CN102366407A - 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, processing behind the cetylate then, bitterness significantly reduces.CPH is a prodrug, and very fast in vivo hydrolysis goes out free clindamycin and works behind the oral administration, and 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 responsive microbial septicemia, bacterial endocarditis, respiratory tract, soft tissue, osteoarthrosis, ear, urogenital infections clinically; Especially penicillin resistant and erythromycin and to the bacterial infection of this susceptibility sense, 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 absorbs than Clindamycin Hydrochloride more easily; Gastrointestinal side effect still less, toxicity is lower, patient's better tolerance.So these article are the antibiotic better kinds of lincomycin series, also are the better kinds 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 made up of drug particles and capsule two large divisions, drug particles is made up 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; Form 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 method for preparing adopts granulating process, adds adjuvant simultaneously 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 is meant drug encapsulation made spherical targeted drug carrier formulation of superminiature in the middle of the thin film that the lipoids bimolecular forms, and belongs to a kind of novel form of targeting drug delivery system.Liposome has plurality of advantages as pharmaceutical carrier: can seal fat-soluble medicine like liposome, can seal water soluble drug again; Alleviate allergy and immunoreation; Delay to discharge, reduce elimination speed in the body; Can protect the medicine that is wrapped effectively, improve bioavailability; Change medicine distribution in vivo, and can the release of targeting property, the toxic and side effects of medicine can be reduced; Be fit to multipath administration etc.
The main mechanism of action of liposome is that drug powder or solution are wrapped in the aqueous phase that the liposome bilayer lipid membrane sealed or embed in the liposome bilayer lipid membrane; This microgranule type of having cellularity; Get into the interior back of human body and activated the autoimmune function of body by reticuloendothelial system phagocytic; And change is distributed in the body of entrapped drug; Drug main to be put aside in histoorgans such as liver, spleen, lung and bone marrow, thereby improve the therapeutic index of medicine, reduce the therapeutic dose and the toxicity that reduces medicine of medicine.
If can clindamycin hydrochloride palmitate be processed liposome; Then be expected to overcome a series of problems that existing clindamycin hydrochloride palmitate preparation exists; Improve the dissolubility and the stability of medicine, prolong drug retention time in vivo improves 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 like stability, envelop rate, onset time, in vivo circulation time, bioavailability and toxic and side effects etc.; And the composition of liposome with the pharmaceutical properties that will seal directly closely related; 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 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 said 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 two palmityl choline (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 through 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 through the made clindamycin hydrochloride palmitate lipidosome solid preparation of the specific excipient of the present invention; Improve the dissolution of medicine simultaneously, 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; Process solid preparation with other pharmaceutically acceptable auxiliaries again; Greatly improve the dissolution and the bioavailability of clindamycin hydrochloride palmitate, 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 present 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 promptly 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 said 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 said solid preparation gross weight.
Among the present invention; Described binding agent is selected from one or more in 30 POVIDONE K 30 BP/USP 30, 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 said 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 said 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 said solid preparation gross weight.
The present invention also provides a kind of method for preparing 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 the pyriform bottle, adds organic solvent, and mix homogeneously places Rotary Evaporators 20-120 minute evaporate to dryness film forming;
(2) in the pyriform bottle, add buffer solution, rotation dissolving 30 minutes made solution transparent in ultrasonic 15-30 minute, 0.45 μ m filtering with microporous membrane;
(3) place-20 ℃ to take out after freezing 5-12 hour above-mentioned filtrating, room temperature is melted, and the ultrasonic 5-10 of 40kHz minute again, spray drying promptly 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 method for preparing 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 demands, is advisable can dissolve clindamycin hydrochloride palmitate, two Cetyl Phosphates, fabaceous lecithin, cholesterol, polysorbate40 and Macrogol 600 fully.
In the method for preparing of the present invention, described binder solution is the solution of binding agent in certain density ethanol, and said ethanol can be selected from the alcoholic solution of 10-60%, preferred 30% alcoholic solution.
In the method for preparing 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 PBS.PH is that 5.8 PBS is that the pH of pharmacopeia specification is potassium dihydrogen phosphate-dipotassium hydrogen phosphate buffer solution of 5.8.
In this article, if not explanation especially, content or consumption are all in weight portion; If not explanation especially; The device that is adopted, 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 combine prior art to obtain according to the application's description.
The inventor is through discovering, two Cetyl Phosphates, fabaceous lecithin, cholesterol combination have effect preferably, 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 to regulate the membrane stability and the permeability of liposome.
In clindamycin hydrochloride palmitate liposome of the present invention, use polysorbate40 further to improve the stability and the envelop rate of liposome membrane.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 the 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, and Macrogol 600 has certain viscosity and surface activity effect, can reduce the surface tension between liposome and the gastrointestinal tract mucus; Promote medicine to get into gastrointestinal mucosa, thereby improve bioavailability and therapeutic effect.After deliberation, the inventor finds that Macrogol 600 is superior to other Polyethylene Glycol such as PEG400 or Polyethylene Glycol 800.
Clindamycin hydrochloride palmitate lipidosome solid preparation provided by the invention has greatly improved stability of drug, envelop rate, has improved the dissolution and the bioavailability of medicine simultaneously, 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 possibly be the common and/or synergistic results of these five kinds of materials of two Cetyl Phosphates, fabaceous lecithin, cholesterol, polysorbate40 and Macrogol 600 of specific consumption for 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; All can there be problems such as less stable, envelop rate be low in the clindamycin hydrochloride palmitate liposome for preparing according to this area routine techniques; Especially under 40 ℃ of high temperature, relative humidity 75% ± 5% accelerated test; These shortcomings are more obvious, both have been unfavorable for storing, and also are unfavorable for clinical practice.
Description of drawings
Fig. 1 is the release in vitro curve of the free medicine of sample and clindamycin hydrochloride palmitate of embodiment 1-3, and wherein trunnion axis is represented hour to be the time of unit, and vertical axis is represented the cumulative release percent of clindamycin hydrochloride palmitate.
Fig. 2 is the sample of embodiment 1-3 and the blood drug level and the time relation curve of commercially available clindamycin hydrochloride palmitate sheet (listing example).
The specific embodiment
Further set forth the present invention in detail with reference to embodiment below, but it will be appreciated by those skilled in the art that scope of the present invention is not limited to the method for preparing 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 the pyriform bottle; Add the 1000ml isopropyl alcohol, mix homogeneously places 20 minutes evaporate to dryness film forming of Rotary Evaporators;
(2) in the pyriform bottle, adding 1000ml pH is 5.8 PBS, and rotation dissolving 30 minutes made solution transparent in ultrasonic 15 minutes, 0.45 μ m filtering with microporous membrane;
(3) place-20 ℃ to take out after freezing 5 hours above-mentioned filtrating, be positioned under the room temperature and melt, ultrasonic again 5 minutes, spray drying promptly 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), cross 20 mesh sieve granulate with dried granule and 5g Macrogol 4000 mix homogeneously;
(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 the pyriform bottle; Add 3000ml ethanol, place 120 minutes evaporate to dryness film forming of Rotary Evaporators;
(2) in the pyriform bottle, adding 2000ml pH 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) place-20 ℃ to take out after freezing 5 hours above-mentioned filtrating, melt, ultrasonic again 10 minutes, spray drying promptly 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), cross 20 mesh sieve granulate with dried granule and 10g Macrogol 4000 mix homogeneously;
(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 the pyriform bottle; Add the 2000ml dichloromethane, place 120 minutes evaporate to dryness film forming of Rotary Evaporators;
(2) in the pyriform bottle, adding 2000ml pH 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) place-20 ℃ to take out after freezing 5 hours above-mentioned filtrating, melt, ultrasonic again 10 minutes, spray drying promptly 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), cross 20 mesh sieve granulate with dried granule and 10g Macrogol 4000 mix homogeneously;
(6) filled capsules makes 1000 clindamycin hydrochloride palmitate liposome methods.
Comparative Examples 1-3
Select other composition outside the selected component of the present invention respectively for use; Lecithin like preparation liposome commonly used; And the combination of other component outside the components contents proportioning 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, Comparative Examples 2-3 adopt with embodiment 2-3 in step (1)～(3) prepare the identical production technology of clindamycin hydrochloride palmitate liposome and prepare the clindamycin hydrochloride palmitate liposome.
The 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 Comparative Examples 1-3 clindamycin hydrochloride palmitate liposome respectively by above prescription component.
The investigation of Test Example 1 liposome
With in the embodiment 1-3 step (3) with Comparative Examples 1-3 in prepared an amount of liposome powder sample carry 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 conventional mensuration of liposome, 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, carry out assay with HPLC method and standard control then, calculate entrapment efficiency according to the envelop rate formula to extract medicine.
Each item 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 the seepage phenomenon, 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 the clindamycin hydrochloride palmitate sheet of listing (Chongqing Kai Xing pharmaceutical Co. Ltd, lot number: H20100812) under the condition of 40 ℃ of high temperature, relative humidity 75% 6 months, carry out the accelerated test investigation, result such as table 3.
Table 3 accelerated test result
Can be known that by above result when quickening June, listing preparation dissolution reduces, content reduces, 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 advantages of higher stability.
The test of Test Example 3 release degree is investigated
Each 1g of sample (amount with clindamycin hydrochloride palmitate is as the criterion) that precision takes by weighing 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, and is fixed on the stirring paddle of digestion instrument, and release medium is PBS (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, measures release rate; Draw release profiles, shown in result such as the accompanying drawing 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.
Stability and the release in vitro degree that can be known the lipidosome solid preparation of embodiment by result of the test are superior to Comparative Examples 1-3 and listing preparation, therefore method improvement of the present invention stability of formulation and releasing effect.
Test Example 4 blood drug level are investigated
40 rats are divided into 4 groups at random; Every group of sample of irritating stomach embodiment 1-3 respectively, and commercially available clindamycin hydrochloride palmitate sheet (Chongqing Kai Xing pharmaceutical Co. Ltd; Lot number: H20100812), irritating the stomach 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 and the time relation curve of clindamycin hydrochloride palmitate lipidosome solid preparation of the present invention and commercially available clindamycin hydrochloride palmitate sheet, like Fig. 2.
Can be known that by Fig. 2 clindamycin hydrochloride palmitate lipidosome solid preparation of the present invention discharges slowly, the bioavailability of embodiment 1-3 sample all is higher than the bioavailability of commercially available (listing example among the figure).
Industrial applicibility
Result by the foregoing description and experimental example can know that clindamycin hydrochloride palmitate lipidosome solid preparation of the present invention has good surface appearance, and granule is little; Particle diameter is even, and envelop rate is high, and 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 the favorable industrial using value.
More than through the specific embodiment and embodiment the present invention is specified; But should understand; These explanations do not constitute any restriction to scope of the present invention; Under the situation that does not depart from spirit of the present invention and protection domain, can carry out multiple modification, improvement and replacement to technical scheme of the present invention and embodiment thereof, these are all because of falling in protection scope of the present invention.
Each list of references of mentioning among the application or quoting is incorporated herein by reference at this in full.
Claims (8)
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. according to the clindamycin hydrochloride palmitate lipidosome solid preparation of claim 1, wherein the parts by weight ratio of clindamycin hydrochloride palmitate, two Cetyl Phosphates, fabaceous lecithin, cholesterol, polysorbate40 and Macrogol 600 is:
3. clindamycin hydrochloride palmitate lipidosome solid preparation according to claim 1 and 2; 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.
4. according to each described clindamycin hydrochloride palmitate lipidosome solid preparation among the claim 1-3, it is characterized by said solid preparation is tablet, granule, capsule.
5. clindamycin hydrochloride palmitate lipidosome solid preparation according to claim 4, the specification of wherein said solid preparation is counted 15mg, 37.5mg or 75mg by clindamycin.
6. the method for preparing of each described clindamycin hydrochloride palmitate lipidosome solid preparation among the claim 1-5 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 the pyriform bottle, adds organic solvent, and mix homogeneously places Rotary Evaporators 20-120 minute evaporate to dryness film forming;
(2) in the pyriform bottle, add buffer solution, rotation dissolving 30 minutes made solution transparent in ultrasonic 15-30 minute, 0.45 μ m filtering with microporous membrane;
(3) place-20 ℃ to take out after freezing 5-12 hour above-mentioned filtrating, room temperature is melted, and the ultrasonic 5-10 of 40kHz minute again, spray drying promptly 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.
7. method for preparing according to claim 6 is characterized in that said 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, is preferably isopropyl alcohol.
8. method for preparing according to claim 6 is characterized in that said buffer solution is selected from a kind of in phosphate buffer, citrate buffer, acetate buffer and the carbonate buffer solution, and preferred pH value is 5.8 PBS.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201110271319 CN102366407B (en) | 2011-09-14 | 2011-09-14 | Clindamycin palmitate hydrochloride liposome solid preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201110271319 CN102366407B (en) | 2011-09-14 | 2011-09-14 | Clindamycin palmitate hydrochloride liposome solid preparation |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Non-Patent Citations (3)
| Title |
|---|
| 何剪太等: "克林霉素磷酸酯脂质体的制备", 《中国现代医学杂志》 * |
| 周伟华等: "克林霉素磷酸酯脂质体含量及包封率的测定", 《生物医学工程学杂志》 * |
| 谢建峰等: "HPLC法测定克林霉素磷酸酯脂质体的含量", 《药物生物技术》 * |
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