CN115887462A - Oral pharmaceutical composition - Google Patents
Oral pharmaceutical composition Download PDFInfo
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- CN115887462A CN115887462A CN202211208791.8A CN202211208791A CN115887462A CN 115887462 A CN115887462 A CN 115887462A CN 202211208791 A CN202211208791 A CN 202211208791A CN 115887462 A CN115887462 A CN 115887462A
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- avanafil
- dapoxetine
- particle size
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- fumaric acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
Abstract
The invention relates to an oral pharmaceutical composition, in particular to an oral pharmaceutical composition containing S- (+) -N, N-dimethyl-a- [2- (naphthyloxy) ethyl ] benzylamine and (S) -2- (2 hydroxymethyl-l-pyrrolidinyl) -4- (3-chloro-4-methoxybenzylamino) -5- [ N- (2-pyrimidinylmethyl) carbamoyl ] pyrimidine, wherein the composition contains two compounds in a weight ratio of 6 or 6.
Description
Technical Field
The invention relates to the field of medicines, in particular to an oral medicine composition containing S- (+) -N, N-dimethyl-a- [2- (naphthoxy) ethyl ] benzylamine and (S) -2- (2 hydroxymethyl-l-pyrrolidinyl) -4- (3-chloro-4-methoxybenzylamino) -5- [ N- (2-pyrimidinylmethyl) carbamoyl ] pyrimidine, and application of the composition in preparing medicines for treating erectile dysfunction and premature ejaculation.
Background
The compound (S) -2- (2 hydroxymethyl-l-pyrrolidinyl) -4- (3-chloro-4-methoxybenzylamino) -5- [ N- (2-pyrimidinylmethyl) carbamoyl ] pyrimidine (hereinafter compound a, or avanafil) is a phosphodiesterase-5 (PDE 5) inhibitor for the treatment of male Erectile Dysfunction (ED) and has the following structure:
the chemical name is S- (+) -N, N-dimethyl-a- [2- (naphthoxy) ethyl ] benzylamine or hydrochloride thereof (hereinafter referred to as compound B, or dapoxetine), is a Selective 5-hydroxytryptamine reuptake inhibitor (SSRI). Is clinically used for treating depression and Premature Ejaculation (PE), and has the following structural formula
S- (+) -N, N-dimethyl-a- [2- (naphthyloxy) ethyl group]The oral administration of the benzylamine can realize rapid absorption and rapid metabolism. Oral administration of Compound I C max The dosage is 1h, and the oral preparation on the market contains 30mg and 60mg of dapoxetine hydrochloride in terms of free base.
Patent document 1 discloses a combination of compound B and compound a, in a ratio of 1.2 to 10, useful for preventing or treating impotence and premature ejaculation and avoiding adverse changes in the body, which are unnecessary excessive and/or prolonged reductions in blood pressure, due to the use of avanafil. In the examples of patent document 1, it is further disclosed that the ratio of dapoxetine hydrochloride to avanafil includes 1 (45mg, 90mg), 2.
Patent document 3 discloses effervescent tablets containing dapoxetine and PDE5 inhibitors, including lodenafil (lodenafil), sildenafil, tadalafil and the like, wherein the ratio of the two is described in the range of 6. The formulation containing compound B and compound a is described in example 4 of the specification, and the ratio of the two is not specifically described.
Although the prior art discloses the combination of S- (+) -N, N-dimethyl-a- [2- (naphthoxy) ethyl ] benzylamine and different PDE5 inhibitors, the combination of the two drugs with optimal dosage is not involved, and the optimal effect of the combination of the two drugs cannot be achieved.
Patent document 1: CN 103340869A
Patent document 2: EP 2698145B 1
Patent document 3: US20150231092 A1
Disclosure of Invention
The present invention provides a fixed dose pharmaceutical composition of S- (+) -N, N-dimethyl-a- [2- (naphthoxy) ethyl ] benzylamine or its hydrochloride salt and (S) -2- (2 hydroxymethyl-l-pyrrolidinyl) -4- (3-chloro-4-methoxybenzylamino) -5- [ N- (2-pyrimidinylmethyl) carbamoyl ] pyrimidine, such that the two form a synergistic effect, optimally for the treatment of male erectile dysfunction, premature ejaculation or patients suffering from both erectile dysfunction and premature ejaculation.
Therefore, the invention achieves the above purpose by the following technical scheme:
according to a first aspect of the invention, a pharmaceutical composition is provided, wherein the composition contains dapoxetine and avanafil, and the weight ratio of the dapoxetine to the avanafil in the composition is from 6.
Preferably, the composition contains dapoxetine and avanafil, and the weight ratio of the dapoxetine to the avanafil in the composition is 6.
Preferably, the composition contains dapoxetine and avanafil, and the weight ratio of the dapoxetine to the avanafil in the composition is 3.
The pharmaceutical composition of the dapoxetine and the avanafil preferably contains 60mg or 30mg of the dapoxetine and 200mg or 100mg of the avanafil. Particularly preferably contains 60mg or 30mg of dapoxetine and 200mg of avanafil. The dapoxetine comprises dapoxetine hydrochloride, and the content of the dapoxetine in the composition is calculated by the content of free alkali. If the dapoxetine hydrochloride contains 60mg of dapoxetine, the corresponding amount is 67.16mg of dapoxetine hydrochloride.
When the composition contains 60mg or 30mg of dapoxetine and 100mg or 200mg of avanafil, particularly 60mg or 30mg of dapoxetine and 200mg of avanafil, the optimal dosage combination of the two can be realized to form a synergistic effect.
In a second aspect of the present invention, there is provided an oral pharmaceutical formulation comprising dapoxetine and avanafil, wherein the pharmaceutical formulation comprises dapoxetine in a weight ratio to avanafil of 6.
Preferably, the pharmaceutical preparation contains 60mg of dapoxetine and 100mg of avanafil, or contains 60mg of dapoxetine and 200mg of avanafil, or contains 30mg of dapoxetine and 200mg of avanafil.
Preferably, the pharmaceutical preparation contains dapoxetine containing 60mg of dapoxetine and 200mg of avanafil; or 30mg of dapoxetine and 200mg of avanafil.
The oral medicinal preparation further contains pharmaceutically acceptable auxiliary materials. The auxiliary materials can be selected or added according to the requirements of preparing the composition, and the auxiliary materials comprise the following non-limiting materials: excipient, binder, disintegrating agent, lubricant, etc., and can be made into solid oral dosage forms such as tablet, capsule, granule, pill, etc. by conventional method.
The excipient is selected from one or more of lactose, mannitol, sucrose, glucose, microcrystalline cellulose and starch; the binder is selected from polyvinylpyrrolidone, polyvinyl alcohol, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, etc.; the disintegrating agent comprises microcrystalline cellulose, low-substituted hydroxypropyl cellulose, cross-linked carboxymethyl cellulose, etc.; lubricants include magnesium stearate, calcium stearate, talc, polyethylene glycol, sodium lauryl sulfate, and the like.
In some embodiments of the invention, the excipient is one or more of lactose, mannitol, sucrose, glucose, microcrystalline cellulose.
In some embodiments of the invention, the binder is hydroxypropyl cellulose.
In some embodiments of the invention, the disintegrant is low-substituted hydroxypropylcellulose, croscarmellose sodium.
In some embodiments of the invention, the lubricant is magnesium stearate.
In some embodiments of the present invention, the pharmaceutical preparation further comprises an organic acid; preferred organic acids include: fumaric acid, malic acid, and citric acid.
In some embodiments of the invention, the pharmaceutical formulation further comprises a glidant, the glidant being optionally selected from colloidal silicon dioxide and magnesium stearate.
In some embodiments of the present invention, the pharmaceutical formulation further comprises a carbonate salt, wherein the carbonate salt comprises: sodium carbonate, sodium bicarbonate, calcium carbonate. A further preferred carbonate is calcium carbonate. The carbonate is in the pharmaceutical preparation, and the weight ratio is 0.1-5% based on the total weight of the pharmaceutical preparation; the preferred weight ratio is 0.5% to 3%.
The invention contains 1-15% weight of disintegrant based on the total weight of the pharmaceutical preparation; preferably 1-10% by weight of a disintegrant;
contains excipient 10-60 wt%, preferably excipient 15-50 wt%;
contains 0.5-5 wt% of binder, preferably 1.0-3.0 wt% of binder;
contains 0.1-3.0 wt% of glidant, preferably 0.2-2.0 wt% of glidant;
contains 0.1-5.0 wt% of lubricant, preferably 1.0-3.0 wt% of lubricant.
In some embodiments of the invention, the pharmaceutical formulation comprises: 60mg of dapoxetine and 200mg of avanafil; or 30mg of dapoxetine and 200mg of avanafil; and an excipient selected from mannitol, lactose, microcrystalline cellulose, a binder selected from hydroxypropylcellulose; a lubricant selected from magnesium stearate; a disintegrant selected from low-substituted hydroxypropyl cellulose and croscarmellose sodium.
According to the invention, researches also find that in an oral medicinal preparation containing the avanafil and the dapoxetine hydrochloride, the particle size of the avanafil has a remarkable influence on the dissolution rate of the medicinal preparation, and the dissolution rates of the avanafil and the dapoxetine hydrochloride medicinal preparation can be further effectively improved by controlling the particle size range of the avanafil, so that the in-vivo bioavailability of the medicine is improved. This is completely unexpected as particle size in avanafil single formulations, such as avanafil tablets, does not take into account the effect of particle size on dissolution.
Therefore, in a further aspect of the present invention, in an oral pharmaceutical formulation comprising avanafil and dapoxetine hydrochloride, said avanafil is present in said pharmaceutical composition in a specific particle size range, and said avanafil particle size D 90 Is 10 to 150 mu m. In some embodiments of the invention, the particle size D of the avanafil 90 15-120 μm;
in some embodiments, the particle size D of the avanafil 90 20-90 μm;
in some embodiments, the particle size D of the avanafil 90 20-70 μm;
in some embodiments, the particle size D of the avanafil 90 20 to 50 μm.
In some embodiments of the invention, an oral pharmaceutical formulation comprises: 60mg of dapoxetine and 200mg of avanafil; or 30mg of dapoxetine and 200mg of avanafil; and an excipient selected from mannitol, lactose, microcrystalline cellulose, a binder selected from hydroxypropylcellulose; a lubricant selected from magnesium stearate; a disintegrant selected from the group consisting of low-substituted hydroxypropyl cellulose, croscarmellose sodium; and the particle diameter D of the avanafil 90 Is 10 to 150 mu m.
In some embodiments, the avanafil is prepared into avanafil granules with excipients and binders by wet granulation; the excipient is optionally selected from lactose, mannitol, sucrose, glucose, microcrystalline cellulose; the adhesive is hydroxypropyl cellulose.
In the oral medicinal preparation containing the avanafil and the dapoxetine hydrochloride, when organic acid exists, if the particle size of the organic acid is too small, the granulation process is difficult to carry out, and materials are aggregated into hard spheres; when the particle size of the organic acid is too large, the particles cannot be granulated effectively, and the flowability and compressibility of the particles are affected. The present inventors have unexpectedly found that the aforementioned problems can be effectively avoided when the particle size of the organic acid is controlled within a specific range.
Therefore, in a further aspect of the present invention, in the oral pharmaceutical preparation containing avanafil and dapoxetine hydrochloride, an organic acid is further contained, and the particle size D of the organic acid is 90 50-200 μm;
in some embodiments, the particle size D of the organic acid 90 60-160 μm; preferably, in some embodiments, the particle size D of the organic acid 90 Is 80-150 μm.
In some embodiments of the invention, the organic acid is preferably fumaric acid; the pharmaceutical preparation contains 5-30% by weight of fumaric acid based on the total weight of the pharmaceutical preparation.
In some embodiments of the invention, the fumaric acid is prepared with a binder by wet granulation to form fumaric acid granules. Preferably, the binder is hydroxypropyl cellulose.
In some embodiments of the invention, the oral pharmaceutical formulation comprises particles of avanafil, particles of fumaric acid; and the particle diameter D of the avanafil in the avanafil particles 90 10 to 150 mu m, and the particle diameter D of the fumaric acid in the fumaric acid particles 90 Is 50 to 200 mu m.
In some embodiments of the invention, the oral pharmaceutical formulation comprises avanafil particles, fumaric acid particles and calcium carbonate; particle size D of avanafil in the particles 90 15 to 120 mu m, the particle diameter D of the fumaric acid 90 60 to 160 μm.
In some embodiments of the invention, an oral pharmaceutical formulation comprises: 60mg of pomalidine and 200mg of avanafil; or 30mg of dapoxetine and 200mg of avanafil; and contains organic acid selected from fumaric acid, excipient selected from mannitol, lactose, microcrystalline cellulose, and binder selected from hydroxypropyl cellulose; a lubricant selected from magnesium stearate; a disintegrant selected from the group consisting of low-substituted hydroxypropyl cellulose, croscarmellose sodium; particle diameter D of the organic acid 90 Is 50-200 mu m, and the organic acid and the adhesive are prepared into particles.
In some embodiments of the invention, an oral pharmaceutical formulation comprises: 60mg of dapoxetine and 200mg of avanafil; or 30mg of dapoxetine and 200mg of avanafil; and an excipient comprising an organic acid selected from fumaric acid, an excipient selected from mannitol, lactose, microcrystalline cellulose, a binder selected from hydroxypropylcellulose; a lubricant selected from magnesium stearate; a disintegrant selected from the group consisting of low-substituted hydroxypropyl cellulose, croscarmellose sodium; the particle size D of the avanafil 90 The particle size of the avanafil is 10-150 mu m, and the avanafil, excipient and adhesive are prepared into the avanafil particle.
The pharmaceutical preparation auxiliary material contains carbonate, and dapoxetine exists in the form of hydrochloride, if the carbonate and the dapoxetine hydrochloride are directly mixed with the auxiliary material, and then granulation and tabletting are carried out, the carbonate can potentially slowly act with the dapoxetine hydrochloride, so that the long-term stability and the stability under high humidity of the preparation are poor, and the dissolution rate in vivo is reduced after the pharmaceutical preparation is applied, so that the optimal treatment effect cannot be exerted. According to the invention, the avanafil and the dapoxetine hydrochloride are respectively placed in the two layers, so that the problems can be effectively solved, and the medicinal preparation with the stability and the dissolution rate meeting the requirements can be obtained.
Accordingly, in a further aspect of the present invention there is provided a bilayer tablet comprising avanafil and dapoxetine, the bilayer tablet comprising a first active layer and a second active layer; the first active layer contains avanafil; the second active layer comprises dapoxetine;
in some embodiments of the invention, the first active ingredient layer further comprises a carbonate, an organic acid; preferred organic acids include: fumaric acid, malic acid, citric acid; further preferred organic acids are fumaric acid; preferred carbonates include: calcium carbonate, sodium bicarbonate, sodium carbonate; a further preferred carbonate is calcium carbonate. Based on the total weight of the pharmaceutical composition, the pharmaceutical composition contains 5 to 30 weight percent of organic acid and 0.1 to 5 weight percent of carbonate; preferably, the carbonate is present in an amount of 0.5% to 3% by weight.
In some embodiments of the invention, the first active ingredient layer and/or the second active ingredient layer further comprises a pharmaceutically acceptable excipient comprising: excipients (or called fillers), binders, disintegrants, lubricants, glidants and the like.
In some embodiments of the invention, the excipients in the first or second active ingredient layer are each independently optionally selected from one or more of lactose, mannitol, sucrose, glucose, microcrystalline cellulose, starch.
In some embodiments of the invention, the binder in the first or second active ingredient layer is hydroxypropyl cellulose.
In some embodiments of the invention, the disintegrant in the first or second active ingredient layer is each independently optionally selected from low substituted hydroxypropylcellulose, croscarmellose sodium.
In some embodiments of the invention, the disintegrant of the first active ingredient layer is selected from low substituted hydroxypropylcellulose; the second active ingredient layer disintegrant is selected from croscarmellose sodium.
In some embodiments of the invention, the lubricant in the first active ingredient layer or the second active ingredient layer is magnesium stearate.
In some embodiments of the invention, the excipient of the first active ingredient layer is mannitol and the excipient of the second active ingredient layer is lactose and/or microcrystalline cellulose.
In some embodiments of the invention, the second active ingredient layer contains a glidant selected from colloidal silicon dioxide.
In a further aspect of the invention, there is provided a bilayer tablet comprising avanafil and dapoxetine, the bilayer tablet comprising a first active ingredient layer and a second active ingredient layer; the first active ingredient layer contains avanafil; the second active ingredient layer contains dapoxetine;
the first active ingredient layer contains avanafil 100mg or 200mg; the second active ingredient layer contains 30mg or 60mg of dapoxetine;
the first active ingredient layer may further contain an organic acid and/or a carbonate; preferably, the first active ingredient layer may further contain fumaric acid and/or calcium carbonate.
Particle diameter D of avanafil in the first active ingredient layer 90 10-150 μm; and/or the particle size D of the fumaric acid of the first active ingredient layer 90 50-200 μm;
in the first active ingredient layer, avanafil and fumaric acid are respectively granulated with auxiliary materials by a wet method to form avanafil granules and fumaric acid granules; the avanafil particles contain avanafil, excipient and adhesive; the excipient comprises lactose, mannitol, sucrose, glucose, microcrystalline cellulose and starch, and the preferable excipient is mannitol; the binder comprises polyvinylpyrrolidone, polyvinyl alcohol, hydroxypropyl cellulose, methyl cellulose, and ethyl cellulose; a preferred binder is hydroxypropyl cellulose.
The fumaric acid particles contain fumaric acid and a binder; the adhesive comprises polyvinylpyrrolidone, polyvinyl alcohol, hydroxypropyl cellulose, methyl cellulose and ethyl cellulose; a preferred binder is hydroxypropyl cellulose.
In some embodiments of the invention, the bilayer tablet comprises particles of avanafil and particles of fumaric acid, and the particle size D of the avanafil 90 10 to 150 mu m, the particle diameter D of the fumaric acid 90 Is 50 to 200 mu m.
In some embodiments of the invention, the bilayer tablet comprises particles of avanafil, particles of fumaric acid, and a carbonate salt, and the particle size D of the avanafil 90 10 to 150 mu m, the particle diameter D of the fumaric acid 90 Is 50 to 200 μm.
In some embodiments of the invention, the bilayer tablet comprises particles of avanafil, particles of fumaric acid and a carbonate salt, and the particle size D of the avanafil 90 20 to 90 mu m, the particle diameter D of the fumaric acid 90 60 to 160 μm.
In some embodiments of the present invention, the bilayer tablet comprises 5 to 30% by weight of fumaric acid based on the total weight of the tablet.
In some embodiments of the invention, the weight ratio of carbonate in the bilayer tablet is 0.1% to 5% based on the total weight of the tablet; the preferred weight ratio is 0.5% to 3%.
In some embodiments of the present invention, the first active ingredient layer contains avanafil granules, fumaric acid granules, carbonate, a disintegrating agent and a lubricant. The second active ingredient layer contains dapoxetine, excipient, disintegrant, lubricant and glidant.
Based on the total weight of the double-layer tablet, the invention contains 1 to 15 percent of disintegrant; preferably 1-10% by weight of a disintegrant;
contains 10-60 wt% of excipient, preferably 15-50 wt% of excipient;
contains 0.5-5 wt% of binder, preferably 1.0-3.0 wt% of binder;
contains 0.1-3.0 wt% of glidant, preferably 0.2-2.0 wt% of glidant;
contains 0.1-5.0 wt% of lubricant, preferably 1.0-3.0 wt% of lubricant.
In still another aspect of the present invention, there is provided a method for preparing a bilayer tablet containing dapoxetine and avanafil, the method comprising the steps of:
(1) Respectively crushing the avanafil and the organic acid to a target particle size range;
(2) Carrying out wet granulation on the avanafil, an excipient and an adhesive to obtain avanafil granules;
(3) Carrying out wet granulation on organic acid and a binding agent to obtain fumaric acid granules;
(4) Uniformly mixing the avanafil particles, the organic acid particles, the carbonate and the auxiliary materials to obtain a first layer of mixed powder;
(5) Uniformly mixing dapoxetine and auxiliary materials to obtain a second layer of mixed powder;
(6) Performing double-layer tablet pressing on the first layer of mixed powder and the second layer of mixed powder to obtain a double-layer tablet;
(7) Optionally, the bilayer tablet is coated.
In the preparation method, the auxiliary materials of the first layer and the second layer are the same or different and are selected from a disintegrating agent, an excipient, a lubricant and a glidant.
In another aspect of the invention, the invention provides a use of a bilayer tablet containing dapoxetine and avanafil in preparing a medicament for treating male erectile dysfunction, premature ejaculation and erectile dysfunction with premature ejaculation. The bilayer tablet contains dapoxetine in a weight ratio to avanafil of 6. Preferably, the bilayer tablet contains 60mg of dapoxetine and 100mg of avanafil, or the bilayer tablet contains 60mg of dapoxetine and 200mg of avanafil. Or the bilayer tablet contains 30mg of dapoxetine and 200mg of avanafil.
Drawings
Figure 1 bar graph of total number of Wistar rat ejaculation <0.001 within 30min after PCA induction, N =3 compared to the Vehicle group.
Figure 2 bar graph of Wistar rats' primary ejaculation latency within 30min after PCA induction, # P <0.01, # P <0.001, compared to Vehicle group, # P <0.05, H065 group compared to dapoxetine group, N =3.
Figure 3 bar graph of number of Wistar rat seminal vesicle contractions within 30min after PCA induction, _ P <0.001, N =3 compared to the Vehicle group.
Detailed Description
The present invention is illustrated by the above preferred embodiments for the purpose of illustrating the spirit of the invention, and not for the purpose of further limiting the scope of the invention. Unless otherwise specified, the experimental materials and experimental animals used in the examples of the present invention can be obtained by a method generally used in the art. Dapoxetine or avanafil can be prepared by the method disclosed in CN1020093C and in WO 0119802.
Interpretation of terms
In the present invention, "D 90 "means a particle diameter corresponding to a cumulative particle size distribution of 90%.
The ejaculatory number and the ejaculatory frequency can be expressed by the ejaculation number and the ejaculation frequency.
Example 1
The present invention screens dapoxetine and avanafil in the following different ratios.
| Dapoxetine/mg | Avanafil/mg | |
| Combination A | 60 | 200 |
| Combination B | 60 | 100 |
| Combination C | 60 | 50 |
| Combination D | 30 | 200 |
| Combination E | 30 | 100 |
| Combination F | 30 | 50 |
| Combination G | 45 | 180 |
| Combination H | 60 | 0 |
| |
0 | 200 |
Example 2
Animal behavior Observation experiment
The animal for evaluating the effect of the medicine adopts a primary premature ejaculation rat animal model, and the establishment method can adopt a method reported in the literature, such as the method described in the journal of Chinese andrology, 2016 (7), 22 (7), 579-583. Screening 50 male SD rats with the average EF (ejaculatory frequency) value of more than 3, namely male rats with overquick ejaculation, dividing 5 rats into 10 groups, and injecting for administration, wherein a control group is injected with physiological saline, the administration dose is calculated by 60kg corresponding to a human body, and the conversion ratio is 0.162, for example, for the combination A, the administration dose of the rats is 260 mg/(60kg 0.162) =26.7mg/kg.
The different combinations of the invention were dissolved and injected intravenously into male SD rats for 1 experiment per week for a total of 4 weeks. The rats were housed 15 minutes after administration in the same cage as the female in heat, and the sexual behavior of the male and female rats was recorded and observed. The effectiveness of the drug of the invention is evaluated by the following 3 indexes:
1. straddle latency (ML): represents the time (unit: second) required for cage-sharing with the female mouse to the 1 st climbing or mounting;
2. number of straddling (mount frequency, MF): number of straddling events before the 1 st ejaculation. The MF of the male mouse with too fast ejaculation is low, and the MF value of the male mouse with delayed ejaculation is high. This index can be used to reflect the penile sensitivity correlation of a patient (human).
3. Ejaculatory Latency (EL): the time (unit: second) required for the 1 st insertion to ejaculation was indicated, and if ejaculation was not observed, the statistics were excluded; the index can be used for reflecting whether the ejaculation time of a PE patient (human) can be prolonged or not;
the average of the 3 indices was calculated for each group of male mice in the experiment and the data is shown in the table below.
The animal model experiment shows that (1) compared with a control group of male mice, the combination of dapoxetine and avanafil with different doses can shorten the straddle latency (ML) to a certain extent, and the combination has no obvious difference except for the combination A and the combination D; (2) in the combination, the riding times (MF) are obviously increased, which shows that the combination A or D can reduce the sensitivity of the penis of the male mouse and is beneficial to delaying ejaculation; (3) in the combinations of the present invention, combination a or combination D was able to significantly increase the prolongation of Ejaculation Latency (EL), indicating that combination a or combination D of the present invention is able to prolong the ejaculation time in male mice.
Example 3
Experiment of erection function of animal
Male rabbits were tested for erectile stimulating activity with different ratios of the composition, for Experimental procedures see the literature Clinical and Experimental Pharmacology and Physiology,20,1993,177-183. 50 male rabbits (in mm) weighing 2.5-3.0kg and having a week age of 21-23 were used, and the drugs of combination A to combination J were suspended in 0.5% CMC-Na and fed to 5 male rabbits each in 10 groups, and the penis length (in mm) of the male rabbits was measured with a vernier caliper in a blank control group. The results are as follows:
N/A indicates that the male rabbit penis is not erect or measurable.
The animal model experiment shows that the combination A (60 mg of dapoxetine and 200mg of avanafil) or the combination D (30 mg of dapoxetine and 200mg of avanafil) can quickly take effect to erect the male rabbits, the duration of the erection is obviously prolonged, and the penis length of the male rabbits can be measured in a longer time range.
Example 4
Tablet preparation method
1) Avanafil total mixed particles:
(1) respectively crushing avanafil and fumaric acid, and controlling the target particle size;
(2) fumaric acid particles: preparing a binding agent, granulating fumaric acid by adopting a binding agent solution, drying, and carrying out dry granulation for later use;
(3) avanafil particles: carrying out wet granulation on mannitol and avanafil by adopting an adhesive solution, drying, and carrying out dry granulation for later use;
(4) mixing: uniformly mixing fumaric acid particles, low-substituted hydroxypropyl cellulose, calcium carbonate, avanafil particles and magnesium stearate for later use;
2) Mixing powder of dapoxetine: mixing croscarmellose sodium, lactose microcrystalline cellulose, dapoxetine hydrochloride, colloidal silicon dioxide and magnesium stearate for later use;
3) Tabletting: and (3) compressing the avanafil total mixed particles and the dapoxetine mixed powder into a double-layer tablet for later use.
4) Coating film
Particle size measuring method
Taking a proper amount of samples, using a laser particle size instrument according to a third method for measuring the particle size and the particle size distribution, continuously measuring for 3 times to obtain an average value, wherein the light shielding ratio of a detector is within the range of 5-15 percent, the dispersion pressure is 6-8 bar,
example 5 particle size screening
Particle size of avanafil
The prepared avanafil with different particle sizes is studied to influence the compressibility of the particles and the dissolution rate of the tablets, and the results are shown in the table below.
Dissolution, compressibility of tablets prepared with different particle sizes Avanafil (Paddle 50rpm, purified Water, 900 mL)
| 1 | 2 | 3 | 4 | 5 | 6 | |
| Particle size (D) 90 ) | 120μm | 90μm | 46μm | 35μm | 27μm | 16μm |
| Hardness of | 49N | 59N | 70N | 75N | 83N | 103N |
| Number of tablets | N＝3 | N＝3 | N＝3 | N＝3 | N＝3 | N＝3 |
| Time (min) | Dissolution (%) | Dissolution (%) | Dissolution (%) | Dissolution (%) | Dissolution (%) | Dissolution (%) |
| 5 | 13.2 | 16.1 | 19.9 | 31.5 | 24.2 | 30.2 |
| 10 | 20.4 | 29.9 | 34.6 | 43.1 | 35.9 | 38.7 |
| 15 | 30.2 | 39.1 | 43.0 | 50.2 | 43.2 | 43.3 |
| 30 | 44.6 | 54.9 | 56.8 | 63.3 | 59.4 | 63.8 |
| 45 | 50.5 | 63.0 | 62.7 | 70.2 | 68.3 | 70.8 |
| 60 | 60.1 | 70.2 | 68.6 | 74.6 | 72.5 | 75.0 |
According to the results, when the particle size of the avanafil is in the range D 90 When the particle size is 20-90 mu m, the avanafil in the double-layer tablet has better dissolution rate. But in D 90 At 90 μm, the compressibility of the prepared particles was slightly poor (hardness less than 60N). When D is present 90 At 16 μm, the resulting granules resulted in slugging when compressed.
Particle size of fumaric acid
Fumaric acid of different particle sizes was prepared and the effect of particle size on tablet compressibility and granulation process was studied and the results are shown in the table below.
When the particle diameter of fumaric acid is in the range of 80 to 160 μm, the tablet has compressibility, and particularly when the particle diameter is in the range of 80 to 130 μm, good compressibility is exhibited.
Example 6
With reference to the preparation method of example 4 and the preferred particle size range of example 5, avanafil dapoxetine bilayer tablets (200 mg/60 mg) were prepared according to the following raw material composition.
Example 7
With reference to the preparation method of example 4 and the preferred particle size range of example 5, avanafil dapoxetine bilayer tablets (200 mg/30 mg) were prepared according to the following raw material composition.
Example 8
Dissolution test
Taking the double-layer tablet of the example 6, in vitro dissolution study was performed according to a dissolution method (a second method (paddle method) of the four 0931 dissolution and release methods in the 2020 edition of Chinese pharmacopoeia), and a device of the second method (paddle method) of the dissolution and release methods was adopted, wherein 900mL of hydrochloric acid solution with pH of 1.0 is used as a medium, the rotating speed is 50rpm, the medium temperature is 37 ℃ +/-0.5 ℃, and the solution is taken at time points of 5min, 10min, 15min, 30min, 45min and 60min for filtration, so as to determine the content of avanafil and dapoxetine. The cumulative dissolution of each tablet at different times was calculated separately. Dissolution profile results are as follows:
dissolution Profile of bilayer tablet in pH1.0 dissolution Medium at 0 day (Paddle 50 rpm)
Bilayer tablet accelerates dissolution profile in pH1.0 dissolution media for 3 months (Paddle 50 rpm)
Example 9
Stability test
The two-layer tablet formulations of examples 6 and 7 were subjected to accelerated 40 + -2 deg.C, RH75 + -5% and prolonged 30 + -2 deg.C, RH65 + -5% stability studies, corresponding stability-related material data (all impurities corresponding to the avanafil and dapoxetine two-layer tablets) were as follows:
example 10
The following animal models and methods were used to study the in vivo effects of the pharmaceutical formulations of the present invention.
The experimental steps are as follows:
male Wistar rats, weighing around 300g, are acclimatized for one week before starting the experiment. On the day of the experiment, dapoxetine, a formulation of the invention (200mg. When PE molding is induced (PCA is injected into abdominal cavity for 5 mg/kg), each animal is ensured to be dosed for 1.5h, and data change of each index within 30min after induction is continuously recorded.
Data analysis
Recording the seminal vesicle pressure and the cavernous muscle myoelectric change caused by animal ejaculation
A.30min, the number of times of actual ejaculation (ejaculatory number) and the first ejaculation latency period (ejaculatory latency) of the animal
B.30min, the number of seminal vesicle contractions, the latency of the initial contraction, the peak pressure and duration
Within C.30min, cavernous myoelectricity is related: the number of muscle contractions, the latency of the initial contraction, the peak pressure and duration
Experimental data were expressed as Mean ± s.e.m. using GraphPad Prism 8.0 software for statistical analysis. Statistical analysis was performed by One-way ANOVA, tukey's multiple complexes test. P <0.05 is statistically different, P <0.01 is statistically different with significance, and P <0.001 is statistically different with extreme significance.
Results of the experiment
The study monitored the potential effect of the tested drugs by inducing the premature ejaculation model of Wistar rats by PCA. According to statistical analysis of relevant indexes such as the ejaculation frequency of a rat, the initial ejaculation latency period, the seminal vesicle contraction frequency and the like, the pharmaceutical composition disclosed by the invention can prolong the ejaculation latency period to the maximum extent and greatly reduce the ejaculation frequency. Compared with the effect of treating PE by dapoxetine, the medicinal preparation has better effect of treating PE.
Claims (19)
1. A pharmaceutical composition, which contains dapoxetine and avanafil, wherein the weight ratio of the dapoxetine to the avanafil in the composition is 6, 20, 3.
2. The pharmaceutical composition according to claim 1, wherein the weight ratio of dapoxetine to avanafil is 6.
3. The pharmaceutical composition according to claim 2, wherein the composition comprises 60mg or 30mg of dapoxetine and 200mg of avanafil.
4. Use of the pharmaceutical composition of claim 1 for the preparation of a medicament for the treatment of erectile dysfunction, premature ejaculation, erectile dysfunction with premature ejaculation.
5. The use according to claim 4, wherein the pharmaceutical composition comprises dapoxetine and avanafil in a weight ratio of 6.
6. The use according to claim 4, wherein the pharmaceutical composition comprises 60mg or 30mg of dapoxetine and 200mg of avanafil.
7. A pharmaceutical preparation comprising the pharmaceutical composition according to claim 1, and an excipient, a binder, a disintegrant, and a lubricant.
8. The pharmaceutical preparation according to claim 7, further comprising an organic acid, and/or a carbonate.
9. The pharmaceutical formulation of claim 8, wherein the particle size D of the organic acid 90 50-200 μm;
and/or the particle size D of the avanafil 90 Is 10 to 150 mu m.
10. A bilayer tablet comprising the pharmaceutical composition of claim 1, said bilayer tablet comprising a first active ingredient layer and a second active ingredient layer; the first active layer contains avanafil, an organic acid and carbonate; the second active layer contains dapoxetine.
11. The bilayer tablet of claim 10 wherein the organic acid is fumaric acid and the carbonate is calcium carbonate.
12. The bilayer tablet of claim 10, the particle size D of the organic acid 90 50-200 μm;
and/or the particle size D of the organic acid 90 80-150 μm;
and/or the particle size D of the avanafil 90 10-150 μm;
and/or the particle size D of the avanafil 90 15-120 μm;
and/or the particle size D of the avanafil 90 20 to 90 μm.
13. The bilayer tablet of claim 10, wherein in the first active ingredient layer, avanafil particles, fumaric acid particles and carbonate are contained; the second active ingredient layer contains dapoxetine; the particle size D of the avanafil 90 10 to 150 mu m, the particle diameter D of the fumaric acid 90 Is 50 to 200 mu m.
14. The bilayer tablet of claim 10 wherein the first active ingredient layer contains avanafil 100mg or 200mg; the second active ingredient layer contains 60mg or 30mg of dapoxetine.
15. The bilayer tablet according to claim 10 comprising in the first active ingredient layer 5 to 30% by weight, based on the total weight of the bilayer tablet, of fumaric acid; and/or, 0.1% to 5% by weight carbonate.
16. A bilayer tablet comprises a first active ingredient layer and a second active ingredient layer; the first active layer contains avanafil particles, fumaric acid particles and carbonate; the second active layer contains dapoxetine; the first active layer contains avanafil 200mg; and particle size D of avanafil 90 10-150 μm; the second active ingredient layer contains 60mg or 30mg of dapoxetine.
17. The bilayer tablet of claim 16 comprising 5 to 30% by weight fumaric acid and 0.1% to 5% by weight carbonate in the first active ingredient layer, based on the total weight of the bilayer tablet.
18. The bilayer tablet of claim 16 comprising, based on the total weight of the bilayer tablet
1-15% by weight of a disintegrant;
10-60% by weight of excipients;
0.5-5% by weight of a binder;
glidant 0.1-3.0 wt%;
0.1-5.0 wt% of lubricant.
19. A process for the preparation of a bilayer tablet according to claim 16 comprising the steps of:
(1) Crushing the avanafil and the fumaric acid to the required particle size;
(2) Carrying out wet granulation on the avanafil, the adhesive and the excipient to obtain avanafil granules;
(3) Carrying out wet granulation on fumaric acid and an adhesive to obtain fumaric acid granules;
(4) Uniformly mixing the avanafil granules, the fumaric acid granules, the carbonate, the lubricant and the disintegrant;
(5) Mixing dapoxetine, excipient, disintegrant, glidant and lubricant;
(6) And (5) pressing the powder obtained in the step (4) and the powder obtained in the step (5) into a double-layer tablet to obtain the double-layer tablet.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111162584 | 2021-09-30 | ||
| CN2021111625849 | 2021-09-30 |
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| Publication Number | Publication Date |
|---|---|
| CN115887462A true CN115887462A (en) | 2023-04-04 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202211208791.8A Pending CN115887462A (en) | 2021-09-30 | 2022-09-30 | Oral pharmaceutical composition |
Country Status (2)
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| WO (1) | WO2023051780A1 (en) |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2012157127A (en) * | 2010-07-06 | 2014-08-20 | Навифарм. Ко., Лтд. | PHARMACEUTICAL COMPOSITION CONTAINING DAPOXETINE FOR ORAL ADMINISTRATION WITH SLOW DELIVERY |
| US20150231092A1 (en) * | 2012-08-17 | 2015-08-20 | Sanovell IIac Sanayi Ve Ticaret Anonim Sirketi | Novel effervescent sachet formulations of dapoxetine and a pde5 inhibitor |
| CN103340869B (en) * | 2013-06-28 | 2015-04-01 | 王立强 | Composition for impotence and premature ejaculation |
| WO2020006606A1 (en) * | 2018-07-05 | 2020-01-09 | Helium 3 Resources Pty Ltd | A pharmaceutical composition and method of use of same |
| CN114917200A (en) * | 2022-06-09 | 2022-08-19 | 广东万年青制药股份有限公司 | Solid preparation of medicine for treating impotence and premature ejaculation and preparation method thereof |
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2022
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