IMMEDIATE RELEASE FORMULATION OF A TRIPLE COMBINATION OF ACTIVE PHARMACEUTICAL INGREDIENTS USEFUL IN THE TREATMENT OF POLYCYSTIC OVARY SYNDROME

Abstract

Immediate release formulation of a triple combination of active pharmaceutical ingredients useful in the treatment of polycystic ovarysyndrome It relates to an immediate release formulation for oral administration, comprising; a) a combination of three active pharmaceutical ingredients which are spironolactone; pioglitazone or a salt thereof; and metformin or a salt thereof; and b) solid polyethylene glycol having an average molecular weight from 3350 to 8000 g/mol; wherein: each of the active pharmaceutical ingredients are present in a therapeutically effective amount; and the polyethylene glycol is present in an amount such that decreases the dissolution profiles in vitro of each one of the active pharmaceutical ingredients without modifying the disintegration time of the formulation compared with the dissolution profiles of each one of the active pharmaceutical ingredients of a formulation having the same composition but without the solid polyethylene glycol, as well as, to its preparation process.

Claims

1. An immediate release formulation for oral administration, comprising; a) a combination of three active pharmaceutical ingredients which are spironolactone; piogllitazone or a salt thereof; and metformin or a salt thereof; and b) solid polyethylene glycol having an average molecular weight selected from 3350 to 8000 g/mol; wherein: each of the active pharmaceutical ingredients are present in a therapeutically effective amount; and the polyethylene glycol is present in an amount that decreases the dissolution profiles in vitro of each one of the active pharmaceutical ingredients without modifying the disintegration time of the formulation when compared with the dissolution profiles of each one of the active pharmaceutical ingredients of a formulation having the same composition but without the solid polyethylene glycol.

2. The oral immediate release formulation according to claim 1, wherein the formulation comprises an outer coating which is a film-forming coating.

3. The oral immediate release formulation according to claim 1, wherein the formulation is a tablet.

4. The immediate release formulation according to claim 3, wherein the polyethylene glycol is in an amount selected from 4 to 10% by weight with respect to the total weight of the formulation.

5. The oral immediate release formulation according to claim 4, wherein the solid polyethylene glycol is present in an amount selected from 6 to 8% by weight with respect to the total weight of the formulation.

6. The oral immediate release formulation according to claim 5, wherein the solid polyethylene glycol (PEG) is polyethylene glycol having an average molecular weight selected from 4000-6000 g/mol.

7. The oral immediate release formulation according to claim 6, wherein the solid polyethylene glycol (PEG) is polyethylene glycol having an average molecular weight of 4000 g/mol.

8. The oral immediate release formulation according to claim 7, which further comprises at least one additional pharmaceutical excipient selected from the group consisting of: a binder, a diluent, a disintegrant.

9. The oral immediate release formulation according to claim 8, wherein it comprises a binder which is polyvinylpirrolidone; a diluent which is microcrystalline cellulose, a disintegrant which is croscarmellose sodium, and lubricant which is magnesium stearate.

10. The oral immediate release formulation according to claim 9, wherein the active pharmaceutical ingredients are spironolactone, pioglitazone hydrochloride, and metformin hydrochloride.

11. The oral immediate release formulation according to claim 1, wherein: a) the therapeutically effective amount of spironolactone is selected from 25 to 100 mg; b) the therapeutically effective amount of pioglitazone or the salt thereof is selected from 5-15 mg; and c) the therapeutically effective amount of metformin or the salt thereof is selected from 500-1500 mg.

12. The immediate release formulation according to claim 1, comprising the binder, the diluent, the disintegrant, and the lubricant, and wherein the binder is in an amount selected from 5.5 -7.5% by weight, the diluent is in an amount selected from 1.5 to 3% by weight, the disintegrant is in an amount selected from 3 to 4.5% by weight, and the lubricant is in an amount selected from 0.5 to 1.5% by weight, with respect to the total weight of the formulation.

13. The oral immediate release formulation according to claim 1, which is a film-coated tablet for per administration once a day, wherein a) the spironolactone is in an amount of 50 mg; b) the pioglitazone hydrochloride is in an amount of 8.3 mg; c) the metformin hydrochloride is in an amount of 850 mg; and d) the polyethylene glycol 4000 is in an amount of 80 mg.

14. The oral immediate release formulation according to claim 13, further comprising: e) 76.8 mg of polyvinylpyrrolidone; f) 26.4 mg of microcrystalline cellulose; g) 42.8 mg of croscarmellose sodium; and h) 15.7 mg of magnesium stearate.

15. A process for preparing the immediate release formulation according to claim 1, comprising: a) wet granulating the appropriate amounts of spironolactone, pioglitazone or the salt thereof, and metformin or the salt thereof with the appropriate amount of solid polyethylene glycol having an average molecular weight selected from 3350 to 8000 g/mol, and with one or more additional excipients; b) compressing the mixture; and c) optionally coating the formulation with a film-forming coating.

16. The oral immediate release formulation according to claim 1, wherein the solid polyethylene glycol is present in an amount selected from 4 to 10% by weight with respect to the total weight of the formulation.

17. The oral immediate release formulation according to claim 2, wherein the formulation is a tablet.

18. The oral immediate release formulation according to claim 17, wherein the solid polyethylene glycol is present in an amount selected from 4 to 10% by weight with respect to the total weight of the formulation.

19. The oral immediate release formulation according to claim 18, wherein the solid polyethylene glycol (PEG) is polyethylene glycol having an average molecular weight selected from 4000-6000 g/mol.

20. The oral immediate release formulation according to claim 19, wherein the active pharmaceutical ingredients are spironolactone, pioglitazone hydrochloride, and metformin hydrochloride.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0015] FIG. 1 shows comparative in vitro dissolution profiles of Table 1 and Table 2 SPIOMET formulations of batch size of 8.5 kg (G201801911 (with solid PEG) versus 6201801910 (without solid PEG) for spironolactone.

[0016] FIG. 2 shows comparative in vitro dissolution profiles of Table 1 and Table 2 SPIOMET formulations of batch size of 8.5 kg (G201801911 versus 6201801910) for metformin. FIG. 3 shows comparative in vitro dissolution profiles of Table 1 and Table 2 SPIOMET formulations of batch size of 8.5 kg (G201801911 versus G201801910) for pioglitazone.

DETAILED DESCRIPTION OF PARTICULAR EMBODIMENTS

[0017] Spironolactone refers to a synthetic steroidal compound named 7α-Acetylthio-3-oxo-17α-pregn-4-ene-21,17β-carbolactone, which has the CAS number 52-01-7 and the formula (I) below. In most countries spironolactone is marketed within a drug formulation branded as Aldactone®.

##STR00001##

[0018] Pioglitazone refers to a compound of the class thiazolidinedione named ((±)-5-[p-[2-(5-Ethyl-2-pyridyl)ethoxy]benzyl]-2,4-thiazolidinedione, marketed as monohydrochloride and, which has the CAS number 112529-15-4 and formula (II) below. In most countries pioglitazone is marketed within a drug formulation branded as Actos®.

##STR00002##

[0019] Metformin refers to a compound named 1,1-Dimethylbiguanide marketed s monohydrochloride, which has the CAS number 1115-70-4 and the formula (III) below. In most countries metformin is marketed within a drug formulation branded as Dianben® or Glucophage®.

##STR00003##

[0020] Other pharmaceutically acceptable salts of the previous compounds may be used for the purposes of the invention. As used herein, and unless otherwise specified, the term “pharmaceutically acceptable salt” refers to salts prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Examples of suitable non-toxic acids include hydrochloride, hydrochloric, hydrobromic, phosphoric, sulfuric, acetic, benzenosulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, formic, fumaric, lactic, maleic, malic, methanesulfonic, nicotinic, stearic, succinic, tartaric, p-toluensulfonic, and the like.

[0021] The compounds of formula (I), (II), and (III) may be in crystalline form either as free solvation compounds or as solvates (e.g. hydrates), or may be in the form of cocrystals and it is intended that these forms are within the scope of the present invention.

[0022] The term “solvate” refers to a molecular complex comprising the compounds mentioned above or a salt thereof, and a stoichiometric or non-stoichiometric amount of one or more solvent molecules bound by non-covalent intermolecular forces. When the one or more solvent molecules forming part of the molecular complex is water, the solvate is a hydrate.

[0023] The term “cocrystal” refers herein to a crystalline entity with at least two different components constituting the unit cell at room temperature (20-25 ° C.) and interacting by weak interactions. Thus, in a cocrystal the active pharmaceutical ingredient crystallizes with one or more neutral components. The cocrystal may include one or more solvent molecules in the crystal lattice. The term “weak interaction” refers herein as an interaction which is neither ionic nor covalent, and includes for example: hydrogen bonds, van der Waals interactions, and rr-rr stacking.

[0024] Polyethylene glycol (PEG), also known as macrogol, is a polyether composed of repeated ethylene glycol units —[(CH2—CH2—O)n]—. CAS n°: 25322-68-3 (all PEGs). Ph. Eur n°: 1444E. Commercial PEGs are available with different degrees of polymerization and activated functional groups. For the purposes of the invention it is used solid PEG having an average molecular weight comprised between 3350 and 8000 g/mol (i.e. PEG3350-PEG 8000), preferably PEG having an average molecular weight of 4000 g/mol (PEG 4000). This polyethylene glycol is also named Polyglykol 4000 PS (powder spray) or Polyethylene glycol 4000 or Macrogol 4000. The average molecular weight of the polyethylene glycol may be determined by gel permeation chromatography using the universal calibration method (cf. European pharmacopeia 9.0, 2.2.30).

[0025] The term “percentage (%) by weight” refers to the percentage of each ingredient of the formulation in relation to the total weight of the formulation. If the formulation is a coated formulation, then the total weight refers to the total weight of the coated formulation. If the formulation is an uncoated formulation, then the total weight refers to the total weight of the uncoated formulation.

[0026] The expression “therapeutically effective amount” as used herein, refers to the amount of a compound that, when administered, alone or in combination with other active compounds, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the disease which is addressed. The particular dose of compound administered according to this invention will of course be determined by the particular circumstances surrounding the case, including the compound administered, the route of administration, the particular condition being treated, and the similar considerations.

[0027] The expression “pharmaceutically acceptable excipients or carriers” refers to pharmaceutically acceptable materials, compositions or vehicles. Each component must be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the immediate release formulation. It must also be suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity or other problems or complications commensurate with a reasonable benefit/risk ratio.

[0028] As mentioned above, it is provided an oral immediate release formulation for oral administration, comprising; a) a combination of three active pharmaceutical ingredients which are spironolactone; pioglitazone or a salt thereof; and metformin or a salt thereof; and b) a solid polyethylene glycol having an average molecular weight from 3350 to 8000 g/mol; wherein: each of the active pharmaceutical ingredients are present in a therapeutically effective amount; and the polyethylene glycol is in an amount such that decrease the dissolution profiles in vitro of each one of the active pharmaceutical ingredients without modifying the disintegration time of the formulation compared with the dissolution profiles of each one of the active pharmaceutical ingredients of a formulation having the same composition but without the solid polyethylene glycol. The oral immediate release formulation of the present invention is an oral disintegrating tablet.

[0029] In a particular embodiment, optionally in combination with one or more features of the particular embodiments defined above or below, the oral immediate release formulation of the present invention is that which comprises an outer coating: In another particular embodiment, optionally in combination with one or more features of the particular embodiments defined above or below, the oral immediate release formulation of the present invention is that where the outer coating is a film-forming coating.

[0030] In another particular embodiment, optionally in combination with one or more features of the particular embodiments defined above or below, the oral immediate release formulation of the present invention is that wherein the formulation is a tablet or capsule, preferably a tablet.

[0031] In another particular embodiment, optionally in combination with one or more features of the particular embodiments defined above or below, the oral immediate release formulation is that which is a film coated tablet.

[0032] In a particular embodiment, it is provided an immediate release formulation for oral administration, comprising a) a combination of three active pharmaceutical ingredients which are spironolactone; pioglitazone or a salt thereof; and metformin or a salt thereof; and b) a solid polyethylene glycol having an average molecular weight from 3350 to 8000 g/mol; wherein: each of the active pharmaceutical ingredients are present in a therapeutically effective amount; and the polyethylene glycol is present in an amount from 4 to 10% by weight with respect to the total weight of the formulation. When the formulation is coated, then it refers to the total weight of the coated formulation.

[0033] In another particular embodiment, optionally in combination with one or more features of the particular embodiments defined above or below, the oral immediate release formulation of the present invention is that wherein the polyethylene glycol is present in an amount from 6 to 8% by weight with respect to the total weight of the coated formulation.

[0034] In another particular embodiment, optionally in combination with one or more features of the particular embodiments defined above or below, the oral immediate release formulation of the present invention is that wherein the polyethylene glycol is present in an amount of from 7% by weight with respect to the total weight of the coated formulation.

[0035] In another particular embodiment, optionally in combination with one or more features of the particular embodiments defined above or below, the oral immediate release formulation of the present invention is that where the solid polyethylene glycol (PEG) is polyethylene glycol having an average molecular weight of 4000-6000 g/mol. In another particular embodiment, optionally in combination with one or more features of the particular embodiments defined above or below, the oral immediate release formulation of the present invention is that where the solid polyethylene glycol (PEG) is polyethylene glycol having an average molecular weight of 4000 g/mol.

[0036] In a particular embodiment, optionally in combination with one or more features of the particular embodiments defined above or below, the oral immediate release formulation of the present invention is that which further comprises at least one additional pharmaceutical excipient selected from the group consisting of: a binder, a diluent, a disintegrant, and a lubricant.

[0037] In another particular embodiment, optionally in combination with one or more features of the particular embodiments defined above or below, the oral immediate release formulation of the present invention is that which comprises: at least a binder, at least a diluent, at least a disintegrant, and at least a lubricant.

[0038] Examples of binders appropriate for the present invention are polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropylcellulose, or carboxymethylcellulose.

[0039] Examples of diluents appropriate for the present invention are microcrystalline cellulose, silicifed microcrystalline cellulose, powdered cellulose, anhydrous lactose, lactose monohydrate, modified lactose, dibasic calcium phosphate, tribasic calcium phosphate, maize starch, pregelatinized starch, calcium carbonate, sucrose, glucose, dextrates, dextrins, dextrose, fructose, lactitol, mannitol, sorbitol, or starch.

[0040] Examples of disintegrants appropriate for the present invention are croscarmellose sodium, crospovidone, sodium starch glycolate, corn starch, potato starch, calcium silicated, or low substituted hydroxypropyl cellulose.

[0041] Examples of lubricants appropriate for the present invention are magnesium stearate, magnesium lauryl sulfate, sodium stearyl fumarate, sucrose esters, fatty acids, or stearic acid.

[0042] Additionally, the compositions of the present invention may contain other ingredients, such as fragrances, colorants, and other components known in the state of the art for use in formulations for oral administration.

[0043] In another particular embodiment, optionally in combination with one or more features of the particular embodiments defined above or below, the oral immediate release formulation of the present invention is that which comprises a binder which is polyvinylpyrrolidone; a diluent which is microcrystalline cellulose, a disintegrant which is croscarmellose sodium, and lubricant which is magnesium stearate.

[0044] In another particular embodiment, the immediate release formulation of the present invention is that where the binder is in an amount from 5.5 -7.5% by weight, the diluent is in an amount from 1.5 to 3% by weight, the disgregant is in an amount from 3 to 4.5% by weight, and the lubricant is in an amount from 0.5 to 1.5% by weight, with respect to the total weight of the formulation. When the formulation is coated, then it refers to the total weight of the coated formulation.

[0045] In another particular embodiment, optionally in combination with one or more features of the particular embodiments defined above or below, the oral immediate release formulation of the present invention is that where: the spironolactone, the pioglitazone or a salt thereof, and the metformin or a salt thereof, are the only active pharmaceutical ingredients of the formulation.

[0046] In another particular embodiment, optionally in combination with one or more features of the particular embodiments defined above or below, the oral immediate release formulation of the present invention is that where: the active pharmaceutical ingredients are spironolactone, pioglitazone hydrochloride; and metformin hydrochloride.

[0047] In another particular embodiment, optionally in combination with one or more features of the particular embodiments defined above or below, the oral immediate release formulation of the present invention is that wherein: a) the therapeutically effective amount of spironolactone is 4-5% by weight; b) the therapeutically effective amount of piogllitazone or a salt thereof is 0.5-1% by weight; and c) the therapeutically effective amount of metformin or a salt thereof is 73-75% by weight, with respect to the total weight of the formulation. In another particular embodiment, the oral immediate release formulation of the present invention is that wherein: a) the therapeutically effective amount of spironolactone or a salt thereof is 4.3t% by weight; b) the therapeutically effective amount of piogllitazone or a salt thereof is 0.7% by weight; and c) the therapeutically effective amount of metformin or a salt thereof is 73% by weight, with respect to the total weight of the formulation (coated formulation).

[0048] In a particular embodiment, optionally in combination with one or more features of the particular embodiments defined above or below, the oral immediate release formulation of the present invention is that where: a) the therapeutically effective amount of spironolactone is from 25 to 100 mg; b) the therapeutically effective amount of pioglitazone or a salt thereof is 5-15 mg; and c) the therapeutically effective amount of metformin or a salt thereof is 500-1500 mg. In another particular embodiment, optionally in combination with one or more features of the particular embodiments defined above or below, the immediate release formulation of the present invention typically comprises between 30-60 mg of spironolactone, 5-10 mg of pioglitazone hydrochloride, 600-1000 mg metformin hydrochloride. Generally, the previous amounts correspond to a daily dose of each of the active ingredients.

[0049] It is preferred that a daily dose of the immediate release formulation according to the present invention comprising the required daily dose of spironolactone, pioglitazone or a salt thereof, and metformin or a salt thereof is formulated in a unit single dose, i.e. comprises a therapeutically effective amount of each active pharmaceutical ingredient for a single dose administration: Particularly, the unit single dose are single tablets or capsules, which can be coated and which can be readily ingested.

[0050] In another particular embodiment, the oral immediate release formulation of the present invention is that which is a film-coated tablet per administration once a day, wherein a) the spironolactone is in an amount of 50 mg; b) the pioglitazone hydrochloride is in an amount of 8.3 mg (8.3 mg Pioglitazone HCl corresponds to 7.5 mg of Pioglitazone base); c) the metformin hydrochloride is in an amount of 850 mg; and d) the polyethylene glycol 4000 is in amount of 80 mg. The dose of pioglitazone is around half of the commercial one (7.5 mg vs.15 mg), the dose of metformin is also lower (850 mg vs. the normal dose that is two tablets of 850mg per day or 1 tablet per day of 1000 mg), the dose of spironolactone is 50 mg vs. the commercial one (25 or 100 mg).

[0051] In another particular embodiment, the oral immediate release formulation of the present invention further comprises: e) 76.8 mg of polyvinylpyrrolidone; f) 26.4 mg of microcrystalline cellulose; g) 42.8 mg of croscarmellose sodium; and h) 15.7 mg of magnesium stearate.

[0052] The immediate release formulation of the present invention can be prepared according to methods well known in the state of the art. In a particular embodiment, the immediate release formulation of the present invention is prepared by wet granulation. The oral immediate release formulation of the present invention, wherein the formulation is prepared by wet granulation is also part of the invention.

[0053] In a particular embodiment, the immediate release formulation of the present invention is prepared by a process comprising the steps of: a) wet granulating the appropriate amounts of spironolactone, pioglitazone or a salt thereof, and metformin or a salt thereof with the appropriate amount of solid polyethylene glycol having an average molecular weight from 3350 to 8000 g/mol, and with one or more additional excipients; b) compressing the mixture; c) optionally coating the formulation with a film-forming coating. The term appropriate amounts of spironolactone, pioglitazone or a salt thereof, and metformin or a salt thereof refers to the therapeutically effective amounts of each of the active pharmaceutical ingredients. The appropriate amount of polyethylene glycol is such that decreases the dissolution profiles in vitro of each one of the active pharmaceutical ingredients without modifying the disintegration time of the formulation compared with the dissolution profiles of each one of the active pharmaceutical ingredients of a formulation having the same composition but without the solid polyethylene glycol.

[0054] In a particular embodiment, the immediate release formulation of the present invention can be prepared by a process comprising the steps of: a) wet granulating the active pharmaceutical ingredients with solid polyethylene glycol having an average molecular weight from 3350 to 8000 g/mol; wherein the polyethylene glycol is in an amount from 6 to 8% by weight with respect to the total weight of the formulation, and with one or more additional excipients; b) compressing the mixture; and c) optionally coating the formulation with a film-forming coating.

[0055] The use of solid PEG in the immediate release formulation of the present invention, increases the compressibility of the granule using a wide range of compression force at industrial scale, generally the compression range being from 18 to 32 KN. This wide range is advantageous since it means that any small variation on the equipment when scaling the process, does not affect the process, which ensures the robustness of the compression.

[0056] In a particular embodiment, a suspension of a pigmented film coating based on polymer with the following composition Polyvinyl alcohol (PVA) partially hydrolysed, Talc, Titanium dioxide, Polyethylene glycol, Red iron oxide previously dispersed in purified water is used to coat the formulation.

[0057] In another particular embodiment, the process includes mixing metformin hydrochloride, spironolactone, pioglitazone hydrochloride, povidone k-30 and half of the croscarmellose sodium; then granulating the mixture with purified water, sieving the wet granulate, drying the sieved wet granulate, sieving the dried granulate, mixing it with croscarmellose sodium, polyethylene glycol 4000 PS, microcrystalline cellulose, and magnesium stearate and tablet the final blend. Finally, film-coat the cores thus obtained with a suspension of the pigmented film coating based on PVA polymer previously dispersed in purified water.

[0058] Throughout the description and claims the word “comprise” and variations of the word, are not intended to exclude other technical features, additives, components, or steps. Furthermore, the word “comprise” encompasses the case of “consisting of”. Additional objects, advantages and features of the invention will become apparent to those skilled in the art upon examination of the description or may be learned by practice of the invention. The following examples and drawings are provided by way of illustration, and they are not intended to be limiting of the present invention. Furthermore, the present invention covers all possible combinations of particular and preferred embodiments described herein.

EXAMPLES

Example 1

Preparation of the SPIOMET Immediate Release Oral Formulation with Polyethylene Glycol 4000

[0059] The immediate release oral formulation of the present invention was prepared by wet granulation followed by compression and film coating following the method illustrated below:

[0060] 1. Metformin hydrochloride is placed it in the high shear and mix 10 min.

[0061] 2. Put together Spironolactone, Pioglitazone hydrochloride, Povidone k-30 and half of the croscarmellose sodium and place the mixture in the high shear mixer together with Metformin hydrochloride

[0062] 3. Mix the blend of step 2 in the high shear mixer

[0063] 4. Granulate the mixture of step 3 in the high shear mixer with purified water.

[0064] 5. Sieve the wet granulate from step 4

[0065] 6. Dry in a fluid bed the wet granulate sieved from step 5.

[0066] 7. Sieve the dry granulate from step 6.

[0067] 8. Mix the sieved dried granulate with the previously sieved croscarmellose sodium, Polyethylene glycol 4000 PS and microcrystalline cellulose.

[0068] 9. Mix the blend of step 8 with the previously sieved magnesium stearate.

[0069] 10. Tablet the final blend obtained in step 9.

[0070] 11. Film-coat the cores obtained in step 10 with a suspension of pigmented film coating based on PVA polymer previously dispersed in purified water.

[0071] Table 1 below show the content of the immediate release formulations prepared according to the steps above at two different scales 8.5 kg and 40 kg:

TABLE-US-00001 TABLE 1 List of components of SPIOMET immediate release mg/film-coated oral formulation with PEG and its function tablets % in the film Batch size 8.5 Kg G201801911 coated tablet Batch size 40 Kg H1756A (w/w) Metformin HCl (active substance) 850.00 72.56%  Spironolactone (active substance) 50.00 4.27% Pioglitazone HCl (active substance) 8.27(1) 0.71% Povidone K-30 (binder) 76.80 6.56% Microcrystalline cellulose (diluent) 26.38 2.25% Croscarmellose sodium (disintegrant) 42.80 3.65% Polyethylene glycol 4000 PS (binder, plasticizer) 80.00 6.83% Magnesium stearate (lubricant) 15.75 1.34% Purified water(2) (solvent) q.s.(2) — Total core weight 1150.00 mg — pigmented film coating based on PVA polymer 21.40 1.83 Purified water(2) (solvent) q.s.(2) — Total weight 1171.40 mg  100% (1)8.27 mg Pioglitazone HCl corresponds to 7.5 mg of Pioglitazone base (2)Evaporated during the process. Not present in the final formulation

Example 2

Preparation of the SPIOMET Immediate Release Oral Formulation without Polyethylene Glycol 4000

[0072] The immediate release oral formulation of the present invention was prepared by wet granulation followed by compression and film coating following the method illustrated below:

[0073] 1. Metformin hydrochloride is placed it in the high shear and mix 10 min.

[0074] 2. Put together Spironolactone, Pioglitazone hydrochloride, Povidone k-30 and half of the croscarmellose sodium and place the mixture in the high shear mixer together with Metformin hydrochloride

[0075] 3. Mix the blend of step 2 in the high shear mixer

[0076] 4. Granulate the mixture of step 3 in the high shear mixer with purified water.

[0077] 5. Sieve the wet granulate from step 4

[0078] 6. Dry in a fluid bed the wet granulate sieved from step 5.

[0079] 7. Sieve the dry granulate from step 6.

[0080] 8. Mix the sieved dried granulate with the previously sieved croscarmellose sodium and microcrystalline cellulose.

[0081] 9. Mix the blend of step 8 with the previously sieved magnesium stearate.

[0082] 10. Tablet the final blend obtained in step 9.

[0083] 11. Film-coat the cores obtained in step 10 with a suspension of pigmented film coating based on PVA polymer previously dispersed in purified water.

[0084] Table 2 below show the content of the immediate release formulations without polyethylene glycol 4000 prepared according to the steps at two different scales 8.5 kg and 40 kg.

[0085] Note that the 40 kg scale-up batch the resulted granules and the final mixture couldn't be compressed into tablets because it turned out to be a process dependent formulation where granulation step is critical.

TABLE-US-00002 TABLE 2 List of components of SPIOMET immediate release mg/film-coated oral formulation without PEG and its function tablets % in the film Batch size 8.5 Kg G201801910 coated tablet Batch size 40 Kg H1756B (w/w) Metformin HCl (active substance) 850.00 77.88%  Spironolactone (active substance) 50.00 4.58% Pioglitazone HCl (active substance) 8.27(1) 0.76% Povidone K-30 (binder) 76.80 7.04% Microcrystalline cellulose (diluent) 26.38 2.42% Croscarmellose sodium (disintegrant) 42.80 3.92% Magnesium stearate (lubricant) 15.75 1.44% Purified water(2) (solvent) q.s.(2) — Total core weight 1070.00 mg — pigmented film coating based on PVA polymer 21.40 1.96% Purified water(2) (solvent) q.s.(2) Total weight 1091.40 mg  100% (1)8.27 mg Pioglitazone HCl corresponds to 7.5 mg of Pioglitazone base (2)Evaporated during the process. Not present in the final formulation

Example 3

Dissolution test of spironolactone of SPIOMET immediate release oral formulation

[0086] Dissolution test of spironolactone was performed according to EP 2.9.3 Dissolution test for solid dosage forms, current edition.

[0087] Dissolution medium: Buffer solution pH 4.5 (According to EP 5.9.17 Recommendations on methods for dosage forms testing, current edition) with 0.5% tween.

[0088] Apparatus 2 (EP 2.9.3): Paddle

[0089] Volume: 1000 mL

[0090] Temperature: 37±0.5° C.

[0091] Stirring speed: 75 rpm

[0092] Sampling times: 5, 10, 15, 30, 45 and 60 minutes.

[0093] The content of Spironolactone from the extracted samples is analyzed by reverse-phase

[0094] HPLC with UV detection method.

[0095] FIG. 1 shows comparative in vitro dissolution profiles of Table 1 and Table 2 SPIOMET formulations of batch size of 8.5 kg (G201801911 versus G201801910) for spironolactone. These results in FIG. 1 show that the release profile of spironolactone is significantly decreased (p<0.05) at 10 and 15 minutes in SPIOMET immediate release formulation with PEG (G201801911) compared with the same formulation without PEG (G201801910). The results are statistically significant.

Example 4

Dissolution test of Metformin of SPIOMET Immediate Release Oral Formulation

[0096] Dissolution test of metformin was performed according to EP 2.9.3 Dissolution test for solid dosage forms, current edition.

[0097] Dissolution medium: Buffer solution pH 4.5 (According to EP 5.9.17 Recommendations on methods for dosage forms testing, current edition) with 0.5% tween.

[0098] Apparatus 2 (EP 2.9.3): Paddle

[0099] Volume: 1000 mL

[0100] Temperature: 37±0.5° C.

[0101] Stirring speed: 75 rpm

[0102] Sampling times: 5, 10, 15, 30, 45 and 60 minutes.

[0103] The content of Metformin from the extracted samples is analyzed by reverse-phase HPLC with UV detection method.

[0104] FIG. 2 shows comparative in vitro dissolution profiles of Table 1 and Table 2 SPIOMET formulations of batch size of 8.5 kg (G201801911 versus 201801910) for metformin. These results in FIG. 2 show that the release profile of metformin is significantly decreased (p<0.05) at 5, 10 and 15 minutes in SPIOMET immediate release formulation with PEG (G201801911) compared with the same formulation without PEG (G201801910). The results are statistically significant.

Example 5

Dissolution Test of Pioglitazone of SPIOMET Immediate Release Oral Formulation

[0105] The dissolution test of pioiglitazone was performed According to EP 2.9.3 Dissolution test for solid dosage forms, current edition.

[0106] Dissolution medium: Buffer solution pH 3.0 (see preparation of the solution).

[0107] Preparation of buffer solution pH3.0: Weight 8.5g of citric acid monohydrate and 3.2 g of NaOH pellets, dissolve with 800.0 mL of purified water, add 4.4 mL HCl 37% and shake 20 minutes. Dilute to 1000.0 mL with purified water. Adjust to pH3.0±0.05 with HCl 1 M.

[0108] Apparatus 2 (EP 2.9.3.): Paddle

[0109] Volume: 1000 mL

[0110] Temperature: 37±0.5° C.

[0111] Stirring speed: 100 rpm

[0112] Sampling times: 5, 10, 15, 30, 45 and 60 minutes.

[0113] The content of Pioglitazone from the extracted samples is analyzed by reverse-phase HPLC with UV detection method.

[0114] FIG. 3 show comparative in vitro dissolution profiles of Table 1 and Table 2 SPIOMET formulations of batch size of 8.5 kg (G201801911 versus G201801910) for pioglitazone.

[0115] These results in FIG. 3 show that the release profile of pioglitazone is significantly decreased (p<0.05) at 5, 10 and 15 minutes in SPIOMET immediate release formulation with PEG (G201801911) compared with the same formulation without PEG (G201801910). The results are statistically significant.

Example 6

Disintegration Test of SPIOMET Immediate Release Oral Formulation

[0116] The disintegration test was performed according to Ph. Eur. 2.9.1 current edition (Disintegration of Tablets and capsules).

[0117] Tables 3 and 4 show disintegration data obtained with the SPIOMET formulations with PEG (G201801911, H1756A) and without PEG (G201801910), respectively.

[0118] The results in Table 3 and Table 4 show that there's no difference in the physical parameter (disintegration) of SPIOMET immediate release formulation with PEG (G201801911) and formulation without PEG (G201801910), despite the difference found between both formulations on the release profile.

TABLE-US-00003 TABLE 3 Film coated tablets SPIOMET immediate release formulation IPC-5 with PEG Batch number G201801911 H1756A Batch size 8.5 kg 40 kg Disintegration: Mean (min) <11 <11 N 6 6

TABLE-US-00004 TABLE 4 Film coated tablets SPIOMET immediate release formulation IPC-5 without PEG Batch number G201801910 H1756B(1) Batch size 8.5 kg 40 kg Disintegration: Mean (min) <11 — N 6 — (1)Note: not enough hardness was achieved (<140N) to pass friability test. Hence, no tablets were obtained

REFERENCES CITED IN THE APPLICATION

[0119] WO2017/072243A1

[0120] Handbook of Pharmaceutical Excipients, Third Edition, Edited by Arthur H. Kibbe. Ph.D. (page 393)

[0121] A. Anisha et al in Expert Opinion on drug delivery, vol. 13, no. 9, pp.1257-1275

[0122] European Pharmacopea 9.0, 2.2.30