, wherein - the manufacturing method is direct compression process, - the composition comprises microcrystalline cellulose as diluent, - the total amount of microcrystalline cellulose is processed in ratio of 1:1 through two steps in direct compression process. While the invention has been described with respect to the above specific embodiments, it should be recognized that various modifications and changes may be made to the invention by those skilled in the art which also fall within the scope of the invention as defined by the appended claims.

Claims

CLAIMS 1. A stable pharmaceutical composition comprising dapagliflozin base in amorphous form and at least one pharmaceutically acceptable excipient except any excipient having binder function, wherein; - the manufacturing method is direct compression process, - the composition comprises microcrystalline cellulose as a diluent, - the total amount of microcrystalline cellulose is processed in a ratio of 1:1 through two steps in direct compression process.

2. A stable pharmaceutical composition according to Claim 1, wherein the composition comprises dapagliflozin base in amorphous form equivalent to 5 mg to 10 mg dapagliflozin.

3. A stable pharmaceutical composition according to any one of the preceding claims, wherein at least one pharmaceutically acceptable excipient is selected from diluent, disintegrant, glidant and lubricant.

4. A stable pharmaceutical composition according to Claim 3, wherein at least one pharmaceutically acceptable excipient is diluent selected from compressible sugar, dextrates, dextrin, dextrose, lactose, mannitol, microcrystalline cellulose, powdered cellulose, sorbitol, sucrose, talc and mixtures thereof.

5. A stable pharmaceutical composition according to Claim 4, wherein the diluents are lactose and microcrystalline cellulose.

6. A stable pharmaceutical composition according to Claim 3, wherein at least one pharmaceutically acceptable excipient is a disintegrant selected from croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, starch, sodium starch glycolate, carmellose and mixtures thereof.

7. A stable pharmaceutical composition according to Claim 6, wherein the disintegrant is crospovidone.

8. A stable pharmaceutical composition according to Claim 3, wherein at least one pharmaceutically acceptable excipient is a glidant selected from silicon dioxide, colloidal silicon dioxide, magnesium silicate, magnesium trisilicate, talc and mixtures thereof.

9. A stable pharmaceutical composition according to Claim 8, wherein the glidant is silicon dioxide.

10. A stable pharmaceutical composition according to Claim 3, wherein at least one pharmaceutically acceptable excipient is a lubricant selected from magnesium stearate, calcium stearate, stearic acid, talc, polyethylene glycol, sodium lauryl sulphate and magnesium lauryl sulphate and mixtures thereof.

11. A stable pharmaceutical composition according to Claim 10, wherein the lubricant is magnesium stearate.

12. A stable pharmaceutical composition according to any one of the preceding claims, wherein the composition is in solid dosage form.

13. A stable pharmaceutical composition according to any one of the preceding claims for use in the treatment of the Type 2 diabetes.

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