CN102366407B - Clindamycin palmitate hydrochloride liposome solid preparation - Google Patents
Clindamycin palmitate hydrochloride liposome solid preparation Download PDFInfo
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Abstract
The invention discloses a clindamycin palmitate hydrochloride liposome solid preparation and a preparation method thereof. The clindamycin palmitate hydrochloride liposome solid preparation comprises 15 parts of clindamycin palmitate hydrochloride, 20 to 150 parts of dicetyl phosphate, 15 to 100 parts of soybean phospholipid, 10 to 50 parts of cholesterol, 15 to 120 parts of tween 40, 20 to 160 parts of polyethylene glycol 600, and 90 to 160 parts of other pharmaceutic adjuvants. The clindamycin palmitate hydrochloride liposome solid preparation can be processed into tablets, particles and capsules. The clindamycin palmitate hydrochloride liposome solid preparation has the advantages of high entrapment rate, uniform particle sizes, long retention time of drugs in blood circulation, improvement of preparation product quality and bioavailability, and reduction of toxic and side effects. The preparation method of the clindamycin palmitate hydrochloride liposome solid preparation has the advantages of simple equipment, easiness of operation and good applicability for industrialized production.
Description
Technical field
The present invention relates to a kind of clindamycin hydrochloride palmitate lipidosome solid preparation and method for making thereof, belong to medical technical field.
Background technology
Clindamycin hydrochloride palmitate (CPH) is clinical antibiotic commonly used, be suitable for each section's medication, its chemistry is called 6-(1-methyl-anti--4 propyl group-L-2-pyrrolidine formamido)-1-sulfo--7 (S)-chloro-6,7, the hot pyranoside of 8-three deoxidations-L-Su Shi-α-D-gala-2-cetylate hydrochlorate, structural formula:
It is to be obtained through chemical modification by clindamycin, because the clindamycin taste is extremely bitter, making behind the cetylate then, bitterness significantly reduces.CPH is a prodrug, the free clindamycin of very fast hydrolysis and working in vivo behind the oral administration, it has higher antibacterial action, be lincomycin 2-8 doubly, many gram positive aerobic bacterias, anaerobic bacillus(cillus anaerobicus), chlamydia, mycoplasma are all had activity.Be used for clinically responsive microbial septicemia, bacterial endocarditis, respiratory tract, soft tissue, osteoarthrosis, ear, urogenital infections, especially penicillin resistant and erythromycin and the antibacterial of this susceptibility sense is infected, and to the patient of penicillin anaphylaxis; In addition, particularly suitable to various anaerobic infections, especially the microbial vaginitis of anaerobism, salpingitis, pelvioperitonitis, endometritis and pelvic cavity combined postoperative infect, and are widely used in the microbial ulcer of anaerobism, and various types of osteomyelitis are more had positive effect.
Clindamycin hydrochloride palmitate is compared with Clindamycin Hydrochloride, and indication is basic identical, but Clindamycin Hydrochloride bitter in the mouth poor stability, and clindamycin hydrochloride palmitate is than the easier absorption of Clindamycin Hydrochloride, gastrointestinal side effect still less, toxicity is lower, patient's better tolerance.So this product is the antibiotic better kind of lincomycin series, also is the better kind of Pediatrics Department medication.At present, domestic only have a clindamycin hydrochloride palmitate granule, and clindamycin palmitate hydrochloride dispersion tablet and clindamycin hydrochloride palmitate dry suspension appear on the market, and dosage form is single, and patient's selection face is less.
CN101152161A discloses a kind of hydrochloric clindamycinum palmitate capsule and manufacturing process thereof, be comprised of drug particles and capsule two large divisions, drug particles is comprised of 46% effective active composition, 20-40% diluent, the disintegrating agent of 1-10%, the solubilizing agent of 1-10%, the coating materials of 2-10%; CN100546572C discloses a kind of hydrochloride clindamycin palmitate soft capsule and manufacturing process thereof, formed by medicinal liquid and capsule two large divisions, medicinal liquid contains clindamycin hydrochloride palmitate, acceptable solvent, substrate, stabilizing agent, contains bright amine or arabic gum, glycerol, water, antiseptic and plasticizer in the softgel shell; CN1559431A discloses a kind of clindamycin palmitate hydrochloride dispersion tablet and preparation method thereof, and preparation method adopts granulating process, adds simultaneously adjuvant and mixes compacting in flakes; Yet the clindamycin hydrochloride palmitate preparation of traditional method method preparation type steady in a long-term is undesirable, and bioavailability is low.
Liposome refers to drug encapsulation made spherical targeted drug carrier formulation of superminiature in the middle of the thin film that the lipoids bimolecular forms is belonged to a kind of novel form of targeting drug delivery system.Liposome has plurality of advantages as pharmaceutical carrier: can seal fat-soluble medicine such as liposome, can seal water soluble drug again; Alleviate allergy and immunoreation; Delay to discharge, reduce elimination speed in the body; Can effectively protect and be wrapped medicine, improve bioavailability; Change medicine distribution in vivo, and can the targeting release, the toxic and side effects of medicine can be reduced; Be fit to multipath administration etc.
Liposome Main Function mechanism is drug powder or solution are wrapped in the aqueous phase that the liposome bilayer lipid membrane seals or embed in the liposome bilayer lipid membrane, this microgranule has the class cellularity, activated the autoimmune function of body after entering in the human body by reticuloendothelial system phagocytic, and the interior distribution of the body that changes encapsulated medicine, drug main will be put aside in the histoorgans such as liver, spleen, lung and bone marrow, thereby improve the therapeutic index of medicine, reduce the toxicity of therapeutic dose and the reduction medicine of medicine.
If clindamycin hydrochloride palmitate can be made liposome, then be expected to overcome the series of problems that existing clindamycin hydrochloride palmitate preparation exists, improve dissolubility and the stability of medicine, prolong drug retention time in vivo, improve bioavailability, reduce toxic and side effects, improve treatment speed and therapeutic effect.
But, the challenge of preparation liposome is to select suitable liposome constituent and method for making.Because the character of liposome is directly closely related with the composition of liposome such as stability, envelop rate, onset time, in vivo circulation time, bioavailability and toxic and side effects etc., and the composition of liposome is directly closely related with the pharmaceutical properties that will seal, therefore, selecting which type of composition to form the clindamycin hydrochloride palmitate liposome with better quality is the problem that needs to be resolved hurrily.
CN101530393A discloses a kind of clindamycin phosphate lipidosome freeze-dried preparation, it is characterized in that mainly being prepared from through lyophilizing by clindamycin phosphate, two myristic acid lecithin, cholesterol, antioxidant and frozen-dried supporting agent.
CN101095659A discloses a kind of clindamycin liposome composite medicine and preparation method thereof that relates to, it is characterized in that described liposome composite medicine is any one or a few the liposome of arbitrary proportion mixture that is enclosed with in clindamycin and fleroxacin, left oxygen fleroxacin, the ciprofloxacin.Wherein membrane material is soybean lecithin and DPPC (3: 1) mixture 0.05mol and cholesterol and cupreol (1: 1) mixture 0.05mol.
What is cut too, and " contemporary Chinese medical journal ", 2008,18 (1) disclosed a kind of clindamycin phosphate lipidosome, phospholipid: cholesterol is 5: 1, phospholipid: clindamycin is 5: 3, phospholipid: sucrose is 2: 1, particle diameter is 210 ± 34nm.
The applicant finds by a large amount of experiments, use the prescription of above-mentioned document, can not prepare and give birth to good clindamycin hydrochloride palmitate liposome of fine quality, the applicant is unexpected to be found, effectively overcome the problem of principal agent poor stability by the made clindamycin hydrochloride palmitate lipidosome solid preparation of the specific excipient of the present invention, improve simultaneously the dissolution of medicine, delayed to discharge, increased medicine retention time in vivo.
Summary of the invention
The object of the present invention is to provide a kind of clindamycin hydrochloride palmitate lipidosome solid preparation, clindamycin hydrochloride palmitate and two Cetyl Phosphates, fabaceous lecithin, cholesterol, polysorbate40 and Macrogol 600 are prepared into clindamycin hydrochloride palmitate liposome powder together, make solid preparation with other pharmaceutically acceptable auxiliaries again, dissolution and the bioavailability of clindamycin hydrochloride palmitate have greatly been improved, improved the quality of formulation products, reduced toxic and side effects, the time that has prolonged medicine distribution in the body circulation is longer, and curative effect obviously improves.
Clindamycin hydrochloride palmitate lipidosome solid preparation provided by the invention, it is characterized in that comprising clindamycin hydrochloride palmitate, two Cetyl Phosphates, fabaceous lecithin, cholesterol, polysorbate40, Macrogol 600 and other pharmaceutically acceptable auxiliaries, wherein the parts by weight ratio of clindamycin hydrochloride palmitate, two Cetyl Phosphates, fabaceous lecithin, cholesterol, polysorbate40 and Macrogol 600 is:
Clindamycin hydrochloride palmitate lipidosome solid preparation provided by the invention, preferably, wherein the parts by weight ratio of clindamycin hydrochloride palmitate, two Cetyl Phosphates, fabaceous lecithin, cholesterol, polysorbate40 and Macrogol 600 is:
In a preferred embodiment of the invention, described clindamycin hydrochloride palmitate lipidosome solid preparation comprises 15 parts of clindamycin hydrochloride palmitates, 40 parts of two Cetyl Phosphates, 30 parts of fabaceous lecithins, 20 parts, 30 parts polysorbate40s of cholesterol and 40 parts of Macrogol 600s.
In another preferred embodiment of the present invention, described clindamycin hydrochloride palmitate lipidosome solid preparation comprises 15 parts of clindamycin hydrochloride palmitates, 80 parts of two Cetyl Phosphates, 50 parts of fabaceous lecithins, 40 parts, 70 parts polysorbate40s of cholesterol and 80 parts of Macrogol 600s.
Go back in the preferred embodiment of the present invention, described clindamycin hydrochloride palmitate lipidosome solid preparation comprises 15 parts of clindamycin hydrochloride palmitates, 60 parts of two Cetyl Phosphates, 40 parts of fabaceous lecithins, 30 parts, 50 parts polysorbate40s of cholesterol and 60 parts of Macrogol 600s.
The invention provides the clindamycin hydrochloride palmitate lipidosome solid preparation, the content of wherein said other pharmaceutically acceptable auxiliaries in the above-mentioned lipidosome solid preparation of the present invention is counted 90-160 part with parts by weight, these parts by weight are in respect to 15 parts of clindamycin hydrochloride palmitates, and namely 15 parts of clindamycin hydrochloride palmitates are used other pharmaceutically acceptable auxiliaries of 90-160 parts; Wherein said other pharmaceutically acceptable auxiliaries is selected from diluent, disintegrating agent, sweeting agent, binding agent, lubricant and combination thereof, and every kind of independent concrete consumption of adjuvant can be selected according to the general consumption of various adjuvants in solid preparation by those skilled in the art.
Clindamycin hydrochloride palmitate lipidosome solid preparation provided by the invention is tablet or granule, and the specification of wherein said solid preparation is counted 15mg, 37.5mg, 75mg by clindamycin.
Among the present invention, described diluent is selected from one or more in starch, lactose, sorbitol, microcrystalline Cellulose, the dextrin, is preferably lactose, and its consumption can be the 20-65% (w/w) of described solid preparation gross weight.
Among the present invention, described disintegrating agent is selected from one or more of low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, carboxymethylstach sodium, cross-linking sodium carboxymethyl cellulose, polyvinylpolypyrrolidone, preferred polyvinylpolypyrrolidone, its consumption can be the 1.5-8% (w/w) of described solid preparation gross weight.
Among the present invention, described binding agent is selected from one or more in PVP K30, starch slurry, hypromellose, sodium carboxymethyl cellulose, ethyl cellulose, arabic gum, the xanthan gum, be preferably arabic gum, its consumption can be the 1-8% (w/w) of described solid preparation gross weight.
Among the present invention, described lubricant is selected from one or more in magnesium stearate, zinc stearate, Pulvis Talci, micropowder silica gel, Macrogol 4000, the stearic acid, is preferably Macrogol 4000.Its consumption can be the 0.5-5% (w/w) of described solid preparation gross weight.
Among the present invention, described sweeting agent is selected from sucrose, Aspartane, saccharin sodium, sucralose, stevioside, the steviosin and their combination, is preferably stevioside.Its consumption can be the 0.1-5% (w/w) of described solid preparation gross weight.
The present invention also provides a kind of preparation method of clindamycin hydrochloride palmitate lipidosome solid preparation, specifically comprises the steps:
(1) precision takes by weighing clindamycin hydrochloride palmitate, two Cetyl Phosphates, fabaceous lecithin, cholesterol, polysorbate40 and Macrogol 600, places pear shape bottle, adds organic solvent, and mix homogeneously places Rotary Evaporators 20-120 minute evaporate to dryness film forming;
(2) add buffer solution in pear shape bottle, rotation dissolving 30 minutes made solution transparent in ultrasonic 15-30 minute, 0.45 μ m filtering with microporous membrane;
(3) above-mentioned filtrate is placed-20 ℃ take out after freezing 5-12 hour, room temperature is melted, and the ultrasonic 5-10 of 40kHz minute again, spray drying namely got clindamycin hydrochloride palmitate liposome powder;
(4) clindamycin hydrochloride palmitate liposome powder and diluent, disintegrating agent, sweeting agent are mixed, cross 80 mesh sieve mix homogeneously, add binder solution and prepare soft material, cross 20 mesh sieves and granulate, drying obtains dried granule;
(5) dried granule and mix lubricant is even, cross 20 mesh sieve granulate;
(6) tabletting, pack, filled capsules make the clindamycin hydrochloride palmitate lipidosome solid preparation.
In the preparation method of the present invention, described organic solvent is selected from one or more in chloroform, ethanol, benzyl alcohol, methanol, the tert-butyl alcohol, n-butyl alcohol, isopropyl alcohol, acetone, normal hexane and the dichloromethane, preferred isopropyl alcohol, wherein the consumption of organic solvent does not have special requirement, is advisable can dissolve clindamycin hydrochloride palmitate, two Cetyl Phosphates, fabaceous lecithin, cholesterol, polysorbate40 and Macrogol 600 fully.
In the preparation method of the present invention, described binder solution is the solution of binding agent in certain density ethanol, and described ethanol can be selected from the alcoholic solution of 10-60%, preferred 30% alcoholic solution.
In the preparation method of the present invention, described buffer solution is selected from a kind of in phosphate buffer, citrate buffer, acetate buffer and the carbonate buffer solution, and preferred pH is 5.8 phosphate buffered solution.PH is that 5.8 phosphate buffered solution is that the pH of pharmacopeia specification is 5.8 potassium dihydrogen phosphate-dipotassium hydrogen phosphate buffer solution.
In this article, if not especially explanation, content or consumption are all in weight portion; If not especially explanation, the device that adopts, instrument, raw material, material, consumption, method, time, temperature and other condition etc. all are well-known in the art, or those skilled in the art can obtain in conjunction with prior art according to the application's description.
The inventor finds that through research two Cetyl Phosphates, fabaceous lecithin, cholesterol combination have preferably effect, and wherein two Cetyl Phosphates are similar to " buffering stabilizing agent ", play the effect of regulating membrane structure, and liposome stability is significantly strengthened.
In liposome of the present invention, Macrogol 600 and polysorbate40 are used for regulating membrane stability and the permeability of liposome.
In clindamycin hydrochloride palmitate liposome of the present invention, further improve stability and the envelop rate of liposome membrane with polysorbate40.Polysorbate40 is a kind of non-ionic surface active agent, when being used for the duplicature of phospholipid and cholesterol combination phospholipid formation, can not only further improving the dissolubility of clindamycin hydrochloride palmitate, thereby improve envelop rate; And can improve chemical energy between this duplicature, thus the chemical stability of liposome in waterborne liquid improved, and then improve the stability of clindamycin hydrochloride palmitate liposome.
Bound by theory not, the inventor is surprisingly found out that, the adding Macrogol 600 can change the pharmaceutical properties of clindamycin hydrochloride palmitate liposome, Macrogol 600 has certain viscosity and surface-active action, can reduce the surface tension between liposome and the gastrointestinal tract mucus, promote that medicine enters gastrointestinal mucosa, thereby improve bioavailability and therapeutic effect.After deliberation, the inventor finds that Macrogol 600 is better than other Polyethylene Glycol such as PEG400 or Polyethylene Glycol 800.
Clindamycin hydrochloride palmitate lipidosome solid preparation provided by the invention has greatly improved stability, the envelop rate of medicine, has improved simultaneously dissolution and the bioavailability of medicine, has reduced toxic and side effects, has improved the formulation products quality, more remarkable treatment effect.Bound by theory not, the advantageous property of lipidosome solid preparation of the present invention may be that these five kinds of materials of two Cetyl Phosphates, fabaceous lecithin, cholesterol, polysorbate40 and Macrogol 600 of specific consumption are for the common and/or synergistic result of concrete medicine clindamycin hydrochloride palmitate.And application this area other membrane material phospholipid (for example adopting wherein one or both natural phospholipids and synthetic phospholipid) commonly used, combined material with cholesterol and other surfactant except polysorbate40, the problem such as that the clindamycin hydrochloride palmitate liposome for preparing according to this area routine techniques all can existence and stability is relatively poor, envelop rate is low, especially under 40 ℃ of high temperature, relative humidity 75% ± 5% accelerated test, these shortcomings are more obvious, both be unfavorable for storing, also be unfavorable for clinical practice.
Description of drawings
Fig. 1 is the release in vitro curve of the sample of embodiment 1-3 and the free medicine of clindamycin hydrochloride palmitate, and wherein trunnion axis represents hour to be the time of unit, and vertical axis represents the cumulative release percent of clindamycin hydrochloride palmitate.
Fig. 2 is sample and the blood drug level of commercially available clindamycin hydrochloride palmitate sheet (listing example) and the relation curve of time of embodiment 1-3.
The specific embodiment
Further elaborate the present invention below with reference to embodiment, but it will be appreciated by those skilled in the art that scope of the present invention is not limited to the preparation method of these embodiment and use.And those skilled in the art can be equal to replacement, combination, improvement or modification to the present invention according to description of the invention, and all these will comprise within the scope of the invention.
Example 1 clindamycin hydrochloride palmitate liposome sheet
Prescription (1000)
Preparation technology:
(1) precision takes by weighing 15g clindamycin hydrochloride palmitate, 40g two Cetyl Phosphates, 30g fabaceous lecithin, 20g cholesterol, 30g polysorbate40,40g Macrogol 600, place pear shape bottle, add the 1000ml isopropyl alcohol, mix homogeneously places 20 minutes evaporate to dryness film forming of Rotary Evaporators;
(2) adding 1000ml pH in the pear shape bottle is 5.8 phosphate buffered solution, and rotation dissolving 30 minutes made solution transparent in ultrasonic 15 minutes, 0.45 μ m filtering with microporous membrane;
(3) above-mentioned filtrate is placed-20 ℃ take out after freezing 5 hours, be positioned under the room temperature and melt, ultrasonic 5 minutes again, spray drying namely got clindamycin hydrochloride palmitate liposome powder;
(4) clindamycin hydrochloride palmitate liposome powder and 120g lactose, 20g polyvinylpolypyrrolidone and 2g stevioside are mixed, cross 80 mesh sieve mix homogeneously, add 30% the alcoholic solution 100ml contain 10% arabic gum and prepare soft material, cross 20 mesh sieves and granulate drying;
(5) with dried granule and 5g Macrogol 4000 mix homogeneously, cross 20 mesh sieve granulate;
(6) tabletting makes clindamycin hydrochloride palmitate liposome sheet.
Prescription (1000 bags)
Preparation technology:
(1) takes by weighing 37.5g clindamycin hydrochloride palmitate, 200g two Cetyl Phosphates, 125g fabaceous lecithin, 100g cholesterol, 175g polysorbate40,200g Macrogol 600, place pear shape bottle, add 3000ml ethanol, place 120 minutes evaporate to dryness film forming of Rotary Evaporators;
(2) adding 2000ml pH in the pear shape bottle is 5.8 citrate buffer, and rotation dissolving 30 minutes made solution transparent in ultrasonic 30 minutes, 0.45 μ m filtering with microporous membrane;
(3) above-mentioned filtrate is placed-20 ℃ take out after freezing 5 hours, melt, ultrasonic 10 minutes again, spray drying namely got clindamycin hydrochloride palmitate liposome powder;
(4) clindamycin hydrochloride palmitate liposome powder and 240g lactose, 20g polyvinylpolypyrrolidone and 3g stevioside are mixed, cross 80 mesh sieve mix homogeneously, 30% the alcoholic solution 120ml that adds 10% arabic gum prepares soft material, crosses 20 mesh sieves and granulates drying;
(5) with dried granule and 10g Macrogol 4000 mix homogeneously, cross 20 mesh sieve granulate;
(6) pack makes the clindamycin hydrochloride palmitate liposome particles.
Embodiment 3 clindamycin hydrochloride palmitate liposome methods
Prescription (1000)
Preparation technology:
(1) takes by weighing 37.5g clindamycin hydrochloride palmitate, 150g two Cetyl Phosphates, 100g fabaceous lecithin, 75g cholesterol, 125g polysorbate40,150g Macrogol 600, place pear shape bottle, add the 2000ml dichloromethane, place 120 minutes evaporate to dryness film forming of Rotary Evaporators;
(2) adding 2000ml pH in the pear shape bottle is 5.8 phosphate buffer, and rotation dissolving 30 minutes made solution transparent in ultrasonic 30 minutes, 0.45 μ m filtering with microporous membrane;
(3) above-mentioned filtrate is placed-20 ℃ take out after freezing 5 hours, melt, ultrasonic 10 minutes again, spray drying namely got clindamycin hydrochloride palmitate liposome powder;
(4) clindamycin hydrochloride palmitate liposome powder and 240g lactose, 20g polyvinylpolypyrrolidone and 1g stevioside are mixed, cross 80 mesh sieve mix homogeneously, 30% the alcoholic solution 120ml that adds 10% arabic gum prepares soft material, crosses 20 mesh sieves and granulates drying;
(5) with dried granule and 10g Macrogol 4000 mix homogeneously, cross 20 mesh sieve granulate;
(6) filled capsules makes 1000 clindamycin hydrochloride palmitate liposome methods.
Comparative Examples 1-3
Select respectively other composition outside the selected component of the present invention, lecithin such as preparation liposome commonly used, and the combination of other component outside the content proportioning of component of the present invention, compare the example test, wherein Comparative Examples 1 prepares the clindamycin hydrochloride palmitate liposome according to the method for CN101530393A embodiment 1, and Comparative Examples 2-3 adopts the production technology identical with step (1)～(3) preparation clindamycin hydrochloride palmitate liposome among the embodiment 2-3 to prepare the clindamycin hydrochloride palmitate liposome.
Component and the content of each Comparative Examples are as shown in the table:
The test of table 1 Comparative Examples
Wherein, "/" expression is not used.
Prepare respectively Comparative Examples 1-3 clindamycin hydrochloride palmitate liposome by above prescription component.
The investigation of test example 1 liposome
Prepared an amount of liposome powder sample in the embodiment 1-3 step (3) and among the Comparative Examples 1-3 is carried out quality investigation, mainly carry out liposome morphologic observation, particle size determination and liposome encapsulation and measure.
Wherein liposome form and particle size determination adopt optical microscopy and the computing of statistica5.0 statistical software to observe about 1000 to average.
Entrapment efficiency determination is the mensuration of liposome routine, adopts ultrafiltration to measure the envelop rate of clindamycin hydrochloride palmitate liposome.In brief, utilize ultrafiltration to isolate free drug; Utilize methanol to destroy liposome to extract medicine, then carry out assay with HPLC method and standard control, calculate entrapment efficiency according to the envelop rate formula.
Every statistical result such as following table
The investigation of table 2 liposome
Percolation ratio is by formula Q
Ooze%=(W
Bag-W
Storage)/W
Bag* 100% calculates percolation ratio.The sample percolation ratio of inventive embodiments 1-3 preparation is very low, and less than 3% or almost there is not Seepage, and the sample permeability of Comparative Examples 1-3 preparation increases gradually, and percolation ratio can reach about 23%.
Above result has proved absolutely that the liposome of embodiment of the invention 1-3 preparation is effective than the liposome of Comparative Examples 1-3 preparation, the form rule, and the size homogeneous, envelop rate is higher, and percolation ratio is very low, has proved practical feasibility of the present invention.
Test example 2 stability and dissolution are investigated
With the sample of above embodiment preparation and clindamycin hydrochloride palmitate sheet (the Chongqing Kai Xing pharmaceutical Co. Ltd of listing, lot number: H20100812) under the condition of 40 ℃ of high temperature, relative humidity 75% 6 months, carry out accelerated test and investigate result such as table 3.
Table 3 accelerated test result
By above result as can be known, when accelerating June, listing preparation dissolution reduces, content, and related substance raises; And that sample dissolution of the present invention, content and related substance change is all not obvious, proves absolutely that the product of the present invention preparation that goes on the market has higher stability.
Test example 3 dissolution tests are investigated
Each 1g of sample (amount with clindamycin hydrochloride palmitate is as the criterion) that precision takes by weighing the free medicine of clindamycin hydrochloride palmitate and embodiment 1-3 is dissolved in the 10ml water, accurate each 2ml of suspension that draws places bag filter to tighten, be fixed on the stirring paddle of digestion instrument, release medium is phosphate buffered solution (containing 0.25% the polysorbas20) 100ml of pH6.8, bath temperature is 37 ℃, speed of agitator is 300rpm, respectively at 0.5,1,2,4,6,8,12,18, the 24h 1ml that takes a sample, measure release rate, draw release profiles, the result as shown in Figure 1.
The result shows that the free medicine rate of release of clindamycin hydrochloride palmitate is fast, reaches more than 93% in 4 hours; And the release of gained clindamycin hydrochloride palmitate lipidosome solid preparation is slow among the embodiment of the invention 1-3, just reaches release in about 90%, 24 hour fully, and has reached the effect of slow release in 18 hours.
The stability of the lipidosome solid preparation of embodiment and vitro release are better than Comparative Examples 1-3 and listing preparation as seen from the experiment, therefore method improvement of the present invention stability and the releasing effect of preparation.
Test example 4 blood drug level are investigated
40 rats are divided into 4 groups at random, every group of respectively sample, and commercially available clindamycin hydrochloride palmitate sheet (the Chongqing Kai Xing pharmaceutical Co. Ltd of gavage embodiment 1-3, lot number: H20100812), the gavage amount is tablet, capsule, dry suspension or the granule of 15mg clindamycin hydrochloride palmitate.Respectively at 0.5h, 1h, 1.3h, 1.5h, 2h, 4h, 8h, 12h, 20h and 25h, take a blood sample after the administration, blood sample is measured blood drug level with the HPLC-MS method after treatment.Make the average blood drug level of clindamycin hydrochloride palmitate lipidosome solid preparation of the present invention and commercially available clindamycin hydrochloride palmitate sheet and the relation curve of time, such as Fig. 2.
As shown in Figure 2, clindamycin hydrochloride palmitate lipidosome solid preparation of the present invention discharges slowly, and the bioavailability of embodiment 1-3 sample all is higher than the bioavailability of commercially available (listing example among the figure).
Industrial applicibility
By the result of above-described embodiment and experimental example as can be known, clindamycin hydrochloride palmitate lipidosome solid preparation of the present invention has good outward appearance, granule is little, and particle diameter is even, and envelop rate is high, stability is high, stripping property is good, and percolation ratio is low, and the time of staying in vivo is long, bioavailability is high, has good industrial application value.
Below through the specific embodiment and the embodiment the present invention is had been described in detail; but should understand; these explanations do not consist of any restriction to scope of the present invention; in the case of without departing from the spirit and scope of protection of the present invention; can carry out multiple modification, improvement and replacement to technical solutions and their implementation methods of the present invention, these are all because falling within the scope of protection of the present invention.
Each list of references of mentioning among the application or quoting, which is hereby incorporated by reference.
Claims (7)
1. clindamycin hydrochloride palmitate lipidosome solid preparation, it is characterized in that comprising clindamycin hydrochloride palmitate, two Cetyl Phosphates, fabaceous lecithin, cholesterol, polysorbate40, Macrogol 600 and other pharmaceutically acceptable auxiliaries, wherein the parts by weight ratio of clindamycin hydrochloride palmitate, two Cetyl Phosphates, fabaceous lecithin, cholesterol, polysorbate40 and Macrogol 600 is:
2. clindamycin hydrochloride palmitate lipidosome solid preparation according to claim 1, it is characterized in that described other pharmaceutically acceptable auxiliaries is selected from diluent, disintegrating agent, sweeting agent, binding agent, lubricant and combination thereof, the content of described other pharmaceutically acceptable auxiliaries is counted 90-160 part with parts by weight.
3. each described clindamycin hydrochloride palmitate lipidosome solid preparation according to claim 1-2, it is characterized by described solid preparation is tablet, granule, capsule.
4. clindamycin hydrochloride palmitate lipidosome solid preparation according to claim 3, the specification of wherein said solid preparation is counted 15mg, 37.5mg or 75mg by clindamycin.
5. the preparation method of each described clindamycin hydrochloride palmitate lipidosome solid preparation among the claim 2-4 is characterized in that comprising the steps:
(1) precision takes by weighing clindamycin hydrochloride palmitate, two Cetyl Phosphates, fabaceous lecithin, cholesterol, polysorbate40 and Macrogol 600, places pear shape bottle, adds organic solvent, and mix homogeneously places Rotary Evaporators 20-120 minute evaporate to dryness film forming;
(2) add buffer solution in pear shape bottle, rotation dissolving 30 minutes made solution transparent in ultrasonic 15-30 minute, 0.45 μ m filtering with microporous membrane;
(3) above-mentioned filtrate is placed-20 ℃ take out after freezing 5-12 hour, room temperature is melted, and the ultrasonic 5-10 of 40kHz minute again, spray drying namely got clindamycin hydrochloride palmitate liposome powder;
(4) clindamycin hydrochloride palmitate liposome powder and diluent, disintegrating agent, sweeting agent are mixed, cross 80 mesh sieve mix homogeneously, add binder solution and prepare soft material, cross 20 mesh sieves and granulate, drying obtains dried granule;
(5) dried granule and mix lubricant is even, cross 20 mesh sieve granulate;
(6) tabletting, filled capsules or pack make the clindamycin hydrochloride palmitate lipidosome solid preparation.
6. preparation method according to claim 5 is characterized in that described organic solvent is selected from isopropyl alcohol.
7. preparation method according to claim 5 is characterized in that it is 5.8 phosphate buffered solution that described buffer solution is selected from pH value.
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Citations (3)
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| US5679374A (en) * | 1993-12-30 | 1997-10-21 | L'oreal | Anti-acne composition for the simultaneous treatment of the surface layers and deep layers of the skin, and use thereof |
| CN101095659A (en) * | 2006-06-28 | 2008-01-02 | 蔡海德 | Liposome combined medicine and method for preparing the same |
| CN101530393A (en) * | 2009-04-07 | 2009-09-16 | 王明 | Clindamycin phosphate lipidosome freeze-dried preparation and preparation method thereof |
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| 克林霉素磷酸酯脂质体含量及包封率的测定;周伟华等;《生物医学工程学杂志》;20090625(第03期);566-568 * |
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