CN102327226B - Solid cefprozi lipid nanoparticle preparation - Google Patents
Solid cefprozi lipid nanoparticle preparation Download PDFInfo
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- CN102327226B CN102327226B CN 201110196242 CN201110196242A CN102327226B CN 102327226 B CN102327226 B CN 102327226B CN 201110196242 CN201110196242 CN 201110196242 CN 201110196242 A CN201110196242 A CN 201110196242A CN 102327226 B CN102327226 B CN 102327226B
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- cefprozil
- solid lipid
- lipid nanoparticle
- stirring
- preparation
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses a solid cefprozi lipid nanoparticle preparation and a preparation method thereof. Cefprozi, palmitic acid and glycerol tristearate are dissolved in an organic solvent to form an oil phase; and with a water solution of polyoxyethylene 40 stearate as water phase, the cefprozi is entrapped in a solid lipid nanoparticle to obtain the solid cefprozi lipid nanoparticle preparation by adopting a mixed emulsifying and high-pressure uniformly-emulsifying combined method. The solid lipid nanoparticle preparation provided by the invention has the advantages of high drug loading amount, uniformity in grain size, long reservation time of a medicament in blood circulation and better slowly-releasing and controlled-release effects; and the quality of a preparation product is improved and toxic or side effects are reduced. In addition, equipment used by a preparation method is simple, easy for operation and suitable for industrial large-scale production.
Description
Technical Field
The invention relates to a lipid nanoparticle solid preparation, in particular to a cefprozil lipid nanoparticle preparation and a solid preparation method thereof, belonging to the technical field of medicines. .
Background
Cefprozil with the chemical name of (6R, 7R) -3-propenyl-7- [ (R) -2-amino-2- (4-hydroxyphenyl) acetamido]-8-oxo-5-thia-1-azabicyclo [4.2.0]Oct-2-ene-2-carboxylic acid monohydrate, molecular formula C18H19N3O5S·H2O, molecular weight 407.44, structural formula:
cefprozil is a non-ester cephalosporin developed by Tokyo research institute of Bristol-Myers company in 1983, and is an antibiotic with oral effectiveness, wider antibacterial spectrum and higher activity than the first generation of cefalexin and cefadroxil. The antibacterial spectrum of cefprozil comprises the main gram-positive bacteria and gram-negative bacteria of common respiratory tract infection and urinary tract infection, and is superior to cefalexin and cefadroxil and similar to cefaclor. But the activity against staphylococcus, hemolytic streptococcus and streptococcus pneumoniae is better than that of cefaclor, and the activity against haemophilus influenzae and branhamella catarrhalis is comparable to that of cefaclor. Clinically, cefprozil is mainly used for treating bacterial pneumonia, pediatric infection, skin soft tissue infection, tonsil pharyngitis and the like.
The cefprozil preparation on the market at present comprises capsules, tablets, dispersible tablets, chewable tablets, granules and dry suspensions, which are all traditional oral administration dosage forms, and because the cefprozil has poor stability and relatively low bioavailability, the absorption and distribution of the medicine in the body are slow, the treatment speed and the effect of the medicine are influenced, and the instability problem of the cefprozil in the preparation process and the placement process cannot be solved by the common preparation technology.
The cefprozil preparations have the problems of poor stability, relatively low bioavailability, slow absorption and distribution of the medicine in vivo, influence on the treatment speed and effect of the medicine and the like.
In a drug carrier delivery system, research on submicron particles such as microemulsion, microspheres, nanoparticles, liposomes, pharmacosomes and the like has become a very active field in research on new drug formulations. The medicine is encapsulated in the submicron particles, so that the distribution of the medicine in the body can be changed, and the distribution amount of the medicine in a target organ can be increased, thereby improving the curative effect and relieving the toxic and side effects.
In a targeted drug delivery system, the research of liposome is relatively extensive, and the liposome has good targeting property and biocompatibility in vivo, but the common liposome has the defects of instability in vitro and in vivo, easy leakage of drugs and the like. The drug-containing submicroemulsion has limited further development due to problems of physical stability, solubility of oil to the drug, and the like.
Chinese patent application CN101032489 discloses a cefprozil dispersible tablet and a preparation method thereof, which is composed of cefprozil, microcrystalline cellulose, cross-linked polyvinylpyrrolidone, aerosil, magnesium stearate and the like; chinese patent application CN101700232 discloses a cefprozil submicron emulsion solid preparation and a new application thereof in the medicine for treating acute plasma cell mastitis, which consists of cefprozil, yolk lecithin, poloxamer and deoxysodium cholate; CN101953790A discloses a cefprozil liposome granule and a preparation method thereof.
CN101953791A discloses a cefprozil liposome, a preparation method thereof and a capsule containing the cefprozil liposome; CN101953788A discloses a cefprozil liposome dispersible tablet and a preparation method thereof; CN101953787A discloses a cefprozil liposome tablet and a preparation method thereof; CN101953789A discloses a cefprozil dry suspension and a preparation method thereof; CN101953780 discloses a cefprozil solid preparation and a preparation method thereof, wherein the calcium preparation contains cefprozil nano-microcapsules and pharmaceutic adjuvants.
The patent applications relate to solid preparations of cefprozil, mainly screen some specific auxiliary materials for preparation, have certain advantages, but the long-term stability of the sample is not ideal, is not favorable for long-term storage; the release speed and the release process of the medicine can not be controlled, thereby bringing hidden troubles to clinical use. Therefore, the cefprozil solid preparation with high stability and high drug safety is clinically needed to be provided.
The solid lipid nanoparticles are solid colloidal particle drug delivery systems with the particle size of 50-1000nm prepared by different methods, compared with liposome and microemulsion, the drug achieves better controlled release and sustained release effects because the drug is encapsulated in a solid skeleton, and the solubility of the insoluble drug can be improved. In addition, the solid lipid nanoparticle also shows advantages in multiple aspects of biotoxicity, degradability, long-term stability and the like, and is a novel drug delivery system carrier with great development prospect.
However, the challenge in preparing solid lipid nanoparticles is to select the appropriate ingredients and methods of preparation. Because the properties of the solid lipid nanoparticles, such as drug loading capacity, drug solubility, stability, dissolution, controlled release, bioavailability, toxic and side effects, are directly and closely related to the composition of the solid lipid nanoparticles, and the composition of the solid lipid nanoparticles is directly and closely related to the properties of the drug to be loaded, it is an urgent subject to be solved to select which components form the cefprozil solid lipid nanoparticles with good quality.
Through a large number of researches and experiments, the inventor discovers that the solid lipid nanoparticles prepared from the specific components and the cefprozil effectively inhibit the problems of easy hydrolysis and poor stability of the cefprozil, simultaneously improve the dissolution rate of the medicine and have good controlled release effect.
Disclosure of Invention
The inventor of the invention has found through keen research that cefprozil, palmitic acid, tristearin and polyoxyethylene 40 stearate in specific weight ratio can be selected to form cefprozil solid lipid nanoparticles with excellent quality, namely cefprozil and a lipid which is difficult to dissolve in water are dissolved in an organic solvent to form an oil phase, an aqueous solution of a hydrophilic surfactant is taken as a water phase, a method of combining stirring emulsification and high-pressure emulsion homogenization is adopted to wrap cefprozil in the solid lipid nanoparticles to prepare cefprozil solid lipid nanoparticles, and then the solid lipid nanoparticles are prepared into a solid preparation by a general preparation method, so that the cefprozil solid lipid nanoparticles are prepared. The invention improves the solubility of the cefprozil, improves the controlled release effect, improves the bioavailability of the medicament, improves the quality of the preparation product, reduces the toxic and side effect, increases the concentration of the medicament in target organs, prolongs the distribution time of the medicament in systemic circulation and obviously improves the curative effect.
The invention aims to provide cefprozil solid lipid nanoparticles, which are prepared from the following raw materials in parts by weight:
with the following conditions:
the weight ratio of the palmitic acid to the tristearin is 2: 1;
the weight ratio of the palmitic acid to the polyoxyethylene 40 stearate is 5: 2 to 4: 3.
The invention also aims to provide a preparation method of the cefprozil solid lipid nanoparticle, which comprises the following steps:
(a) adding palmitic acid and tristearin into an organic solvent, heating in a constant-temperature water bath at 50 ℃, stirring to completely dissolve, then adding cefprozil, and fully stirring to dissolve to form an organic phase;
(b) dissolving polyoxyethylene 40 stearate in water, heating in a constant-temperature water bath at 50 ℃, and stirring to dissolve to form a water phase;
(c) slowly adding the organic phase into the water phase under stirring, keeping the temperature at 50 ℃, and continuously stirring for 1 h;
(d) removing the organic solvent under reduced pressure to obtain translucent primary emulsion;
(e) rapidly adding the colostrum obtained in the step into a proper amount of cold water under the stirring condition of 2000 r/min, and carrying out high-pressure homogeneous emulsification for 5 times to obtain a cefprozil solid lipid nanoparticle suspension;
(f) freeze drying to obtain cefprozil solid lipid nanoparticles.
Still another object of the present invention is to provide a cefprozil solid lipid nanoparticle preparation, which is prepared from cefprozil solid lipid nanoparticles and other pharmaceutical excipients,
the cefprozil solid lipid nanoparticle is prepared from the following raw materials in parts by weight:
with the following conditions:
the weight ratio of the palmitic acid to the tristearin is 2: 1;
the weight ratio of the palmitic acid to the polyoxyethylene 40 stearate is 5: 2-4: 3;
the amount of the other pharmaceutical excipients was 165-267 parts by weight, based on 125 parts by weight of cefprozil.
The invention also aims to provide a preparation method of the cefprozil solid lipid nanoparticle preparation, which comprises the following steps:
(1) preparing cefprozil solid lipid nanoparticles: preparing cefprozil, palmitic acid, tristearin and polyoxyethylene 40 stearate hard together into cefprozil solid lipid nanoparticles;
(2) preparing a cefprozil solid lipid nanoparticle preparation: the cefprozil solid lipid nanoparticle and other pharmaceutic adjuvants are mixed to prepare the cefprozil solid lipid nanoparticle preparation.
Wherein the pharmaceutical excipient is selected from the group consisting of diluents, disintegrants, sweeteners, binders, lubricants and combinations thereof.
The preparation of cefprozil solid lipid nanoparticles in step (1) preferably comprises the following substeps:
(a) adding palmitic acid and tristearin into an organic solvent, heating in a constant-temperature water bath at 50 ℃, stirring to completely dissolve, then adding cefprozil, and fully stirring to dissolve to form an organic phase;
(b) dissolving polyoxyethylene 40 stearate in water, heating in a constant-temperature water bath at 50 ℃, and stirring to dissolve to form a water phase;
(c) slowly adding the organic phase into the water phase under stirring, keeping the temperature at 50 ℃, and continuously stirring for 1 h;
(d) removing the organic solvent under reduced pressure to obtain translucent primary emulsion;
(e) rapidly adding the colostrum obtained in the step into a proper amount of cold water under the stirring condition of 2000 r/min, and carrying out high-pressure homogeneous emulsification for 5 times to obtain a cefprozil solid lipid nanoparticle suspension;
(f) freeze drying to obtain cefprozil solid lipid nanoparticles.
The preparation of the cefprozil solid lipid nanoparticle preparation in the step (2) preferably comprises the following substeps:
(g) mixing cefprozil solid lipid nanoparticles with a diluent and a disintegrating agent, sieving and uniformly mixing, adding an adhesive solution to prepare a soft material, granulating and drying;
(h) mixing the dry granules with the lubricant uniformly, and sieving and granulating;
(i) tabletting, filling into capsules or bagging to obtain the cefprozil solid lipid nanoparticle preparation.
The cefprozil solid lipid nanoparticle preparation prepared by the invention improves the quality of preparation products, improves the solubility of cefprozil, improves the controlled release effect, reduces the toxic and side effects, increases the concentration of the medicine in target organs, prolongs the distribution time of the medicine in systemic circulation, improves the bioavailability of the medicine, and obviously improves the curative effect; and the preparation method is simple and is suitable for industrial mass production.
Drawings
FIG. 1 is a plot of plasma concentration versus time in rats.
Detailed Description
The present invention is further described below in terms of specific embodiments, and features and advantages of the present invention will become apparent as the description proceeds.
The solid lipid nanoparticle is mainly composed of lipid, an emulsifier and a medicament, and the lipid and the emulsifier are selected according to the medicament to be encapsulated. The properties of the solid lipid nanoparticle such as drug loading and drug release are closely related to the composition of the solid lipid nanoparticle.
In order to improve the drug loading of the solid lipid nanometer, proper lipid and emulsifier are selected, so that the drug has high solubility in the lipid, and the lipid is not easy to form regular crystals, so as to avoid the sudden release of the drug caused by the sharp reduction of the drug solubility due to the complete crystallization of the lipid.
In order to achieve the object of the present invention, the inventors have conducted extensive research and implementation to find that cefprozil, palmitic acid, glyceryl tristearate and polyoxyethylene 40 stearate in specific weight ratios can form cefprozil solid lipid nanoparticles with excellent quality, wherein cefprozil as a pharmaceutical active ingredient has high drug loading and good drug release.
As used herein, the terms "drug delivery" and "drug release" are interchangeable and are meant to refer to the property of cefprozil solid lipid nanoparticles to release the active pharmaceutical ingredient cefprozil
On one hand, the invention provides cefprozil solid lipid nanoparticles which are prepared from the following raw materials in parts by weight:
with the following conditions:
the weight ratio of the palmitic acid to the tristearin is 2: 1;
the weight ratio of the palmitic acid to the polyoxyethylene 40 stearate is 5: 2 to 4: 3.
Preferably, the sporylene solid lipid nanoparticle provided by the invention is prepared from the following raw material components in parts by weight:
in the cefprozil solid lipid nanoparticle of the invention, as the lipid, a composition with the weight ratio of palmitic acid to tristearin of 2: 1 is used.
As the lipid for forming the solid lipid, various lipid substances can be used, for example: fatty acid glycerides such as tripalmitin, glyceryl monostearate, glyceryl tristearate, etc.; fatty acids such as stearic acid, palmitic acid, etc.; steroids such as cholesterol, etc.; waxes such as microcrystalline paraffin, cetyl palmitate, and the like.
The inventor finds that, for cefprozil to be entrapped, the combined lipid with the weight ratio of palmitic acid to glyceryl tristearate of 2: 1 is particularly suitable for being used as basic lipid to form a skeleton of solid lipid nanoparticles, and the solid lipid nanoparticles obtained by the method have high drug loading, excellent drug release and high stability. When the composition of palmitic acid and tristearin is used in other weight ratios or other single or combined lipids are used, it is difficult to form solid lipid nanoparticles with excellent quality, and the properties such as drug loading rate, drug release property, stability and the like are poor.
In the cefprozil solid lipid nanoparticle, relative to 125 parts by weight of cefprozil, the dosage of palmitic acid is 50-150 parts by weight, the dosage of tristearin is 25-75 parts by weight, and the weight ratio of the palmitic acid to the tristearin is 2: 1. If the dosage of the palmitic acid is less than 50 parts by weight and the dosage of the tristearin is less than 25 parts by weight, a large amount of free cefprozil is not entrapped due to the insufficient amount of the solid nanoparticle framework; on the contrary, if the amount of palmitic acid is more than 150 parts by weight and the amount of glyceryl tristearate is more than 75 parts by weight, the drug loading of the solid nanoparticles is reduced and the drug release property is deteriorated.
In the cefprozil solid lipid nanoparticle, polyoxyethylene 40 stearate is used as a hydrophilic surfactant and an emulsifier for improving the compatibility between lipid of the solid nanoparticle and a medicament and improving the crystallization performance of a solid nanoparticle framework, so that the medicament release performance of the nanoparticle is improved, and the stability of a nanoparticle framework film can be improved.
When the polyoxyethylene 40 stearate is used in palmitic acid and tristearin lipid, the solubility of cefprozil in the lipid can be improved, so that the drug-loading rate is improved, the stability of the lipid at low temperature and high temperature can be improved, and the stability of the cefprozil solid nanoparticles is further improved, and in addition, the polyoxyethylene 40 stearate is also beneficial to controlling the particle size and distribution of the solid nanoparticles.
The inventor of the invention finds that, for cefprozil to be encapsulated, polyoxyethylene 40 stearate is particularly suitable as an emulsifier for encapsulating cefprozil by a combined lipid of palmitic acid and glyceryl tristearate in a weight ratio of 2: 1 to form solid lipid nanoparticles, and the solid lipid nanoparticles obtained by the method have high drug loading, excellent drug release and high stability. When other surfactants or emulsifiers are used, solid lipid nanoparticles with excellent quality are difficult to form, and the properties of drug loading, drug release, stability and the like are poor.
In the cefprozil solid lipid nanoparticle of the invention, relative to 125 parts by weight of cefprozil, the dosage of polyoxyethylene 40 stearate is 37.5-100 parts by weight, and the weight ratio of palmitic acid to polyoxyethylene 40 stearate is 5: 2-4: 3. If the dosage of the polyoxyethylene 40 stearate is less than 37.5 parts by weight, the lipid is not improved sufficiently due to insufficient dosage of the emulsifier, so that important properties such as drug loading, stability, drug release and the like of the solid lipid nanoparticle are deteriorated; on the contrary, if the amount of polyoxyethylene 40 stearate is more than 100 parts by weight, the stability and drug release of the solid lipid nanoparticle may be affected due to an excessively high emulsifying agent amount.
In the cefprozil solid lipid nanoparticle, the active pharmaceutical ingredient cefprozil to be encapsulated can be formed into the cefprozil solid lipid nanoparticle with excellent drug loading rate, high stability and excellent drug release property through the synergistic regulation and promotion effect of the polyoxyethylene 40 stearate on the combined lipid prepared from palmitic acid and tristearin in a proper proportion, and the cefprozil solid lipid nanoparticle has excellent dissolution property, good controlled release effect and high bioavailability.
On the other hand, the invention provides a preparation method of cefprozil solid lipid nanoparticles, which comprises the following steps:
(a) adding palmitic acid and tristearin into an organic solvent, heating in a constant-temperature water bath at 50 ℃, stirring to completely dissolve, then adding cefprozil, and fully stirring to dissolve to form an organic phase;
(b) dissolving polyoxyethylene 40 stearate in water, heating in a constant-temperature water bath at 50 ℃, and stirring to dissolve to form a water phase;
(c) slowly adding the organic phase into the water phase under stirring, keeping the temperature at 50 ℃, and continuously stirring for 1 h;
(d) removing the organic solvent under reduced pressure to obtain translucent primary emulsion;
(e) rapidly adding the colostrum obtained in the step into a proper amount of cold water under the stirring condition of 2000 r/min, and carrying out high-pressure homogeneous emulsification for 5 times to obtain a cefprozil solid lipid nanoparticle suspension;
(f) freeze drying to obtain cefprozil solid lipid nanoparticles.
In a preferred embodiment of the preparation method of the cefprozil solid lipid nanoparticle of the invention, the organic solvent in step (a) is selected from one or more of chloroform, dichloromethane, ethanol, methanol, tert-butanol, n-butanol, isopropanol, acetone, diethyl ether, benzyl alcohol and n-hexane, and a mixed solution of chloroform and methanol in a volume ratio of 5: 1 is preferred.
In a preferred embodiment of the preparation method of cefprozil solid lipid nanoparticles of the invention, in step (a), the ratio of the weight of palmitic acid to the volume of the organic solvent is 1: 3-10 (g/ml).
In a preferred embodiment of the preparation method of cefprozil solid lipid nanoparticles of the invention, in step (b), the concentration of the polyoxyethylene 40 stearate aqueous solution is 5% -20% (g/ml).
In a preferred embodiment of the preparation method of cefprozil solid lipid nanoparticles of the invention, the pressure for performing the high-pressure homogeneous emulsification in step (e) is 200 MPa.
In the preparation method of the cefprozil solid lipid nanoparticle, cefprozil, palmitic acid and tristearin are dissolved in an organic solvent to form an oil phase, an aqueous solution of polyoxyethylene 40 stearate is used as a water phase, and the cefprozil is encapsulated in the solid lipid nanoparticle by adopting a method of combining stirring emulsification and high-pressure emulsion homogenization to prepare the cefprozil solid lipid nanoparticle preparation.
In the preparation method of the cefprozil solid lipid nanoparticle, the prepared cefprozil solid lipid nanoparticle has uniform particle size distribution, small average particle size, high stability and good drug release performance by selecting proper lipid and emulsifier and selecting proper process conditions such as temperature, rotating speed and the like.
Researches show that the size of the solid lipid nanoparticles is an important factor influencing the distribution, residence time and stability of the solid lipid nanoparticles in vivo, and the smaller the particle size of the solid lipid nanoparticles is, the longer the residence time in vivo is, and the higher the stability is. The cefprozil solid lipid nanoparticles prepared by the method have small particles and uniform particle size distribution, which is one of the factors of low metabolic rate and high bioavailability in vivo.
On the other hand, the invention provides a cefprozil solid lipid nanoparticle preparation which is prepared from cefprozil solid lipid nanoparticles and other pharmaceutic adjuvants,
the cefprozil solid lipid nanoparticle is prepared from the following raw materials in parts by weight:
with the following conditions:
the weight ratio of the palmitic acid to the tristearin is 2: 1;
the weight ratio of the palmitic acid to the polyoxyethylene 40 stearate is 5: 2-4: 3;
the amount of the other pharmaceutical excipients was 165-267 parts by weight, based on 125 parts by weight of cefprozil.
As used herein, the term "other pharmaceutical excipients" or "pharmaceutical excipients" have the same meaning as that of the excipient, and refer to pharmaceutical materials other than cefprozil solid lipid nanoparticles, including diluents, disintegrants, sweeteners, binders, lubricants and combinations thereof, which are used in order to prepare cefprozil solid lipid nanoparticle formulations.
As used herein, the term "amount of other pharmaceutical excipients" refers to the sum of the weights of the above pharmaceutical excipients.
The amount of each pharmaceutical excipient may be selected by those skilled in the art based on the general amount of each excipient in the solid preparation, and is within the ability of those skilled in the art.
In a preferred embodiment of the cefprozil solid lipid nanoparticle formulation of the invention, the diluent can be selected from one or more of starch, powdered sugar, lactose, compressible starch, microcrystalline cellulose and dextrin, and is preferably starch and microcrystalline cellulose. .
In a preferred embodiment of the cefprozil solid lipid nanoparticle formulation of the present invention, the disintegrant may be selected from one or more of sodium carboxymethyl starch, dry starch, low-substituted hydroxypropyl cellulose, croscarmellose sodium, pregelatinized starch, preferably low-substituted hydroxypropyl cellulose.
In a preferred embodiment of the cefprozil solid lipid nanoparticle formulation of the present invention, the sweetener may be selected from one or more of mannitol, sucrose, isomaltulose, lactulose, raffinose, soy oligosaccharide, fructo-oligosaccharide, lactulose-oligosaccharide, sodium saccharin, sodium cyclamate and acesulfame potassium, preferably sucrose and sodium cyclamate.
In a preferred embodiment of the cefprozil solid lipid nanoparticle formulation of the present invention, the binder may be selected from one of hypromellose, povidone K30, sodium carboxymethylcellulose, xanthan gum, acacia gum, methylcellulose, ethylcellulose, preferably povidone K30.
In a preferred embodiment of the cefprozil solid lipid nanoparticle formulation of the present invention, the lubricant is one or more selected from magnesium stearate, zinc stearate, talc, aerosil, polyethylene glycol 4000, stearic acid, preferably talc.
In a preferred embodiment of the cefprozil solid lipid nanoparticle formulation of the present invention, the wetting agent is purified water.
The cefprozil solid lipid nanoparticle preparation provided by the invention is an oral preparation, and comprises tablets, dispersible tablets, chewable tablets, capsules, granules and dry suspensions.
In practice, in consideration of the effective dose of the drug and the convenience of administration, in the preferred embodiment of the cefprozil solid lipid nanoparticle formulation of the invention, the formulation is specified to be 125mg, 250mg, 500mg per unit formulation of cefprozil.
In another aspect, the present invention provides a method for preparing the cefprozil solid lipid nanoparticle preparation, which comprises the following steps:
(1) preparing cefprozil solid lipid nanoparticles: preparing cefprozil, palmitic acid, tristearin and polyoxyethylene 40 stearate hard together into cefprozil solid lipid nanoparticles;
(2) preparing a cefprozil solid lipid nanoparticle preparation: the cefprozil solid lipid nanoparticle and other pharmaceutic adjuvants are mixed to prepare the cefprozil solid lipid nanoparticle preparation.
Wherein the pharmaceutical excipient is selected from the group consisting of diluents, disintegrants, sweeteners, binders, lubricants and combinations thereof.
In a preferred embodiment of the preparation method of cefprozil solid lipid nanoparticles of the present invention, the preparation of cefprozil solid lipid nanoparticles of step (1) comprises the following substeps:
(a) adding palmitic acid and tristearin into an organic solvent, heating in a constant-temperature water bath at 50 ℃, stirring to completely dissolve, then adding cefprozil, and fully stirring to dissolve to form an organic phase;
(b) dissolving polyoxyethylene 40 stearate in water, heating in a constant-temperature water bath at 50 ℃, and stirring to dissolve to form a water phase;
(c) slowly adding the organic phase into the water phase under stirring, keeping the temperature at 50 ℃, and continuously stirring for 1 h;
(d) removing the organic solvent under reduced pressure to obtain translucent primary emulsion;
(e) rapidly adding the colostrum obtained in the step into a proper amount of cold water under the stirring condition of 2000 r/min, and carrying out high-pressure homogeneous emulsification for 5 times to obtain a cefprozil solid lipid nanoparticle suspension;
(f) freeze drying to obtain cefprozil solid lipid nanoparticles.
In a more preferred embodiment of the preparation method of the cefprozil solid lipid nanoparticle formulation of the present invention, the organic solvent in sub-step (a) is selected from one or more of chloroform, dichloromethane, ethanol, methanol, tert-butanol, n-butanol, isopropanol, acetone, diethyl ether, benzyl alcohol, and n-hexane, and preferably a mixed solution of chloroform and methanol in a volume ratio of 5: 1.
In a more preferred embodiment of the method for preparing cefprozil solid lipid nanoparticle formulation of the present invention, in sub-step (a), the ratio of the weight of palmitic acid to the volume of organic solvent is 1: 3-10 (g/ml).
In a more preferred embodiment of the preparation method of cefprozil solid lipid nanoparticle formulation of the present invention, in sub-step (b), the concentration of the polyoxyethylene 40 stearate aqueous solution is 5% -20% (g/ml).
In a more preferred embodiment of the preparation method of cefprozil solid lipid nanoparticle formulation of the present invention, the pressure for performing the high-pressure homogeneous emulsification in sub-step (e) is 200 MPa.
In a preferred embodiment of the preparation method of cefprozil solid lipid nanoparticles of the present invention, the preparation of cefprozil solid lipid nanoparticle preparation in step (2) comprises the following substeps:
(g) mixing cefprozil solid lipid nanoparticles with a diluent and a disintegrating agent, sieving and uniformly mixing, adding an adhesive solution to prepare a soft material, granulating and drying;
(h) mixing the dry granules with the lubricant uniformly, and sieving and granulating;
(i) tabletting, filling into capsules or bagging to obtain the cefprozil solid lipid nanoparticle preparation.
In a more preferred embodiment of the preparation method of the cefprozil solid lipid nanoparticle preparation of the invention, in the substep (g), the cefprozil solid lipid nanoparticle preparation is sieved by a 80-mesh sieve, uniformly mixed, sieved by a 15-mesh sieve and granulated.
In a more preferred embodiment of the preparation method of cefprozil solid lipid nanoparticle formulation of the present invention, in sub-step (h), the granules are sieved through a 20-mesh sieve.
In the method of the present invention, the solid lipid nanoparticle and/or the solid lipid nanoparticle preparation may also be sterilized as needed. The sterilization method has no special requirements, and can use the common solid lipid nanoparticle sterilization method in the pharmaceutical field, such as heating sterilization, filtration sterilization, radiation sterilization or aseptic operation.
The invention firstly prepares solid lipid nanoparticles by the combination of cefprozil, palmitic acid, tristearin and polyoxyethylene 40 stearate which are active ingredients in specific weight, and then mixes the solid lipid nanoparticles with other pharmaceutic adjuvants to prepare the solid preparation. The obtained preparation has high quality, uniform particle size, high stability, high drug loading, good dissolution, good drug release, long retention time of the drug in blood circulation, remarkable curative effect, and reduced toxic and side effects.
The preparation method of the cefprozil solid lipid nanoparticle preparation improves the product quality, has simple process and equipment, is easy to operate, and is suitable for industrial mass production.
In this context, the amounts or use amounts are by weight, unless otherwise specified.
Examples
The invention is further illustrated by the following specific preferred examples. These examples are illustrative only and should not be construed as limiting the invention.
Example 1 preparation of cefprozil solid lipid nanoparticle tablet
The raw materials used were as follows:
the cefprozil solid lipid nanoparticle tablet is prepared by adopting the following production process:
(1) adding 150g of palmitic acid and 75g of glyceryl tristearate into 750ml of a mixed solvent of chloroform and methanol in a volume ratio of 5: 1, heating in a constant-temperature water bath at 50 ℃, stirring to completely dissolve, then adding 125g of cefprozil, and fully stirring to dissolve the cefprozil to form an organic phase;
(2) dissolving 100g polyoxyethylene 40 stearate in 2000ml water, heating in a constant temperature water bath at 50 ℃, and stirring to dissolve to form a water phase;
(3) slowly adding the organic phase into the water phase under stirring, keeping the temperature at 50 ℃, and continuously stirring for 1 h;
(4) removing the organic solvent under reduced pressure to obtain translucent primary emulsion;
(5) rapidly adding the colostrum obtained in the step into a proper amount of cold water under the stirring condition of 2000 r/min, and performing high-pressure homogeneous emulsification for 5 times under the pressure of 200MPa to obtain cefprozil solid lipid nanoparticle suspension;
(6) freeze drying to obtain cefprozil solid lipid nanoparticles;
(7) mixing cefprozil solid lipid nanoparticles with 200g of starch, 50g of microcrystalline cellulose and 10g of low-substituted hydroxypropyl cellulose, sieving, mixing uniformly, adding 50ml of 20% ethanol solution containing 10% povidone to prepare a soft material, granulating and drying;
(8) mixing the dry granules with 2g of superfine silica gel powder uniformly, and sieving and grading;
(9) tabletting to obtain 1000 cefprozil solid lipid nano-particles tablets.
Example 2 preparation of cefprozil solid lipid nanoparticle capsules
The raw materials used were as follows:
the cefprozil solid lipid nanoparticle capsule is prepared by the following production process:
(1) adding 200g of palmitic acid and 100g of glyceryl tristearate into 1000ml of a mixed solvent of chloroform and methanol in a volume ratio of 5: 1, heating in a constant-temperature water bath at 50 ℃, stirring to completely dissolve the palmitic acid and the glyceryl tristearate, adding 250g of cefprozil, and fully stirring to dissolve the cefprozil to form an organic phase;
(2) dissolving 80g polyoxyethylene 40 stearate in 400ml water, heating in a constant temperature water bath at 50 ℃, and stirring to dissolve to form a water phase;
(3) slowly adding the organic phase into the water phase under stirring, keeping the temperature at 50 ℃, and continuously stirring for 1 h;
(4) removing the organic solvent under reduced pressure to obtain translucent primary emulsion;
(5) rapidly adding the colostrum obtained in the step into a proper amount of cold water under the stirring condition of 2000 r/min, and performing high-pressure homogeneous emulsification for 5 times under the pressure of 200MPa to obtain cefprozil solid lipid nanoparticle suspension;
(6) freeze drying to obtain cefprozil solid lipid nanoparticles;
(7) mixing cefprozil solid lipid nanoparticles with 250g of starch, 150g of microcrystalline cellulose and 15g of low-substituted hydroxypropyl cellulose, sieving, mixing uniformly, adding 100ml of 20% ethanol solution containing 10% povidone to prepare a soft material, granulating and drying;
(8) mixing the dry granules with 5g of superfine silica gel powder uniformly, and sieving and grading;
(9) filling the capsule to prepare 1000-particle cefprozil solid lipid nanoparticle capsules.
Example 3 preparation of cefprozil solid lipid nanoparticle granules
The raw materials used were as follows:
the cefprozil solid lipid nanoparticle is prepared by adopting the following production process:
(1) adding 200g of palmitic acid and 100g of glyceryl tristearate into 2000ml of a mixed solvent of chloroform and methanol in a volume ratio of 5: 1, heating in a constant-temperature water bath at 50 ℃, stirring to completely dissolve the palmitic acid and the glyceryl tristearate, adding 500g of cefprozil, and fully stirring to dissolve the cefprozil to form an organic phase;
(2) dissolving 150g of polyoxyethylene 40 stearate in 1000ml of water, heating in a constant-temperature water bath at 50 ℃, and stirring to dissolve the polyoxyethylene 40 stearate to form a water phase;
(3) slowly adding the organic phase into the water phase under stirring, keeping the temperature at 50 ℃, and continuously stirring for 1 h;
(4) removing the organic solvent under reduced pressure to obtain translucent primary emulsion;
(5) rapidly adding the colostrum obtained in the step into a proper amount of cold water under the stirring condition of 2000 r/min, and performing high-pressure homogeneous emulsification for 5 times under the pressure of 200MPa to obtain cefprozil solid lipid nanoparticle suspension;
(6) freeze drying to obtain cefprozil solid lipid nanoparticles;
(7) mixing cefprozil solid lipid nanoparticles with 200g of starch, 350g of sucrose, 50g of sodium cyclamate and 30g of low-substituted hydroxypropylcellulose, sieving, mixing uniformly, adding 200ml of 20% ethanol solution containing 10% povidone to prepare soft materials, granulating and drying;
(8) mixing the dry granules with 10g of superfine silica gel powder uniformly, and sieving and grading;
(9) bagging to obtain 1000 bags of cefprozil solid lipid nanoparticles.
Comparative examples 1 to 3
The raw material ingredients in comparative examples 1 to 3 shown in the following table 1 were prepared into cefprozil solid lipid nanoparticle tablets, capsules and granules, respectively, using the same production processes as in examples 1 to 3, respectively:
TABLE 1 raw Material Components used in comparative examples 1 to 3
Where "/" indicates not used.
Test example 1 detection of particle diameter of cefprozil solid nanoparticle
Under the condition of room temperature, taking 1ml of the nanoparticle suspension obtained in the step (5) of the examples 1-3 and the comparative examples 1-4, diluting the suspension by 100 times with physiological saline, placing the diluted suspension in a sample tube of a Submicron Particle Sizer Model 370 Particle size detector, and measuring the Particle size distribution and the average Particle size; the particle morphology was observed with a projection electron microscope. The results are shown in table 2 below.
Table 2 particle size measurement results
As can be seen from Table 2, the average particle size of the cefprozil solid nanoparticles obtained in examples 1-3 of the present invention is much smaller than that of the solid lipid nanoparticles obtained in comparative examples 1-3, and the cefprozil solid nanoparticles have uniform particle size and better appearance.
Comparing examples 1-2 with comparative examples 1-2, it can be seen that the solid lipid nanoparticles of the present invention have a smaller average particle size, a more uniform particle size distribution, and a better appearance. This indicates that the particle size of cefprozil solid nanoparticles is directly related to the type of ingredients used to form the nanoparticles. When the components except the components used in the invention are used, the properties of the cefprozil solid nanoparticles, such as average particle size, particle size distribution, appearance and the like, are obviously inferior to those of the cefprozil solid nanoparticles.
As can be seen from comparison of examples 1 to 3 with comparative examples 1 to 3, in which the weight ratio is out of the range of the present invention, the solid nanoparticles of the present invention have a smaller average particle size, a more uniform particle size distribution, and a better appearance. This shows that the particle size of the cefprozil solid nanoparticles is not only related to the types of components used for forming the nanoparticles, but also directly related to the dosage of each component. When the dosage of the components is out of the dosage range defined by the invention, the properties of the cefprozil solid nanoparticles, such as average particle size, particle size distribution, appearance and the like, are obviously inferior to those of the cefprozil solid nanoparticles.
The cefprozil solid nanoparticles disclosed by the invention are small in average particle size and uniform in particle size distribution, and are important factors for further promoting the high drug loading capacity, high stability, good controlled release, long retention time in vivo, excellent bioavailability and other properties.
Test example 2 measurement of drug-loading amount
Precisely absorbing 3ml of cefprozil nanoparticle suspension obtained in the step (5) of the examples 1-3 and the comparative examples 1-3, adding the cefprozil nanoparticle suspension to the top of a Sephadex G-50 gel column, eluting with a physiological saline solution at the flow rate of 1ml/min, collecting the eluent of the free drug part, adding methanol to fix the volume, and shaking up; in addition, 3ml of cefprozil solid lipid nanoparticle suspension is sucked, acetonitrile is added for demulsification, and the volume is determined by methanol. And (4) measuring the content of cefprozil by an HPLC method, and calculating the drug loading rate. The results are shown in table 3 below.
TABLE 3 drug Loading test results
As can be seen from Table 3, the drug loading of cefprozil solid lipid nanoparticles obtained in examples 1-3 of the present invention is significantly higher than that of comparative examples 1-3.
The solid lipid nanoparticles obtained in examples 1 to 2 of the present invention had higher drug loading than those of comparative examples 1 to 2 using ingredients other than those defined in the present invention. This indicates that the drug loading of cefprozil solid nanoparticles is directly related to the type of the components used to form the nanoparticles.
The solid lipid nanoparticles obtained in examples 1 to 3 of the present invention had higher drug loading than those of comparative examples 1 to 3 using component ratios other than the component ratios defined in the present invention. This shows that the drug loading of cefprozil solid nanoparticles is directly related to the amount of the components used to form the nanoparticles.
In conclusion, the drug loading of the examples of the invention is significantly different from that of the comparative examples, and the products of the invention meet the production requirements, while the products prepared by the comparative examples do not.
Test example 3 stability and dissolution measurement
The samples prepared in examples 1-3 above were subjected to accelerated test investigation with marketed cefprozil tablets (Beijing Saik pharmaceutical Co., Ltd., lot H20103126) at a high temperature of 40 ℃ and a relative humidity of 75% + -5% for 6 months, and the results are shown in Table 4.
TABLE 4 stability and dissolution test results
As can be seen from Table 4, the cefprozil tablets on the market have low dissolution rate, the content is obviously reduced when the speed is increased for 6 months, and related substances are increased; the samples prepared in the embodiments 1 to 3 of the invention have high dissolution rate, and the content and related substances have no significant change after the acceleration for 6 months. The superiority of the invention in improving stability and dissolution is fully demonstrated.
Test example 4 measurement of blood concentration in rat
35 rats were randomly divided into 7 groups, and each group was filled with tablets, capsules or granules having a content of cefprozil of 125mg, each tablet having a gastric lavage amount of cefprozil in each of examples 1 to 3, comparative example and 1 to 3 (Shantou gold Shi pharmaceutical Co., Ltd., lot number: H20103104). Blood is collected at 0.5h, 1h, 1.5h, 2h, 3h, 6h, 8h, 12h and 24h after administration, and blood concentration is measured by HP LC-MS method after blood sample treatment. The relation curves of the average blood concentration and the time of the cefprozil solid lipid nanoparticle preparation of the invention, the cefprozil solid lipid nanoparticle preparation of the comparative example and the cefprozil tablet sold in the market are made, as shown in the attached figure 1,
wherein,
it means that the formulations are presented to the market,there is shown in the example 1 that,
there is shown in the example 2 that,there is shown in the example 3 that,
a comparative example 1 is shown in which,a comparative example 2 is shown in which,
comparative example 3 is shown.
As can be seen from the curve of blood concentration in blood of rats versus time, compared with the drugs on the market and the drugs in the comparative examples, the cefprozil solid lipid nanoparticle preparation of the invention has the following characteristics: the elimination speed in vivo is slowed down, the bioavailability is increased, the distribution time in systemic circulation is longer, and the controlled release and sustained release effects are achieved.
Claims (11)
1. The cefprozil solid lipid nanoparticle is prepared from the following raw material components in parts by weight:
with the following conditions:
the weight ratio of palmitic acid to tristearin is 2: 1;
the weight ratio of palmitic acid to polyoxyethylene 40 stearate is 5: 2-4:3,
the cefprozil solid lipid nanoparticle is prepared by the method comprising the following steps:
(a) adding palmitic acid and tristearin into an organic solvent, heating in a constant-temperature water bath at 50 ℃, stirring to completely dissolve, then adding cefprozil, and fully stirring to dissolve to form an organic phase;
(b) dissolving polyoxyethylene 40 stearate in water, heating in a constant-temperature water bath at 50 ℃, and stirring to dissolve to form a water phase;
(c) slowly adding the organic phase into the water phase under stirring, keeping the temperature at 50 ℃, and continuously stirring for 1 h;
(d) removing the organic solvent under reduced pressure to obtain translucent primary emulsion;
(e) rapidly adding the colostrum obtained in the step into a proper amount of cold water under the stirring condition of 2000 r/min, and carrying out high-pressure homogeneous emulsification for 5 times to obtain a cefprozil solid lipid nanoparticle suspension;
(f) freeze drying to obtain cefprozil solid lipid nanoparticles.
2. The cefprozil solid lipid nanoparticle according to claim 1, which is prepared from the following raw materials in parts by weight:
3. a preparation method of cefprozil solid lipid nanoparticles, which are the cefprozil solid lipid nanoparticles according to claim 1 or 2, comprises the following steps:
(a) adding palmitic acid and tristearin into an organic solvent, heating in a constant-temperature water bath at 50 ℃, stirring to completely dissolve, then adding cefprozil, and fully stirring to dissolve to form an organic phase;
(b) dissolving polyoxyethylene 40 stearate in water, heating in a constant-temperature water bath at 50 ℃, and stirring to dissolve to form a water phase;
(c) slowly adding the organic phase into the water phase under stirring, keeping the temperature at 50 ℃, and continuously stirring for 1 h;
(d) removing the organic solvent under reduced pressure to obtain translucent primary emulsion;
(e) rapidly adding the colostrum obtained in the step into a proper amount of cold water under the stirring condition of 2000 r/min, and carrying out high-pressure homogeneous emulsification for 5 times to obtain a cefprozil solid lipid nanoparticle suspension;
(f) freeze drying to obtain cefprozil solid lipid nanoparticles.
4. The method according to claim 3, wherein the organic solvent in step (a) is selected from one or more of chloroform, dichloromethane, ethanol, methanol, tert-butanol, n-butanol, isopropanol, acetone, diethyl ether, benzyl alcohol and n-hexane;
in step (a), the ratio of the weight of palmitic acid to the volume of organic solvent is 1: 3-10 (g/ml);
in the step (b), the concentration of the polyoxyethylene 40 stearate aqueous solution is 5-20% (g/ml);
in step (e), the pressure at which the high-pressure homogeneous emulsification is carried out is 200 MPa.
5. The method according to claim 3, wherein the organic solvent in the step (a) is a mixture of 5: 1, chloroform and methanol.
6. A cefprozil solid lipid nanoparticle preparation is prepared from cefprozil solid lipid nanoparticles and other pharmaceutic adjuvants,
the cefprozil solid lipid nanoparticle is prepared from the following raw materials in parts by weight:
with the following conditions:
the weight ratio of palmitic acid to tristearin is 2: 1;
the weight ratio of palmitic acid to polyoxyethylene 40 stearate is 5: 2-4: 3;
the amount of the other pharmaceutical excipients is 165-267 parts by weight based on 125 parts by weight of cefprozil, and the excipients to be used are selected from diluents, disintegrants, sweeteners, binders, lubricants and combinations thereof,
the cefprozil solid lipid nanoparticle is prepared by the method comprising the following steps:
(a) adding palmitic acid and tristearin into an organic solvent, heating in a constant-temperature water bath at 50 ℃, stirring to completely dissolve, then adding cefprozil, and fully stirring to dissolve to form an organic phase;
(b) dissolving polyoxyethylene 40 stearate in water, heating in a constant-temperature water bath at 50 ℃, and stirring to dissolve to form a water phase;
(c) slowly adding the organic phase into the water phase under stirring, keeping the temperature at 50 ℃, and continuously stirring for 1 h;
(d) removing the organic solvent under reduced pressure to obtain translucent primary emulsion;
(e) rapidly adding the colostrum obtained in the step into a proper amount of cold water under the stirring condition of 2000 r/min, and carrying out high-pressure homogeneous emulsification for 5 times to obtain a cefprozil solid lipid nanoparticle suspension;
(f) freeze drying to obtain cefprozil solid lipid nanoparticles.
7. The cefprozil solid lipid nanoparticle preparation according to claim 6, wherein the cefprozil solid lipid nanoparticle is prepared from the following raw materials in parts by weight:
8. the cefprozil solid lipid nanoparticle formulation according to claim 6, which is a tablet, a capsule, a granule, or a dry suspension.
9. The cefprozil solid lipid nanoparticle formulation according to claim 8, which is a dispersible tablet or a chewable tablet.
10. A preparation method of a cefprozil solid lipid nanoparticle preparation, which is the cefprozil solid lipid nanoparticle preparation according to claim 6 or 7, and comprises the following steps:
(1) preparing cefprozil solid lipid nanoparticles: preparing cefprozil, palmitic acid, tristearin and polyoxyethylene 40 stearate hard together into cefprozil solid lipid nanoparticles;
(2) preparing a cefprozil solid lipid nanoparticle preparation: mixing the cefprozil solid lipid nanoparticles with other pharmaceutic adjuvants to prepare the cefprozil solid lipid nanoparticle preparation, wherein the pharmaceutic adjuvants are selected from diluents, disintegrants, sweeteners, adhesives, lubricants and combinations thereof, and the preparation of the cefprozil solid lipid nanoparticles in the step (1) comprises the following substeps:
(a) adding palmitic acid and tristearin into an organic solvent, heating in a constant-temperature water bath at 50 ℃, stirring to completely dissolve, then adding cefprozil, and fully stirring to dissolve to form an organic phase;
(b) dissolving polyoxyethylene 40 stearate in water, heating in a constant-temperature water bath at 50 ℃, and stirring to dissolve to form a water phase;
(c) slowly adding the organic phase into the water phase under stirring, keeping the temperature at 50 ℃, and continuously stirring for 1 h;
(d) removing the organic solvent under reduced pressure to obtain translucent primary emulsion;
(e) rapidly adding the colostrum obtained in the step into a proper amount of cold water under the stirring condition of 2000 r/min, and carrying out high-pressure homogeneous emulsification for 5 times to obtain a cefprozil solid lipid nanoparticle suspension;
(f) freeze drying to obtain cefprozil solid lipid nanoparticles;
in sub-step (a), the ratio of the weight of palmitic acid to the volume of organic solvent is 1: 3-10 (g/ml);
in sub-step (b), the concentration of the aqueous polyoxyethylene 40 stearate solution is 5% to 20% (g/ml);
in sub-step (e), the pressure at which the high-pressure homogeneous emulsification is carried out is 200 MPa.
11. The method of claim 10, wherein the preparation of the cefprozil solid lipid nanoparticle preparation in step (2) comprises the following substeps:
(g) mixing cefprozil solid lipid nanoparticles with a diluent and a disintegrating agent, sieving and uniformly mixing, adding an adhesive solution to prepare a soft material, granulating and drying;
(h) mixing the dry granules with the lubricant uniformly, and sieving and granulating;
(i) tabletting, filling into capsules or bagging to obtain cefprozil solid lipid nanoparticle preparation;
in the substep (g), sieving with a 80-mesh sieve, mixing well, sieving with a 15-mesh sieve, and granulating;
in substep (h), the granules are sieved through a 20-mesh sieve.
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