DESC:The following specification particularly describes the invention and the manner in which it is to be performed:
NOVEL COMPOSITIONS OF AVANAFIL
FIELD OF INVENTION
The present invention relates to a pharmaceutical formulation comprising avanafil, one or more solubility enhancing substances and one or more other pharmaceutically acceptable excipients.
BACKGROUND
Erectile dysfunction (ED) or impotence is sexual dysfunction characterized by the inability to develop or maintain an erection of the penis during sexual performance. A penile erection is the hydraulic effect of blood entering and being retained in sponge-like bodies within the penis. The process is often initiated as a result of sexual arousal, when signals are transmitted from the brain to nerves in the penis. The most important organic causes are cardiovascular disease and diabetes, neurological problems (for example, trauma from prostatectomy surgery), hormonal insufficiencies (hypogonadism) and drug side effects.
Psychological impotence is where erection or penetration fails due to thoughts or feelings (psychological reasons) rather than physical impossibility; this is somewhat less frequent but often can be helped. Notably in psychological impotence, there is a strong response to placebo treatment. Erectile dysfunction can have severe psychological consequences as it can be tied to relationship difficulties and masculine self-image generally.
Besides treating the underlying causes such as potassium deficiency or arsenic contamination of drinking water, the first line treatment of erectile dysfunction consists of use of phosphodiesterase (PDE5) inhibitor drugs. PDE type 5 (PDE5) is the predominant enzyme in the corpus cavernosum smooth muscle. In men, sexual stimulation causes nitric oxide to be released from nerves and endothelial cell, which diffuses into smooth muscle cells in the walls of penile arteries and spongy erectile tissue. Nitric oxide stimulates the guanylate cyclase enzyme to synthesis cyclic guanosine monophosphate (cGMP) leading to decreased Ca2+ concentrations in smooth muscle cells causing smooth muscle relaxation and increased blood flow, thus causing penile erection to occur. In erectile tissues, cGMP is degraded by PDE5. Administration of a PDE5 inhibitor leads to higher cGMP levels and thus enhanced smooth muscle relaxation and penile blood flow.
Avanafil is a newly approved PDE5 inhibitor for oral administration, which was developed for its high selectivity for the PDE5 isoenzyme relative to other PDE5 inhibitors. However, like other phosphodiesterase inhibitors, avanafil also exhibits pH dependent solubility. Although the solubility of avanafil is high under acidic conditions, it is very low in the neutral to alkali pH.
US patent no. 7,927,623 disclosed intraorally rapidly disintegrating tablets of avanafil and other PDE5 inhibitors, which when ingested, disintegrates in the oral cavity rapidly without presenting unpleasant taste, can be quickly absorbed in the digestive tract and express efficacy are provided. The intraorally rapidly disintegrating tablets were prepared by combining the medicinal substance with a water-soluble acidic substance, coating either or both of the substances with a water-soluble coating agent being insoluble in alcoholic solvent, further adding a water-soluble binding agent being soluble in alcoholic solvent and a water-soluble saccharide, subjecting the resultant mixture to compression, and treating the products with an alcoholic solvent.
Also, US patent publication no. 2011/0229570 disclosed an orally rapidly disintegrating tablet obtained by compressing of a mixture of (a) an active ingredient, (b) an excipient having good water wettability, (c) a water-insoluble polymer that is well compactible and does not substantially cause a decrease in the water wettability of the excipient and (d) a disintegrating agent.
Similarly US patent publication no. 2007/0031349 disclosed oral formulations of a PDE5 inhibitor which provide rapid disintegration after introduction to the oral cavity, followed by buccal and/or sublingual absorption. The orally disintegrating preparations can be formulated in a variety of dosage forms including lingual strip, sublingual strip, oral mist, rapidly disintegrating tablet, lyophilized wafer, granulated particles and gum.
Additionally, US patent no. 7,501,409 disclosed compositions showing enhanced dissolution of avanafil, which comprised use of organic acids along with the drug in free base form. The examples disclose use of fumaric, tartaric, succinic, malic, ascorbic, aspartic acids as organic solubility enhancers.
Developing pharmaceutical formulations of avanafil has not proven to be an easy task. Therefore, there remains a continuing need for preparing stable dosage forms of avanafil for oral administration. Ideally, such formulations are conveniently prepared, and show a faster dissolution and quicker onset of action when administered to a subject in need of therapy through the most acceptable oral route of administration.
SUMMARY OF INVENTION
The present invention provides an alternative pharmaceutical formulation comprising avanafil or a salt thereof with solubility enhancing substance(s). The solubility enhancing substance(s) may be selected from categories of inorganic substance(s) and organic substance(s) with pH value greater than 4. The pharmaceutical formulation may be prepared without using organic acid(s) as an excipient.
An aspect of the present invention relates to a pharmaceutical formulation comprising avanafil, at least one solubility enhancing substance and one or more other pharmaceutically acceptable excipients.
DETAILED DESCRIPTION
The present invention relates to a pharmaceutical formulation comprising avanafil or a salt thereof with solubility enhancing substance, wherein, the solubility enhancing substance(s) may be selected from categories of inorganic substances and organic substances with pH value greater than 4, and other pharmaceutically acceptable excipient(s).
As used herein, the term “pharmaceutical formulation” may include solid preparations suitable for oral administration such as tablets, capsules, pills, films, caplets, granules and pellets and the like. In particular, tablets provide advantages including convenience of administration, masking effect on bitter taste. These solid preparations may be coated with sugar coating or film coating with the aim of, for example, preventing abrasion wear, masking bitterness and improving stability.
In the pharmaceutical formulation of present invention, avanafil may be present in the form of any of its pharmaceutically acceptable salts, solvates, esters and derivatives thereof. In particular, avanafil may be present as free base. Avanafil may be present as amorphous form, crystalline form, or mixtures thereof. In particular, avanafil is present in crystalline form.
In the pharmaceutical formulation of present invention, avanafil may be contained in a proportion of 0.1 to 60 % by weight of the pharmaceutical composition. In particular, avanafil may be may be contained in a proportion of 1 to 40 % by weight of the pharmaceutical composition.
As used herein, the term “solubility enhancing substance” refers to a pharmaceutical additive, which results in partial or complete solubilization of avanafil, wherein the improved solubility results in enhanced dissolution.
In the pharmaceutical formulation of present invention, the “solubility enhancing substance” may be contained in a proportion of 0.01 to 70 % by weight of the pharmaceutical composition. In particular, the “solubility enhancing substance” may be contained in a proportion of 0.10 to 60 % by weight of the pharmaceutical composition.
As used herein, the term “inorganic substance(s)” refers to inorganic substance(s), which may result in enhancement of solubility of avanafil.
In one embodiment, the “inorganic substance(s)” described above may include inorganic acid(s) selected from the group comprising of hydrobromic acid, chlorous acid, hypobromous acid, hydrochloric acid, hypochlorous acid, hypoiodous acid, iodic acid, iodous acid, hyponitrous acid, hydroiodic acid, nitric acid, nitrous acid, pernitric acid, sulfuric acid, sulfurous acid, hyposulfurous acid, chloric acid, bromous acid, bromic acid, persulfuric acid, pyrosulfuric acid, disulfurous acid, dithionous acid, tetrathionic acid, thiosulfurous acid, peroxydisulfuric acid, hydrosulfuric acid, perchloric acid, phosphoric acid, phosphorous acid, hypophosphous acid, perphosphoric acid, hypophosphoric acid, pyrophosphoric acid, hydrophosphoric acid, perchromic acid, boric acid, molybdic acid, arsenic acid, dichromic acid. In particular, the pharmaceutical formulation of the present invention may include “inorganic substances” selected from hydrochloric acid, nitric acid, sulfuric acid and phosphoric acid, used alone or in combinations thereof.
In another embodiment, the “inorganic substances” described above may include inorganic salts. The examples of inorganic salts include and are not limited to sodium carbonate, sodium chloride, sodium bromide, sodium sulfate, sodium sulfite, sodium bicarbonate, sodium phosphate, sodium hydrogen phosphate, sodium dihydrogen phosphate, sodium nitrate, sodium nitrite, potassium carbonate, potassium chloride, potassium bromide, potassium sulfate, potassium sulfite, potassium bicarbonate, potassium phosphate, potassium hydrogen phosphate, potassium dihydrogen phosphate, potassium nitrate, potassium nitrite, and like.
As used herein, the term “organic substances with pH value greater than 4” refers to any organic substances on condition that it shows pH greater than 4.0 when dissolved in water and does not interfere with the efficacy of avanafil. In particular, the term “organic substances with pH value greater than 4” refers to any organic substances on condition that it shows pH greater than 4.5 when dissolved in water and does not interfere with the efficacy of avanafil.
In one embodiment, the term “organic substances with pH value greater than 4.0 may include substances like sodium lauryl sulfate, sodium decyl sulfate, sodium dodecylbenzenesulfonate, sodium tertradecyl sulfate, sodium cetyl sulfate, sodium octadecylsulfate, sucrose fatty acid esters, D-a-tocopheryl polyethylene glycol succinate (Vitamin E TPGS), polyethylene glycol glycerides (for instance, Gelucire 33/01, Gelucire 37/02, Gelucire 39/01, Gelucire 43/01, Gelucire 43/14, Gelucire 50/02, Gelucire 62/02, etc.), PEG hydrogenated castor oils (for instance, Cremophore A25, Cremophore A6, Cremophore RH40, Cremophore RH 410, Cremophore RH60), polyoxyethylene sorbitan monolaurate (Polysorbate 20), polyoxyethylene sorbitan monopalmitate (Polysorbate 40), polyoxyethylene sorbitan monostearate (Polysorbate 60), polyoxyethylene sorbitan monooleate (Polysorbate 80), polyoxyethylene-polyoxypropylene block copolymers (Poloxamer 407, Poloxamer 188 etc.), polyoxyl hydroxyesters (for instance, Solutrol HS 15) and the like.
As used herein, the term “other pharmaceutically acceptable excipient(s)” according to the present invention include, for example, any one or more of pharmaceutical diluents, binders, disintegrants, lubricants and glidants that are useful in preparation of pharmaceutical formulations.
Various pharmaceutical diluents include, but are not limited to, sugars such as lactose monohydrate, lactose anhydrous, mannitol, starches maize starch, corn starch, pregelatinized starches such as PCS PC10 from Signet Chemical Corporation and starch 1500 and cellulose derivatives such as crystalline cellulose and powdered cellulose. Examples of crystalline cellulose products include but are not limited to Ceolus™ KG801, Avicel™ PH101, PH102, PH301, PH302 and PH-F20, PH-112, microcrystalline cellulose 114, and microcrystalline cellulose 112. Other useful diluents include, but are not limited to, sorbitol and xylitol, precipitated calcium carbonate, magnesium carbonate, dibasic calcium phosphate, and tribasic calcium phosphate.
Various pharmaceutical binders include, but are not limited to, hydroxypropylcellulose, also called (HPC-SL), various grades of hydroxypropyl methylcellulose, various grades, polyvinylpyrrolidone or povidone (such as grades K25, K29, K30, and K90), copovidone (e.g., Plasdone™ S 630), powdered acacia, gelatin, guar gum, carbomers (e.g., Carbopol® products), methylcellulose, polymethacrylates, and starches.
Various pharmaceutical disintegrants include, but are not limited to, carmellose calcium, carboxymethyl starch sodium, croscarmellose sodium, crospovidones, examples of commercially available crospovidone products including but not limited to crosslinked povidone, KOLLIDON™ CL from BASF (Germany), POLYPLASDONE™ XL, XL10, and INF-10 from ISP Inc. (USA), and low-substituted hydroxypropylcelluloses (L-HPC). Examples of low-substituted hydroxypropylcelluloses include but are not limited to low-substituted hydroxypropylcellulose LH 11 , LH21 , LH31 , LH22, LH32, LH20, LH30, LH32 and LH33 (all manufactured by Shin-Etsu Chemical Co., Ltd.). Other useful disintegrants include sodium starch glycolate, colloidal silicon dioxide, starches, and any combinations thereof.
Various pharmaceutical lubricants include magnesium stearate, glyceryl monostearate, palmitic acid, talc, carnauba wax, calcium stearate, sodium stearate, zinc stearate, polyoxyethylene monostearate, calcium silicate, silicon dioxide, hydrogenated vegetable oils and fats, stearic acid, and mixtures thereof.
Various pharmaceutical more glidants, which improve the flow of powder blends, pellets, or mini-tablets, and minimize dosage form weight variations, can be used. Useful glidants include, but are not limited to, silicon dioxide, talc, and mixtures thereof.
The pharmaceutical formulation of the present invention can be prepared using conventional methods for preparing pharmaceutical solid formulations including granulation (dry and wet), solid dispersion formation, screw extrusion, hot melt extrusion, formulating avanafil in the form of lipid based drug delivery systems and the like.
In particular, granulation is the traditional method of manufacture and is frequently used in the pharmaceutical industry as it improves flow and cohesion reduces dust and cross contamination and permits the handling of powder blends without loss of homogeneity. All of the required functionality of a compression mix i.e., good flow, good compactibility, uniform distribution of drug and controllable drug release can be built in using wet granulation without relying on the intrinsic properties of the drug or the excipients. Additionally, for high dose drugs, poor flow and compaction of the active mean that wet granulation may be the only feasible means of producing tablets, and for low dose drugs the granulation process is seen as being capable of “locking” drug into granules and thereby minimizing the potential for segregation and poor content uniformity.
Granules can be prepared by any one of known methods for preparing granules such as wet granulation, dry granulation, layering granulation, melt-granulation, impregnated-granulation, etc. The outline of respective granulation methods is described below.
(i) Wet Granulation: A mixture is prepared by mixing the drug, solubility enhancing substance(s) and, and a pharmaceutical additive(s). The drug mixture is combined with an aqueous solution of a binder and subjected to stirring and granulation with a mixer granulator or a high-shear mixer granulator, etc. In alternative process, the drug mixture is combined with an aqueous solution of a binder, kneaded, and subjected to granulation and sizing with an extrusion granulator. In still alternative process, an aqueous solution of a binder is sprayed on the drug mixture under fluid condition with a fluid bed granulator, a tumbling mixer fluid bed granulator, etc. In other alternative processes, non-aqueous solution of a binders may be used.
(ii) Dry Granulation: A drug mixture is prepared, as mentioned above, by mixing a drug, solubility enhancing substance(s) and, and a pharmaceutical additive(s), and subjected to granulation with a roller compactor, an oscillating granulator, etc.
(iii) Layering Granulation: A drug mixture similar to the above is added to inactive carriers while spraying an aqueous binder solution with a centrifugal fluid bed granulator, or the like to make the drug mixture adhere to the carries. Examples of the inactive carrier that used in this method include crystals of sugars or inorganic salts such as crystalline lactose, crystalline cellulose, crystalline sodium chloride, etc., and spherical granules such as spherical granules of crystalline cellulose (brand name: Avicel SP, Asahi Kasei Corporation), spherical granules of crystalline cellulose and lactose (brand name: Nonpareil-NP-5 and NP-7, Freund Co., Ltd.), spherical granules of purified white sugar (brand name: Nonpareil-103, Freund Co., Ltd.), spherical granules of lactose and a starch, etc.
(iv) Hot melt granulation: A drug mixture containing a melting material, which melts under heating, is prepared by mixing a medicinal substance, solubility enhancing substance(s) and, and pharmaceutical additive(s) to a melting material such as polyethylene glycol, fat, wax, etc. The resulting drug mixture is subjected to stirring and granulation with a mixer granulator or a high-shear mixer granulator, etc. at temperature under which the melting material melts. Alternatively, a drug mixture containing a melting material as mentioned above is added to rolling inactive carriers at temperature under which the melting material melts with a centrifugal fluid bed granulator, whereby making the drug mixture adhere to the carries, The same inactive carriers as mentioned above can be used.
(v) Impregnating Granulation: A drug solution containing a medicinal substance, solubility enhancing substance(s) and the like at an appropriate concentration is mixed with porous carriers thereby a sufficient amount of drug solution is made to retain in the cavities of the carrier, which is followed by drying to remove the solvent. Examples of the porous carrier that can be used include magnesium aluminometasilicate (bland name: Neusiline, Fuji Chemical Industry Co., Ltd.), calcium silicate (Florite, Eisai Co., Ltd.), etc. Examples of the solvent in which a medicinal substance, an acidic substance, etc. are dissolved include ethanol, methanol, dichloromethane, chloroform (and mixtures thereof) or the like.
Tablets can be manufactured by either subjecting a drug mixture prepared in the same manner as above to the compression molding as it is, or subjecting said drug mixture to the granulation as mentioned above, and then to the compression molding after adding a disintegrant(s), lubricant(s), etc., if needed. If desired, an additional solubility enhancing substance can be compounded.
Further, in the process wherein a drug mixture is granulated, a drug mixture containing a medicinal substance and a pharmaceutical additive(s) without a solubility enhancing substance can be granulated. The resulting granules are then mixed with solubility enhancing substance(s) and, then subjected to compression molding. In this process, granules of solubility enhancing substance(s) prepared by the granulation method above can be used, whereby tablets comprising different granules each containing a medicinal substance and an acidic substance separately are prepared.
The compression molding can be conducted using a conventional tableting machine such as rotary tableting machine, single punch tableting machine, dual tableting machine, and the like, with a compressing pressure of generally about 50 to 4,000 kg/cm2.
The capsules can be manufactured by filling in hard capsules either a drug mixture obtained by mixing a medicinal substance, solubility enhancing substance(s) and, pharmaceutical additive(s) as it is, or in the form of powders, granules or tablets prepared in a manner as described above.
Various preparations that can be obtained according to the manufacturing methods above can be coated with sugar coating or film coating for the purpose of preventing abrasion wear, masking bitterness, improving stability, and the like. The coating can be carried out in a conventional manner; however, it is preferable to confine the coating amount to such an extent that does not disturb the dissolution of a medicinal substance.
The present invention may relate to a wet granulation process of preparation of a pharmaceutical formulation, wherein the process comprises the steps of:
a) Blending avanafil, at least one solubility enhancing excipient and one or more intra-granular pharmaceutically acceptable excipients;
b) Granulating the blend of step a) using a granulating solvent;
c) Drying and sifting the granules of step b);
d) Blending the granules of step c) with extra-granular excipients; and;
e) Compressing the blend of step d) into tablets or filling the blend of step d) into capsules.
The present invention may also relate to a dry granulation process of preparation of a pharmaceutical formulation of avanafil, wherein the process comprises the steps of:
a) Blending avanafil, at least one solubility enhancing excipient and one or more intra-granular pharmaceutically acceptable excipients;
b) Granulating the blend of a) by using a roll compactor, an oscillating granulator etc.
c) Blending the granules of step c) with extra-granular excipients; and;
d) Compressing the blend of step c) into tablets or filling the blend of step c) into capsules.
The present invention may relate to a fluid bed spray granulation process of preparation a pharmaceutical formulation of avanafil, wherein the process comprises the steps of:
a) Using a non-aqueous or aqueous solvent(s) (or a mixture thereof) to preparing a polymeric solution comprising a polymer (or a mixture of polymers).
b) Granulating drug, solubility enhancing substance(s) and other excipients with binder the solution obtained in step a).
c) Drying the wet mass in fluid bed equipment to get dried granules.
d) Blending the granules of step c) with extra-granular excipients; and;
e) Compressing the blend of step d) into tablets or filling the blend of step d) into capsules.
The present invention may relate to a fluid bed spray granulation process of preparation a pharmaceutical formulation of avanafil, wherein the process comprises the steps of:
a) Using a non-aqueous or aqueous solvent(s) (or a mixture thereof) for preparing a polymeric solution comprising a polymer (or a mixture of polymers).
b) Granulating the drug and other excipients (if required) with the binder solution obtained in step a).
c) Drying the wet mass using a fluid bed equipment to obtain dry granules.
d) Unit operations similar to step a), b) and c), preparing granules of solubility enhancing excipient and other excipients (if required).
e) Mixing appropriate proportions of granules of step c) and step d).
f) Blending the granules of step e) with extra-granular excipients; and;
g) Compressing the blend of step f) into tablets or filling the blend of step f) into capsules.
Various solvents can be used in the processes for preparation of pharmaceutical formulations of the present invention, include but are not limited to, water, methanol, ethanol, acidified ethanol, acetone, diacetone, polyols, polyethers, oils, esters, alkyl ketones, methylene chloride, isopropyl alcohol, butyl alcohol, methyl acetate, ethyl acetate, isopropyl acetate, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethylsulphoxide, N,N-dimethylformamide, tetrahydrofuran, and mixtures thereof.
While this invention has been described with reference to specific embodiments, the scope of the invention is not limited to these embodiments alone. Further some of the embodiments are illustrated as working examples below and are meant to be representative only. The invention may be construed in any other forms and embodiments which may be understood and applied by a person skilled in the art within the scope of the present invention.
EXAMPLES
The following examples use hydrochloric acid as the solubility enhancing substance.
Example 1:
(1) Avanafil and other excipients were sifted across quadro sifter.
(2) Hydrochloric acid was dissolved in water, to which hydroxypropyl cellulose (HPC-SL) was added gradually and dissolved under stirring.
(3) Avanafil and mannitol were dry mixed in a rapid mixer granulator for suitable period of time.
(4) The dry mix of step (3) was granulated with the binder solution of step (2) in a rapid mixer granulator till suitable granules were obtained.
(5) The wet granules were dried in a fluid bed dryer under appropriate drying conditions till attaining desired weight loss on drying (LOD).
(6) Dried granules were subjected to appropriate sizing and milling operations.
(7) HPC-SL and precipitated calcium carbonate were added to the granules of step (6) and mixed in a double cone blender for appropriate time.
(8) Magnesium stearate was used to lubricate the blend of step (7) for suitable time.
(9) Lubricated blend of step (8) was used for compression using oval shaped punches.
Example 2:
(1) Avanafil and other excipients were sifted across quadro sifter.
(2) Hydrochloric acid was dissolved in water, to which HPC-SL was added gradually and dissolved under stirring.
(3) Avanafil and mannitol were dry mixed in a fluid bed equipment for suitable period of time.
(4) The dry mix of step (3) was granulated with the binder solution of step (2) in a fluid bed equipment till suitable granules were obtained.
(5) The wet granules were dried in the fluid bed equipment under appropriate drying conditions till desired LOD.
(6) Dried granules were subjected to appropriate sizing and milling operations.
(7) HPC-SL and precipitated calcium carbonate were added to the granules of step (6) and mixed in a double cone blender for appropriate time.
(8) Magnesium stearate was used to lubricate the blend of step (7) for suitable time.
(9) Lubricated blend of step (8) was used for compression using oval shaped punches.
Example 3:
(1) Avanafil and other excipients were sifted across quadro sifter.
(2) HPC-SL was dissolved in water under stirring to prepare binder solution I.
(3) Hydrochloric acid was dissolved in water, to which HPC-SL was added gradually and dissolved under stirring to prepare binder solution II.
(4) Avanafil and a part of mannitol were dry mixed in a high shear mixer granulator for suitable period of time.
(5) The dry mix of step (4) was granulated with the binder solution I of step (2) in a rapid mixer granulator, till suitable granules were obtained.
(6) The wet granules were dried in a fluid bed dryer under appropriate drying conditions till desired LOD.
(7) Part of mannitol was granulated separately in a rapid mixer granulator using binder solution II from step (3), till desired granules were obtained.
(8) The wet granules of step (7) were dried in a fluid bed equipment till desired LOD is achieved.
(9) Dried active granules of step (6) and mannitol granules of step (8) were subjected to appropriate sizing and milling operations separately.
(10) The milled active granules and the mannitol granules were mixed together for appropriate time.
(11) HPC-SL and precipitated calcium carbonate were added to the granules of step (10) and mixed in a double cone blender for appropriate time.
(12) Magnesium stearate was used to lubricate the blend of step (11) for suitable time.
(13) Lubricated blend of step (12) was used for compression using oval shaped punches.
Example 4:
(1) Avanafil and other excipients were sifted across quadro sifter.
(2) HPC-SL was dissolved in water under stirring to prepare binder solution I.
(3) Hydrochloric acid was dissolved in water to which HPC-SL was added gradually and dissolved under stirring to prepare binder solution II.
(4) Avanafil and a part of mannitol were dry mixed in a fluid bed equipment for suitable period of time.
(5) The dry mix of step (4) was granulated with the binder solution I of step (2) in a fluid bed equipment till suitable granules were obtained.
(6) The wet granules were dried in a fluid bed equipment under appropriate drying conditions till desired LOD.
(7) Part of mannitol was granulated separately in a fluid bed equipment using binder solution II from step (3), till desired granules were obtained.
(8) The wet granules of step (7) were dried in a fluid bed equipment till desired LOD is achieved.
(9) Dried active granules of step (6) and mannitol granules of step (8) were subjected to appropriate sizing and milling operations separately.
(10) The milled active granules and the mannitol granules were mixed together for appropriate time.
(11) HPC-SL and precipitated calcium carbonate were added to the granules of step (10) and mixed in a double cone blender for appropriate time.
(12) Magnesium stearate was used to lubricate the blend of step (11) for suitable time.
(13) Lubricated blend of step (12) was used for compression using oval shaped punches.
Composition of the preparation for Examples 1, 2, 3 and 4 (per tablet):
Ingredients Quantity (mg)
Intragranular Ingredients
Avanafil 100.00
Mannitol 170.00
Hydrochloric acid 0.40
Hydroxypropyl cellulose (HPC-SL) 9.00
Water q.s.
Extragranular Ingredients
Low Substituted Hydroxypropyl Cellulose (L-HPC) 19.20
Precipitated Calcium Carbonate 3.21
Magnesium Stearate 3.21
Tablet Weight 305.00
The following examples use inorganic acid salt (sodium dihydrogen phosphate or potassium dihydrogen phosphate) as the solubility enhancing substance.
Example 5:
(1) Avanafil and other excipients were sifted across quadro sifter.
(2) HPC-SL was added gradually in water and dissolved under stirring.
(3) Avanafil and mannitol were dry mixed in a rapid mixer granulator for suitable period of time.
(4) The dry mix of step (3) was granulated with the binder solution of step (2) in a rapid mixer granulator till suitable granules were obtained.
(5) The wet granules were dried in a fluid bed dryer under appropriate drying conditions till desired LOD.
(6) Sodium dihydrogen phosphate was granulated with the binder solution of step (2) in a rapid mixer granulator till suitable granules are obtained.
(7) The wet sodium dihydrogen phosphate granules of step (6) were dried in a fluid bed equipment till desired LOD is achieved.
(8) Dried active granules of step (5) and sodium dihydrogen phosphate granules of step (7) were subjected to appropriate sizing and milling operations separately.
(9) HPC-SL and precipitated calcium carbonate added to the granules of step (8) and mixed in a double cone blender for appropriate time.
(10) Magnesium stearate was used to lubricate the blend of step (9) for suitable time.
(11) Lubricated blend of step (10) was used for compression using oval shaped punches.
Composition of the preparation for Example 5 (per tablet):
Ingredients Quantity (mg)
Intragranular Ingredients
Avanafil 200.00
Mannitol 240.04
Sodium dihydrogen phosphate 100.00
Hydroxypropyl cellulose (HPC-SL) 18.00
Water q.s.
Extragranular Ingredients
Low Substituted Hydroxypropyl Cellulose (L-HPC) 38.40
Precipitated Calcium Carbonate 6.42
Magnesium Stearate 6.42
Tablet Weight 609.28

Example 6:
(1) Avanafil and other excipients were sifted across quadro sifter.
(2) HPC-SL was added gradually in water and dissolved under stirring.
(3) Avanafil and mannitol were dry mixed in a fluid bed equipment for suitable period of time.
(4) The dry mix of step (3) was granulated with the binder solution of step (2) in a fluid bed equipment till suitable granules were obtained.
(5) The wet granules were dried in a fluid bed equipment under appropriate drying conditions till desired LOD was achieved.
(6) Potassium dihydrogen phosphate was granulated with the binder solution of step (2) in a fluid bed equipment till suitable granules were obtained.
(7) The potassium dihydrogen phosphate granules of step 6 were dried in a fluid bed equipment till desired LOD was achieved.
(8) Dried active granules of step (5) and potassium dihydrogen phosphate granules of step (7) were subjected to appropriate sizing and milling operations separately.
(9) HPC-SL and precipitated calcium carbonate were added to the granules of step (8) and mixed in a double cone blender for appropriate time.
(10) Magnesium stearate was used to lubricate the blend of step (9) for suitable time.
(11) Lubricated blend of step (10) was used for compression using oval shaped punches.
Composition of the preparation for Example 6 (per tablet):
Ingredients Quantity (mg)
Intragranular Ingredients
Avanafil 50.00
Mannitol 78.93
Potassium dihydrogen phosphate 6.25
Hydroxypropyl cellulose (HPC-SL) 4.50
Water q.s.
Extragranular Ingredients
Low Substituted Hydroxypropyl Cellulose (L-HPC) 9.60
Precipitated Calcium Carbonate 1.61
Magnesium Stearate 1.61
Tablet Weight 152.50

The following examples use organic substances with pH greater than 4.0 as the solubility enhancing substance(s).
Example 7:
(1) Avanafil and other excipients were sifted across quadro sifter.
(2) Sodium lauryl sulfate was gently dissolved in water avoiding excessive foaming and HPC-SL was added gradually and dissolved under stirring.
(3) Avanafil and mannitol were dry mixed in a rapid mixer granulator for suitable period of time.
(4) The dry mix of step (3) was granulated with the binder solution of step (2) in a rapid mixer granulator till suitable granules were obtained.
(5) The wet granules were dried in a fluid bed dryer under appropriate drying conditions till desired LOD.
(6) Dried granules were subjected to appropriate sizing and milling operations.
(7) HPC-SL and precipitated calcium carbonate were added to the granules of step (6) and mixed in a double cone blender for appropriate time.
(8) Magnesium stearate (sifted) was used to lubricate the blend of step (7) for suitable time.
(9) Lubricated blend of step 8 used for compression using oval shaped punches.
Composition of the preparation for Example 7 (per tablet):
Ingredients Quantity (mg)
Intragranular Ingredients
Avanafil 200.00
Mannitol 320.04
Sodium lauryl sulfate (SLS) 20.00
Hydroxypropyl cellulose (HPC-SL) 18.00
Water q.s.
Extragranular Ingredients
Low Substituted Hydroxypropyl Cellulose (L-HPC) 38.40
Precipitated Calcium Carbonate 6.42
Magnesium Stearate 6.42
Tablet Weight 609.28

Examples 8-14
(1) Avanafil and mannitol were sifted across suitable mesh.
(2) The solubility enhancing substance(s) were dissolve in purified water under high stirring so as to have a clear solution.
(3) In case of Vitamin E TPGS, Gelucire 44/14, Cremophore RH 40 (where the solubility enhancing substance(s) are insoluble in water), the same were dissolved in organic solvents like dichloromethane, acetone or the like, and then used for granulation.
(4) HPC -SL was dissolved in the solution from step 2, under stirring to have the binder solution.
(5) The granules were dried in a fluid bed dryer till desired LOD.
(6) The extra granular components disintegrants like L-HPC or Polyplasdone XL or a mixture thereof were added to the dried granules of step 5 and blended for appropriate period of time
(7) The blend of step 6 was lubricated with Magnesium stearate.
(8) Compress the lubricated blend of step 7, using appropriate punches.
Compositions of the preparation for Examples 8-14 (per tablet):
Ingredients Example 8 Example 9 Example 10 Example 11 Example 12 Example 13 Example 14
Intragranular
Avanafil 200 200 200 200 200 200 200
Mannitol 87.18 20.18 27.18 127.18 37.18 37.18 37.18
Polysorbate 80 200 200 200 - 200 200 200
Poloxamer 188 - 67 - - - - -
Poloxamer 407 - - 110 110 - - -
Sucrose fatty acid esters - - - 50 50 - -
Vitamin E TPGS - - - - - - -
Gelucire 44/14; Cremophore RH 40 - - - - - 50 -
Solutol HS 15 - - - - - - 50
Hydroxy propyl cellulose (HPC-SL) 18 18 18 18 18 18 18
Water (q.s) q.s. q.s. q.s. q.s. q.s. q.s. q.s.
Extra granular
Low Substituted Hydroxy Propyl Cellulose (L-HPC)/ Crospovidone (Polyplasdone XL) 38.4 38.4 38.4 38.4 38.4 38.4 38.4
Magnesium Stearate 6.42 6.42 6.42 6.42 6.42 6.42 6.42
Tablet Weight 550 550 600 550 550 550 550
,CLAIMS:WE CLAIM
1. A pharmaceutical formulation comprising avanafil or a salt thereof and at least one solubility enhancing substance, wherein the solubility enhancing substance is selected from a group comprising of inorganic substances and organic substances with pH value greater than 4.0.
2. The pharmaceutical formulation as per claim 1, wherein avanafil is contained in a proportion of 0.1 to 60% by weight of the pharmaceutical composition.
3. The pharmaceutical formulation as per claim 1, wherein the solubility enhancing agent is contained in a proportion of 0.01 to 70% by weight of the pharmaceutical composition.
4. The pharmaceutical formulation as per claim 1, wherein the formulation is prepared using conventional methods for preparing pharmaceutical solid formulations including granulation (dry and wet), solid dispersion formation, screw extrusion, hot melt extrusion, formulating avanafil in the form of lipid based drug delivery systems and the like.
5. The pharmaceutical formulation as per claim 1, wherein the inorganic substance is an inorganic acid selected from the group comprising of hydrobromic acid, chlorous acid, hypobromous acid, hydrochloric acid, hypochlorous acid, hypoiodous acid, iodic acid, iodous acid, hyponitrous acid, hydroiodic acid, nitric acid, nitrous acid, pernitric acid, sulfuric acid, sulfurous acid, hyposulfurous acid, chloric acid, bromous acid, bromic acid, persulfuric acid, pyrosulfuric acid, disulfurous acid, dithionous acid, tetrathionic acid, thiosulfurous acid, peroxydisulfuric acid, hydrosulfuric acid, perchloric acid, phosphoric acid, phosphorous acid, hypophosphous acid, perphosphoric acid, hypophosphoric acid, pyrophosphoric acid, hydrophosphoric acid, perchromic acid, boric acid, molybdic acid, arsenic acid, dichromic acid, used alone or in combinations thereof.
6. The pharmaceutical formulation as per claim 1, wherein the inorganic substance is an inorganic salt selected from the group comprising of sodium carbonate, sodium chloride, sodium bromide, sodium sulfate, sodium sulfite, sodium bicarbonate, sodium phosphate, sodium hydrogen phosphate, sodium dihydrogen phosphate, sodium nitrate, sodium nitrite, potassium carbonate, potassium chloride, potassium bromide, potassium sulfate, potassium sulfite, potassium bicarbonate, potassium phosphate, potassium hydrogen phosphate, potassium dihydrogen phosphate, potassium nitrate, potassium nitrite
7. The pharmaceutical formulation as per claim 1, wherein the organic substance with pH values greater than 4.0 is selected from a group comprising of sodium lauryl sulfate, sodium decyl sulfate, sodium dodecylbenzenesulfonate, sodium tertradecyl sulfate, sodium cetyl sulfate, sodium octadecylsulfate, sucrose fatty acid esters, D-a-tocopheryl polyethylene glycol succinate, polyethylene glycol glyceride, PEG hydrogenated castor oils, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan monooleate, polyoxyethylene-polyoxypropylene block copolymers, polyoxyl hydroxyesters.
8. The pharmaceutical formulation of preceding claims further comprising pharmaceutical diluents, binders, disintegrants, lubricants and glidants.
9. A pharmaceutical formulation comprising avanafil or a salt thereof and at least one solubility enhancing substance, wherein the formulation is substantially as hereinbefore described with reference to any one of the Examples.