CN115429766A - Icariin solid dispersion, compound medicine double-layer tablet, preparation method and application thereof - Google Patents
Icariin solid dispersion, compound medicine double-layer tablet, preparation method and application thereof Download PDFInfo
- Publication number
- CN115429766A CN115429766A CN202211092808.8A CN202211092808A CN115429766A CN 115429766 A CN115429766 A CN 115429766A CN 202211092808 A CN202211092808 A CN 202211092808A CN 115429766 A CN115429766 A CN 115429766A
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- Prior art keywords
- icariin
- solid dispersion
- release layer
- drying
- components
- Prior art date
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- TZJALUIVHRYQQB-XFDQAQKOSA-N Icariin Natural products O(C)c1ccc(C2=C(O[C@H]3[C@@H](O)[C@H](O)[C@@H](O)[C@H](C)O3)C(=O)c3c(O)cc(O[C@H]4[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O4)c(C/C=C(\C)/C)c3O2)cc1 TZJALUIVHRYQQB-XFDQAQKOSA-N 0.000 title claims abstract description 100
- TZJALUIVHRYQQB-XLRXWWTNSA-N icariin Chemical compound C1=CC(OC)=CC=C1C1=C(O[C@H]2[C@@H]([C@H](O)[C@@H](O)[C@H](C)O2)O)C(=O)C2=C(O)C=C(O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O3)O)C(CC=C(C)C)=C2O1 TZJALUIVHRYQQB-XLRXWWTNSA-N 0.000 title claims abstract description 100
- TZJALUIVHRYQQB-UHFFFAOYSA-N icariine Natural products C1=CC(OC)=CC=C1C1=C(OC2C(C(O)C(O)C(C)O2)O)C(=O)C2=C(O)C=C(OC3C(C(O)C(O)C(CO)O3)O)C(CC=C(C)C)=C2O1 TZJALUIVHRYQQB-UHFFFAOYSA-N 0.000 title claims abstract description 100
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- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 claims abstract description 19
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 38
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- USRHYDPUVLEVMC-FQEVSTJZSA-N dapoxetine Chemical compound C1([C@H](CCOC=2C3=CC=CC=C3C=CC=2)N(C)C)=CC=CC=C1 USRHYDPUVLEVMC-FQEVSTJZSA-N 0.000 claims description 25
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- ZUAAPNNKRHMPKG-UHFFFAOYSA-N acetic acid;butanedioic acid;methanol;propane-1,2-diol Chemical compound OC.CC(O)=O.CC(O)CO.OC(=O)CCC(O)=O ZUAAPNNKRHMPKG-UHFFFAOYSA-N 0.000 claims description 3
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- Medicinal Preparation (AREA)
Abstract
The invention provides an icariin solid dispersion, which comprises icariin and docusate sodium in a weight ratio of 1 (0.2-1). The solid dispersion obviously improves the solubility and bioavailability of the icariin, also obviously improves the stability of the icariin in gastric juice, and avoids the condition of curative effect reduction caused by that gastric acid damages the structure of the epimedium herb.
Description
Technical Field
The invention relates to the field of medicine research, in particular to an icariin solid dispersion, a compound medicine double-layer tablet, and a preparation method and application thereof.
Background
The Chinese herbal medicine epimedium, also called epimedium herb, has the effects of tonifying kidney, strengthening yang, dispelling wind and removing dampness immediately before. Can be used for treating sexual impotence, dribbling urination, spasm and spasm of muscles and bones, hemiplegia, weakness of waist and knees, rheumatic arthralgia, and myasthenia of limbs. Icariin is a main component of Chinese herbal medicine epimedium herb, is an 8-isopentenyl flavonoid glycoside compound, has extremely low solubility in water, is not dissolved in an aqueous solvent within a physiological pH range, and has poor stability in an acidic environment (such as gastric juice). The icariin has poor solubility and instability in gastric juice, so that the bioavailability of the icariin in vivo is influenced, and the therapeutic effect of the icariin is limited.
Premature Ejaculation (PE) is the ejaculation disorder disease with the highest incidence rate in the andrology, and the incidence rate is next to the penile Erectile Dysfunction (ED) in the diagnosis and treatment of the andrological common sexual dysfunction diseases. The premature ejaculation symptom is mainly characterized in that the penis is involuntary ejaculation after being stimulated in the vagina with minimum stimulation, namely, the latent time of the ejaculation in the vagina is shortened and the automatic control capability of the ejaculation is reduced, thereby generating negative influence on the self-respect and confidence of a patient, further causing the satisfaction of both parties to sexual life to be reduced, generating vicious circle and finally seriously influencing the life quality of couples. The definition of PE in recent years mainly includes three elements: intravaginal Ejaculation Latency (IELT) is short, sexual satisfaction is poor and ejaculatory control is poor. PE has affected the quality of life of patients and has also caused confusion or annoyance to spouses or sexual partners, ultimately leading to even a number of household or social problems. Recent research guidelines classify PEs into 4 major categories: primary, secondary, naturally variant and PE-like ejaculatory dysfunction. According to statistics, the incidence rate of PE in middle-aged and young men in China is up to 35%, but under the influence of the traditional concept of people, the actual incidence rate is higher than the incidence rate, and the clinical diagnosis rate is lower. The current clinical treatments for PE mainly include psychobehavioral therapy, drug therapy and surgical treatment. The psychobehavioral therapy belongs to a common clinical intervention method, the main action mechanism is to improve the control ability of ejaculation by guiding a patient to learn and control the ejaculation skill and adjusting the psychological state of the patient, thereby further improving the satisfaction of the patient and the sexual partner thereof to the sexual life. The clinical operation treatment is mainly circumcision, although the sexual intercourse time can be prolonged, the operation can affect the sensory nerve of the penis, cause sensory hypofunction, even induce erectile dysfunction and the like, and can not effectively improve the sexual life satisfaction of a patient, so that the drug treatment is the main treatment means of the current PE.
The dapoxetine is the first specialized drug for PE treatment in the world at present, and clinical tests show that the ejaculation time of the dapoxetine group is prolonged to 2-3 minutes from about 1.5 minutes compared with that of a placebo group, the actual prolonged time is only 0.5-1.5 min, the drug needs to be taken 1 hour before sexual life, and most patients have various adverse reactions such as headache, dizziness, diarrhea, insomnia, somnolence, orthostatic hypotension and the like in the clinical use process.
In addition, clinically, more patients suffer from the symptoms of PE and ED, and the traditional method adopts the combination of two single medicines, so that the patients are inconvenient to take the medicine, and the body adverse reaction generated by dapoxetine is still obvious. There are no drugs and treatments available for treating the above two disorders simultaneously.
Disclosure of Invention
Based on the above, the invention provides the icariin solid dispersion, which can obviously improve the solubility and bioavailability of the icariin and can also obviously enhance the stability of the icariin in gastric juice.
The invention is realized by the following technical scheme.
An icariin solid dispersion comprises the components of icariin and docusate sodium in a weight ratio of 1 (0.2-1).
In one embodiment, the components comprise icariin and docusate sodium in a weight ratio of 1 (0.5-1).
In one embodiment, the particle size of the icariin solid dispersion is below 100 mu m.
The invention also provides a preparation method of the icariin solid dispersion, which comprises the following steps:
mixing the components with an organic solvent, drying and preparing the micronized solid.
In one embodiment, the organic solvent is selected from one or more of methanol, ethanol, isopropanol, acetone, dichloromethane, chloroform, acetonitrile and ethyl acetate.
In one embodiment, the drying is selected from one or more of spray drying, freeze drying, drying under reduced pressure, and fluidized bed drying.
The invention also provides application of the icariin solid dispersion in preparation of an oral medicament containing icariin.
In one embodiment, the oral medicament is in the form of capsules, tablets or granules.
The invention also provides a compound medicine double-layer tablet, which comprises a quick release layer and a slow release layer which are sequentially laminated;
wherein, the components of the quick release layer comprise an auxiliary agent and the icariin solid dispersion;
the components of the slow release layer comprise dapoxetine hydrochloride and a slow release material.
In one embodiment, the slow release material is selected from one or more of polyacrylic resin, carbomer resin 971P or 974P, hypromellose K4M, hypromellose and hypromellose acetate succinate M.
In one embodiment, the auxiliary agent comprises one or more of a diluent, a disintegrant and a lubricant.
In one embodiment, the auxiliary agent satisfies one or more of the following conditions:
(1) The diluent is selected from one or more of microcrystalline cellulose and lactose;
(2) The disintegrant is selected from one or more of crospovidone and croscarmellose sodium;
(3) The lubricant is selected from one or more of glyceryl behenate, stearic acid and magnesium stearate.
The invention also provides a preparation method of the compound medicine bilayer tablet, which comprises the following steps:
mixing the components of the quick release layer to prepare a first material;
mixing the components of the slow release layer to prepare a second material;
and carrying out double-layer tabletting and coating on the first material and the second material.
Compared with the prior art, the icariin solid dispersion has the following beneficial effects:
according to the invention, the screened docusate sodium is used as a water-soluble auxiliary material to be compounded with the icariin according to a certain mass ratio, so that the prepared solid dispersion obviously improves the solubility and bioavailability of the icariin, and simultaneously, the stability of the icariin in gastric juice is also obviously improved, and the situation that the curative effect is reduced due to the fact that the structure of the epimedium is damaged by gastric acid is avoided.
Furthermore, the icariin solid dispersion can be compounded with dapoxetine hydrochloride to form an upper layer double-layer tablet and a lower layer double-layer tablet, the icariin can be rapidly released to improve the success rate of penile erection, the blood medicine stability of the dapoxetine in a body is ensured by controlling the release rate of the dapoxetine, adverse reaction and side effect caused by the rapid change of the blood medicine concentration of the medicine in the body are avoided, and the combination of the two medicines with different release rates can play the best treatment effect on patients suffering from two indications of ED and PE diseases.
Drawings
FIG. 1 is a graph showing the variation of plasma concentration in rats according to example 8 of the present invention;
FIG. 2 is a graph showing the variation of blood concentration in rats according to example 9 of the present invention;
FIG. 3 is a graph showing the variation of plasma concentration in rats according to example 10 of the present invention;
FIG. 4 is a graph showing the variation of plasma concentration in rats according to comparative example 8 of the present invention;
FIG. 5 is a graph showing the variation of plasma concentration in rats according to comparative example 9 of the present invention.
Detailed Description
To facilitate an understanding of the invention, the invention will now be described more fully with reference to the accompanying drawings. Preferred embodiments of the present invention are shown in the drawings. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.
Furthermore, the terms "first", "second" and "first" are used for descriptive purposes only and are not to be construed as indicating or implying relative importance or implicitly indicating the number of technical features indicated. Thus, a feature defined as "first" or "second" may explicitly or implicitly include at least one such feature. In the description of the invention, "a plurality" means at least two, e.g., two, three, etc., unless explicitly specified otherwise. In the description of the present invention, "a plurality" means at least one, e.g., one, two, etc., unless specifically limited otherwise.
The words "preferably," "more preferably," and the like, in the present disclosure mean embodiments of the disclosure that may, in some instances, provide certain benefits. However, other embodiments may be preferred, under the same or other circumstances. Furthermore, the recitation of one or more preferred embodiments does not imply that other embodiments are not useful, nor is it intended to exclude other embodiments from the scope of the invention.
When a range of values is disclosed herein, the range is considered to be continuous and includes both the minimum and maximum values of the range, as well as each value between such minimum and maximum values. Further, when a range refers to an integer, each integer between the minimum and maximum values of the range is included. Further, when multiple range describing features or characteristics are provided, the ranges may be combined. In other words, unless otherwise indicated, all ranges disclosed herein are to be understood to encompass any and all subranges subsumed therein.
All percentages, fractions and ratios are calculated on the total mass of the composition of the invention, unless otherwise indicated. All qualities relating to the listed ingredients are given to the content of active substance, unless otherwise specified, and therefore they do not include solvents or by-products that may be contained in commercially available materials. The term "mass percent content" herein may be represented by the symbol "%". All molecular weights herein are weight average molecular weights expressed in daltons, unless otherwise indicated. All formulations and tests herein occur at 25 ℃ environment, unless otherwise indicated. The use of "including," "comprising," "containing," "having," or other variations thereof herein, is meant to encompass non-exclusive inclusions, as well as non-exclusive distinctions between such terms. The term "comprising" means that other steps and ingredients can be added that do not affect the end result. The compositions and methods/processes of the present invention comprise, consist of, and consist essentially of the essential elements and limitations described herein, as well as any of the additional or optional ingredients, components, steps, or limitations described herein. The terms "potency", "performance", "effect" and "efficacy" are not distinguished from one another herein.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used herein in the description of the invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items.
The invention provides an icariin solid dispersion, which comprises icariin and docusate sodium in a weight ratio of 1 (0.2-1).
It is understood that, in the present invention, the chemical structure of icariin is as follows:
in a specific example, icariin is obtained by extraction from dried stem and leaf of Chinese herbal medicine. More specifically, the Chinese herbal medicine is selected from Epimedium sagittatum, epimedium pubescens, epimedium wushanense sago or Epimedium koreanum.
In a specific example, icariin is prepared by a chemical or enzymatic artificial synthesis method.
In a specific example, the purity of icariin is 80% or more. Preferably, icariin has a purity of 98% or more.
It is understood that in the present invention, the mass ratio of icariin to docusate sodium includes but is not limited to 1.
Preferably, the components of the icariin solid dispersion comprise icariin and docusate sodium in a weight ratio of 1 (0.5-1).
In a specific example, the average particle diameter of the icariin solid dispersion is 0.5 to 100 μm. Preferably, the average particle size of the icariin solid dispersion is 1 to 50 μm. More preferably, the particle size of the icariin solid dispersion is 2 to 30 μm.
The invention also provides a preparation method of the icariin solid dispersion, which comprises the following steps:
mixing the components with an organic solvent, drying and preparing the micronized solid.
In a specific example, the organic solvent is selected from one or more of methanol, ethanol, isopropanol, acetone, dichloromethane, chloroform, acetonitrile and ethyl acetate. Preferably, the organic solvent is a mixture of methanol or ethanol, and acetone. More preferably, the organic solvent is a mixture of methanol and acetone.
In a more specific example, the volume ratio of methanol to acetone is (1-5): 1. Preferably, the volume ratio of the methanol to the acetone is (1-4): 1. More preferably, the volume ratio of methanol to acetone is 3:1.
In a specific example, the drying manner is selected from one or more of spray drying, freeze drying, reduced pressure drying and fluidized bed drying. Preferably, the drying is by one or more of spray drying and fluidized bed drying. More preferably, the manner of drying is spray drying.
In a more specific example, the preparation method of the icariin solid dispersion comprises the following steps:
dissolving icariin and docusate sodium in a weight ratio of 1 (0.2-1) in a mixed solvent of methanol and acetone in a volume ratio of (1-5) to 1 to prepare a drug solution with a solid content of 10-50%;
atomizing and spraying the medicine solution in a spray dryer at a proper flow rate under the pressure of 1.0-6.0 bar, and drying at the temperature of 50-80 ℃ to remove the solvent, wherein the diameter of a nozzle is 0.5-1.5 mm as the best;
the solid dispersion is used as it is or after grinding to a particle size of not more than 100 μm, depending on the particle size of the solid dispersion after drying.
The invention also provides application of the icariin solid dispersion in preparation of an oral medicament containing icariin.
In a specific example, the dosage form of the oral drug is a capsule, a tablet or a granule.
The invention also provides a compound medicine double-layer tablet, which comprises a quick release layer and a slow release layer which are sequentially stacked;
wherein, the components of the quick release layer comprise an auxiliary agent and the icariin solid dispersion; the components of the slow release layer comprise dapoxetine hydrochloride and a slow release material.
The inventor unexpectedly finds that the double-layer tablet formed by the dapoxetine component prepared by the sustained-release formula and the icariin component prepared by the quick-release formula has better curative effect and lower adverse reaction incidence compared with the common quick-release dosage form.
It is understood that the structural formula of dapoxetine hydrochloride is shown below:
it can be understood that icariin in the invention can be directly purchased from the market, or extracted from dry stems and leaves of crude drugs such as epimedium sagittifolia, epimedium dauricum, epimedium wushanense sago or epimedium koreanum, or artificially synthesized by methods such as chemistry, enzyme catalysis and the like, and dapoxetine hydrochloride is an artificially synthesized chemical drug. The inventor unexpectedly finds that the icariin and the dapoxetine hydrochloride are combined to produce a synergistic effect after being used, can produce a more obvious curative effect than the icariin and the dapoxetine hydrochloride when being used alone at a lower dose, and has more stable blood concentration and better curative effect.
In a specific example, the slow release material is selected from one or more of polyacrylic resin, carbomer resin, hypromellose, hyprolose and hypromellose acetate succinate.
Preferably, the slow release material is a combination of polyacrylic resin and carbomer resin; more preferably, the slow release material is a combination of polyacrylic resin and carbomer resin in a weight ratio of 2:1-5:1.
More specifically, the polyacrylic resin is selected from one or more of methacrylic acid-ethyl acrylate copolymer and ethyl acrylate-methyl methacrylate copolymer. Preferably, the polypropylene resin is an ethyl acrylate-methyl methacrylate (1:1) copolymer.
More specifically, the carbomer resin is Carbopol 971P or Carbopol 974P. Preferably, the carbomer resin is Carbopol 974P.
In a particular example, the adjuvants include one or more of diluents, disintegrants and lubricants.
In one particular example, the adjuvant satisfies one or more of the following conditions:
(1) The diluent is selected from one or more of microcrystalline cellulose and lactose;
(2) The disintegrant is selected from one or more of crospovidone and croscarmellose sodium;
(3) The lubricant is one or more selected from glyceryl behenate, stearic acid and magnesium stearate.
In one particular example, the components of the sustained release layer further include a lubricant; the lubricant is one or more selected from glyceryl behenate, stearic acid and magnesium stearate.
The invention also provides a preparation method of the compound medicine double-layer tablet, which comprises the following steps:
mixing the components of the quick release layer to prepare a first material;
mixing the components of the sustained-release layer to prepare a second material;
and carrying out double-layer tabletting and coating on the first material and the second material.
In a specific example, the preparation method of the compound pharmaceutical bilayer tablet comprises the following steps:
(1) A quick release layer: mixing the icariin solid dispersion with proper diluent (such as microcrystalline cellulose or lactose), disintegrant (such as one or more of crospovidone and croscarmellose sodium) and lubricant (one or more of glyceryl behenate, stearic acid and magnesium stearate);
(2) A slow release layer: mixing dapoxetine hydrochloride, ethyl acrylate-methyl methacrylate (1:1) copolymer and carbomer resin Carbopol 974P uniformly, adding water or ethanol water solution, atomizing, spraying appropriate amount, wet granulating, drying the prepared wet granules at 40-60 deg.C until water content is lower than 5%, adding lubricant (one or more of glyceryl behenate, stearic acid and magnesium stearate), and mixing uniformly;
(3) The tablets were compressed in a bi-layer tablet press, each tablet comprising a quick release layer and a sustained release layer, and then the bi-layer tablets were film coated.
The icariin solid dispersion, the compound pharmaceutical bilayer tablet and the preparation method thereof of the present invention are further described in detail below with reference to specific examples. The starting materials used in the following examples are all commercially available products unless otherwise specified.
Example 1
This example provides a solid dispersion, specifically as follows:
20g of icariin (purity is more than or equal to 98.0%) is dissolved in ethanol under stirring: dichloromethane (volume ratio 5:1), and 10g of docusate sodium was dissolved in ethanol: mixing the two solutions in a mixed solvent of dichloromethane (with a volume ratio of 8:1), stirring uniformly, and drying in a spray dryer to remove the organic solvent to obtain the icariin solid dispersion, wherein the average particle size of the solid dispersion is controlled to be 90-100 mu m.
Example 2
This example provides a solid dispersion, specifically as follows:
20g of icariin (the purity is more than or equal to 98.0%) is dissolved in ethanol by stirring: dissolving 10g of docusate sodium in methanol in a mixed solvent of acetone (the volume ratio is 5:1), combining the two solutions, uniformly stirring, and drying in a spray dryer to remove an organic solvent to obtain the icariin solid dispersion, wherein the average particle size of the solid dispersion is controlled to be 70-80 mu m.
Example 3
This example provides a solid dispersion, specifically as follows:
20g of icariin (purity is more than or equal to 98.0%) is dissolved in methanol under stirring: acetone (5:1 by volume), and 10g of docusate sodium was dissolved in methanol: mixing the two solutions in a mixed solvent of acetone (5:1), stirring uniformly, and drying in a spray dryer to remove organic solvent to obtain icariin solid dispersion with average particle diameter of 70-80 μm.
Example 4
This example provides a solid dispersion, specifically as follows:
20g of icariin (purity more than or equal to 98.0%) is dissolved in methanol with stirring: acetone (4:1 by volume), and 10g of docusate sodium was dissolved in methanol: mixing the two solutions in a mixed solvent of acetone (4:1), stirring uniformly, and drying in a spray dryer to remove organic solvent to obtain icariin solid dispersion with average particle diameter of 70-80 μm.
Example 5
This example provides a solid dispersion, specifically as follows:
20g of icariin (purity more than or equal to 98.0%) is dissolved in methanol with stirring: dissolving 4g of docusate sodium in methanol in a mixed solvent of acetone (the volume ratio is 3:1), combining the two solutions, uniformly stirring, and drying in a spray dryer to remove an organic solvent to obtain the icariin solid dispersion, wherein the average particle size of the solid dispersion is controlled to be 70-80 mu m.
Example 6
This example provides a solid dispersion, specifically as follows:
20g of icariin (purity more than or equal to 98.0%) is dissolved in methanol with stirring: acetone (3:1 by volume), and 20g of docusate sodium was dissolved in methanol: mixing the two solutions in a mixed solvent of acetone (5:1), stirring, and drying in a spray dryer to remove the organic solvent to obtain icariin solid dispersion with average particle size of 40-50 μm.
Example 7
This example provides a solid dispersion, specifically as follows:
20g of icariin (purity is more than or equal to 98.0%) is dissolved in methanol under stirring: acetone (1:1 by volume), and 10g of docusate sodium was dissolved in methanol: mixing the two solutions in a mixed solvent of acetone (2:1), stirring uniformly, and drying in a spray dryer to remove organic solvent to obtain icariin solid dispersion with average particle diameter of 20-30 μm.
Example 8
This example provides a bilayer tablet, as follows:
mixing 48g of the solid dispersion of example 5 with 10g of microcrystalline cellulose, 4.5g of crospovidone, and 0.5g of glyceryl behenate to form a quick release layer granule; mixing 13.43g of dapoxetine hydrochloride, 36g of ethyl acrylate, methyl methacrylate (1:1) copolymer and 18g of carbomer resin Carbopol 974P uniformly, adding a proper amount of purified water for wet granulation, drying the prepared wet granules at 40-60 ℃ until the water content is lower than 5%, finally adding 0.67g of glyceryl behenate for uniformly mixing to form a slow release layer, pressing a double-layer tablet by respectively using about 0.315g of quick release layer granules and about 0.340g of slow release layer granules contained in each tablet, and coating by using yellow gastric-soluble film coating powder.
Example 9
This example provides a bilayer tablet, as follows:
mixing 80g of the solid dispersion of example 6 with 12g of microcrystalline cellulose, 4.5g of crospovidone, and 0.5g of magnesium stearate to form granules of the immediate release layer; 13.43g of dapoxetine hydrochloride, 36g of ethyl acrylate, methyl methacrylate (1:1) copolymer and 18g of carbomer resin Carbopol 974P are uniformly mixed, an appropriate amount of purified water is added for wet granulation, the prepared wet granules are dried at 40-60 ℃ until the water content is lower than 5%, finally 0.67g of magnesium stearate is added for uniform mixing to be used as a slow release layer, about 0.485g of quick release layer granules and 0.340g of slow release layer granules are respectively contained in each tablet to be pressed into a double-layer tablet, and the double-layer tablet is coated by yellow gastric-soluble film coating powder.
Example 10
This example provides a bilayer tablet, as follows:
60g of the solid dispersion of example 7 was mixed with 12g of microcrystalline cellulose, 4.5g of crospovidone and 0.5g of magnesium stearate to form granules for the immediate release layer; 13.43g of dapoxetine hydrochloride, 36g of ethyl acrylate, methyl methacrylate (1:1) copolymer and 18g of carbomer resin Carbopol 974P are mixed uniformly, an appropriate amount of purified water is added for wet granulation, the prepared wet granules are dried at 40-60 ℃ until the moisture content is lower than 5%, finally 0.67g of magnesium stearate is added for uniform mixing to serve as a slow release layer, about 0.385g of quick release layer granules and 0.340g of slow release layer granules are respectively contained in each tablet, the tablets are pressed into double-layer tablets, and the tablets are coated with yellow gastric-soluble film coating powder.
Comparative example 1
This comparative example provides a solid dispersion as follows:
20g of icariin (purity is more than or equal to 98.0%) is dissolved in methanol under stirring: dissolving 20g of polyethylene glycol 6000 in methanol in a mixed solvent of acetone (5:1 in volume ratio), combining the two solutions, uniformly stirring, and drying in a spray dryer to remove the organic solvent to obtain the icariin solid dispersion, wherein the average particle size of the solid dispersion is controlled to be 20-30 mu m.
Comparative example 2
This comparative example provides a solid dispersion as follows:
20g of icariin (purity is more than or equal to 98.0%) is dissolved in methanol under stirring: dissolving 20g of hydroxypropyl cellulose in methanol in a mixed solvent of acetone (the volume ratio is 5:1), combining the two solutions, uniformly stirring, and drying in a spray dryer to remove an organic solvent to obtain the icariin solid dispersion, wherein the average particle size of the solid dispersion is controlled to be 20-30 mu m.
Comparative example 3
This comparative example provides a solid dispersion as follows:
20g of icariin (purity is more than or equal to 98.0%) is dissolved in methanol under stirring: drying in a mixed solvent of acetone (5:1 by volume) in a spray dryer to remove the organic solvent to obtain icariin solid dispersion, wherein the average particle diameter of the solid dispersion is controlled to be 20-30 μm.
Comparative example 4
This comparative example provides a solid dispersion as follows:
20g of icariin (purity more than or equal to 98.0%) is dissolved in methanol with stirring: acetone (5:1 by volume), and 10g of copovidone VA64 was dissolved in methanol: mixing the two solutions in a mixed solvent of acetone (5:1), stirring uniformly, and drying in a spray dryer to remove organic solvent to obtain icariin solid dispersion with average particle diameter of 70-80 μm.
Comparative example 5
The present comparative example provides a solid dispersion prepared by a hot melt extrusion process, specifically as follows:
mixing 200g icariin (purity greater than or equal to 98.0%) and 100g copovidone VA64 powder, and slowly adding into Thermo Scientific TM Preparing a molten material in a Process 11 double-screw hot-melting extruder at 135-165 ℃, extruding and cooling the molten material to form small sheets, and then crushing the small sheets by FizmillGrinding the mixture at a machine speed of 8000-120000 rpm with a screen of 0.5mm to obtain a solid dispersion with an average particle size of 70-80 μm.
Comparative example 6
This comparative example provides a solid dispersion as follows:
20g of icariin (purity more than or equal to 98.0%) is dissolved in methanol with stirring: dissolving 3g of docusate sodium in methanol in a mixed solvent of acetone (3:1 in volume ratio), mixing the two solutions, uniformly stirring, and drying in a spray dryer to remove an organic solvent to obtain the icariin solid dispersion, wherein the average particle size of the solid dispersion is controlled to be 70-80 mu m.
Comparative example 7
This comparative example provides a solid dispersion as follows:
20g of icariin (purity is more than or equal to 98.0%) is dissolved in methanol under stirring: dissolving 22g of docusate sodium in methanol in a mixed solvent of acetone (the volume ratio is 3:1), combining the two solutions, uniformly stirring, and drying in a spray dryer to remove an organic solvent to obtain the icariin solid dispersion, wherein the average particle size of the solid dispersion is controlled to be 40-50 mu m.
Comparative example 8
This comparative example provides a bilayer tablet, as follows:
mixing 40g of the solid dispersion of comparative example 3 with 12g of microcrystalline cellulose, 4.5g of crospovidone and 0.5g of magnesium stearate to form granules of the immediate release layer; 13.43g of dapoxetine hydrochloride, 36g of ethyl acrylate, methyl methacrylate (1:1) copolymer and 18g of carbomer resin Carbopol 974P are uniformly mixed, an appropriate amount of purified water is added for wet granulation, the prepared wet granules are dried at 40-60 ℃ until the water content is lower than 5%, finally 0.67g of magnesium stearate is added for uniform mixing to be used as a slow release layer, about 0.285g of quick release layer granules and 0.340g of slow release layer granules contained in each tablet are respectively pressed into a double-layer tablet, and the double-layer tablet is coated by yellow gastric-soluble film coating powder.
Comparative example 9
This comparative example provides a tablet, specifically as follows:
40g of icariin crystal powder and 13.43g of dapoxetine hydrochloride are mixed uniformly with 12g of microcrystalline cellulose, 4.5g of crospovidone and 0.5g of magnesium stearate, each tablet is compressed into tablets by 0.35g, and the tablets are coated by yellow gastric-soluble film coating powder.
Comparative example 10
Mixing 60g of the solid dispersion of comparative example 4 with 12g of microcrystalline cellulose, 4.5g of crospovidone and 0.5g of magnesium stearate to form granules of the immediate release layer; 13.43g of dapoxetine hydrochloride, 36g of ethyl acrylate, methyl methacrylate (1:1) copolymer and 18g of carbomer resin Carbopol 974P are mixed uniformly, an appropriate amount of purified water is added for wet granulation, the prepared wet granules are dried at 40-60 ℃ until the moisture content is lower than 5%, finally 0.67g of magnesium stearate is added for uniform mixing to serve as a slow release layer, about 0.385g of quick release layer granules and 0.340g of slow release layer granules are respectively contained in each tablet, the tablets are pressed into double-layer tablets, and the tablets are coated with yellow gastric-soluble film coating powder.
Comparative example 11
Mixing 60g of the solid dispersion of comparative example 5 with 12g of microcrystalline cellulose, 4.5g of crospovidone, and 0.5g of magnesium stearate to form granules of the immediate release layer; 13.43g of dapoxetine hydrochloride, 36g of ethyl acrylate, methyl methacrylate (1:1) copolymer and 18g of carbomer resin Carbopol 974P are uniformly mixed, an appropriate amount of purified water is added for wet granulation, the prepared wet granules are dried at 40-60 ℃ until the water content is lower than 5%, finally 0.67g of magnesium stearate is added for uniform mixing to be used as a slow release layer, about 0.385g of quick release layer granules and 0.340g of slow release layer granules are respectively contained in each tablet, the double-layer tablets are pressed, and yellow gastric-soluble film coating powder is used for film coating.
Comparative example 12
Mixing 46g of the solid dispersion of comparative example 6 with 10g of microcrystalline cellulose, 4.5g of crospovidone, and 0.5g of glyceryl behenate to form a quick release layer granule; mixing 13.43g of dapoxetine hydrochloride, 36g of ethyl acrylate, methyl methacrylate (1:1) copolymer and 18g of carbomer resin Carbopol 974P uniformly, adding a proper amount of purified water for wet granulation, drying the prepared wet granules at 40-60 ℃ until the water content is lower than 5%, finally adding 0.67g of glyceryl behenate for uniformly mixing to form a slow release layer, pressing a double-layer tablet by respectively using about 0.305g of quick release layer granules and about 0.340g of slow release layer granules contained in each tablet, and coating by using yellow gastric-soluble film coating powder.
Comparative example 13
Mixing 84g of the solid dispersion of example 7 with 12g of microcrystalline cellulose, 4.5g of crospovidone and 0.5g of magnesium stearate to form granules of the immediate release layer; 13.43g of dapoxetine hydrochloride, 36g of ethyl acrylate, methyl methacrylate (1:1) copolymer and 18g of carbomer resin Carbopol 974P are mixed uniformly, an appropriate amount of purified water is added for wet granulation, the prepared wet granules are dried at 40-60 ℃ until the moisture content is lower than 5%, finally 0.67g of magnesium stearate is added for uniform mixing to form a slow release layer, about 0.505g of quick release layer granules and 0.340g of slow release layer granules are respectively contained in each tablet, the tablets are pressed into double-layer tablets, and the tablets are coated with yellow gastric-soluble film coating powder.
The formulations of the solid dispersions of examples 1 to 7 and comparative examples 1 to 7 are collated with the process parameters as shown in Table 1.
TABLE 1
Effect test
(1) Solubility test
To evaluate the improvement of solubility of the solid dispersions in icariin, the solid dispersions of examples 1 to 7 and comparative examples 1 to 7 were shaken in a 37 ℃ water bath shaker for 0.5h and 24h using Phosphate Buffered Saline (PBS) of pH6.8 as a medium, and after sampling and filtering, a subsequent filtrate was taken and the solubility was measured in HPLC by the external standard method under the following chromatographic conditions:
a chromatographic column: agilent Poroshell 120 EC-C18 (4.6X 150mm,4 μm);
mobile phase: 10mM ammonium acetate (ph 5.5) -acetonitrile = 50;
column temperature: 35 ℃;
sample introduction volume: 10 mu L of the solution;
flow rate: 1.0mL/min;
detection wavelength: 270nm;
operating time: 15min;
elution procedure: water phase: organic phase =50 isocratic elution.
The results of the solubility measurements are shown in Table 2.
TABLE 2 icariin equilibrium solubility in PBS pH6.8 mg/mL (37 ℃ C.)
(2) Evaluation of therapeutic Effect
Adopts a second method-paddle method which accords with the general rule of Chinese pharmacopoeia 0931 as a test device, 1000ml of phosphate buffer salt with the pH value of 6.8 and containing 1.0 percent of Tween 80 is used as a dissolution medium, and the dissolution rotating speed is 100rpm.
SD male rats with ED and PE models weighing 320g +/-30 g are adopted, the experimental group is administrated by intragastric administration according to the icariin dose of 21mg/kg and the dapoxetine dose of 6.3mg/kg, the placebo group is used as a control, the treatment effect and the adverse reaction incidence of the experimental animals in the examples and the comparative examples are respectively evaluated, and the curative effect observation results are shown in the table 3.
TABLE 3 Observation of efficacy of Single and repeated administrations
(3) Stability of icariin in artificial gastric juice
The tablets of examples 8, 9 and 10 and comparative examples 8, 9, 10, 11, 12 and 13 were placed in 900ml of artificial gastric juice and shaken in a thermostatic water bath at 37 ℃ to examine the stability after 1, 2 and 4 hours, respectively, and the stability results are shown in Table 4. The graphs of the plasma concentrations of the tablets prepared in examples 8 to 10 in rats are shown in fig. 1 to 3, respectively, and the graphs of the plasma concentrations of the tablets prepared in comparative examples 8 to 9 in rats are shown in fig. 4 to 5, respectively.
TABLE 4 stability of icariin in Artificial gastric juice
All possible combinations of the technical features of the above embodiments may not be described for the sake of brevity, but should be considered as within the scope of the present disclosure as long as there is no contradiction between the combinations of the technical features.
The above-mentioned embodiments only express several embodiments of the present invention, so as to understand the technical solutions of the present invention specifically and in detail, but not to be understood as the limitation of the protection scope of the invention. It should be noted that various changes and modifications can be made by those skilled in the art without departing from the spirit of the invention, and these changes and modifications are all within the scope of the invention. It should be understood that the technical solutions provided by the present invention, which are obtained by logical analysis, reasoning or limited experiments, are within the scope of the appended claims. Therefore, the protection scope of the present invention should be subject to the content of the appended claims, and the description and the drawings can be used for explaining the content of the claims.
Claims (13)
1. An icariin solid dispersion is characterized in that the components comprise icariin and docusate sodium in a weight ratio of 1 (0.2-1).
2. The icariin solid dispersion as claimed in claim 1, wherein the components comprise icariin and docusate sodium in a weight ratio of 1 (0.5-1).
3. The icariin solid dispersion according to claim 1, wherein the particle diameter of the icariin solid dispersion is 100 μm or less.
4. A process for producing the icariin solid dispersion according to any one of claims 1 to 3, which comprises the steps of:
mixing the components with an organic solvent, drying and preparing the micronized solid.
5. The method for preparing the icariin solid dispersion according to claim 4, wherein the organic solvent is one or more selected from methanol, ethanol, isopropanol, acetone, dichloromethane, chloroform, acetonitrile and ethyl acetate.
6. The method for preparing the icariin solid dispersion according to claim 4, wherein the drying manner is selected from one or more of spray drying, freeze drying, reduced pressure drying and fluidized bed drying.
7. Use of the icariin solid dispersion according to any one of claims 1 to 3 for the preparation of an icariin-containing oral medicament.
8. The application of the icariin solid dispersion in the preparation of an oral medicament containing icariin according to claim 7, wherein the oral medicament is in the form of capsules, tablets or granules.
9. A compound medicine double-layer tablet is characterized by comprising a quick release layer and a sustained release layer which are sequentially laminated;
wherein the components of the quick release layer comprise an auxiliary agent and the icariin solid dispersion as claimed in any one of claims 1 to 3;
the components of the slow release layer comprise dapoxetine hydrochloride and a slow release material.
10. The compound pharmaceutical bilayer tablet of claim 9, wherein the sustained release material is selected from one or more of polyacrylic resin, carbomer resin 971P or 974P, hypromellose K4M, hypromellose and hypromellose acetate succinate M.
11. The compound pharmaceutical bilayer tablet of claim 9, wherein the adjuvant comprises one or more of a diluent, a disintegrant, and a lubricant.
12. The compound pharmaceutical bilayer tablet of claim 11, wherein the adjuvant satisfies one or more of the following conditions:
(1) The diluent is selected from one or more of microcrystalline cellulose and lactose;
(2) The disintegrant is selected from one or more of crospovidone and croscarmellose sodium;
(3) The lubricant is selected from one or more of glyceryl behenate, stearic acid and magnesium stearate.
13. A method for preparing the compound pharmaceutical bilayer tablet according to any one of claims 9 to 12, comprising the steps of:
mixing the components of the quick release layer to prepare a first material;
mixing the components of the slow release layer to prepare a second material;
and carrying out double-layer tabletting and coating on the first material and the second material.
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