CN1903358A - Compound bone peptide medicine composition oral prepn. and prepn. method therefor - Google Patents
Compound bone peptide medicine composition oral prepn. and prepn. method therefor Download PDFInfo
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- CN1903358A CN1903358A CNA2006100411998A CN200610041199A CN1903358A CN 1903358 A CN1903358 A CN 1903358A CN A2006100411998 A CNA2006100411998 A CN A2006100411998A CN 200610041199 A CN200610041199 A CN 200610041199A CN 1903358 A CN1903358 A CN 1903358A
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- Prior art keywords
- bone peptide
- beta
- schardinger dextrin
- complex
- cyclodextrin
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
An orally taken composite osteopeptide medicine is prepared from the composite osteopeptide and cyclodextrin in mass ratio of 1: (4-7) through preparing composite osteopeptide from the limb bone of health pig or fetal calf, and scorpion, mixing cyclodextrin with purified water, adding said composite osteopeptide, stirring and vacuum drying at 45-60 deg.C to obtain included solid.
Description
Technical field
The present invention relates to a kind of pharmaceutical composition, be specifically related to a kind of oral complex bone peptide pharmaceutical composition and this preparation of drug combination method.
Background technology
The complex bone peptide extract is meant: with the health pig of 3 parts of quality or the Scorpio of fetal bovine limb bone and 1 part of mass ratio is raw material, the thickness paste product that extraction obtains, be the semi-finished product that are used to prepare complex bone peptide for injection, the sterile water solution that complex bone peptide for injection is made for its extract, contain polypeptides matter among every 1ml and be not less than 15mg, contain total nitrogen and be not less than 4mg (national drug Western medicine standard WS1-XG-007-2002).Complex bone peptide is rich in multiple skeletal growth factor, main component: polypeptide, aminoacid, organic calcium, phosphorus, inorganic calcium, inorganic salt, trace element etc., each composition has stronger mutual coordinative role, can promote knitting, regulate bone metabolism, the balance osteogenesis has stronger anti-inflammatory and analgesic effect, and there are not gastrointestinal reaction and addiction, safely and effectively releasing osteoporosis patient's misery.Be used for the treatment of diseases such as rheumatism, rheumatoid arthritis, hyperosteogeny, fracture clinically.The polypeptide drug relative molecular mass is bigger, and molecule is easily assembled, and is fat-soluble poor, is difficult for seeing through biomembrane, usually can only drug administration by injection.At present the product of complex bone peptide is a complex bone peptide for injection, but drug administration by injection, especially needs the medicine of long-term or frequent drug administration, and the patient is brought inconvenience.Therefore, the significant and practical value of the development of the non-injection type of polypeptide drug also is the difficult point of studying at present.
The chemistry and the biological stability of polypeptide drug are poor, are difficult to permeable membrane and absorb, and plasma clearance is fast, and immunogenicity etc. it is generally acknowledged that these factors are the main causes that cause polypeptide drug oral absorption difficulty.The product that contains the bone peptide composition at present mainly contains complex bone peptide for injection, bone peptide (folk prescription) injection and bone peptide sheet (folk prescription), and complex bone peptide does not have oral formulations at present, also not about complex bone peptide extract non-injection report on the way.At present under the technical conditions, reach the effect identical with non-oral administration, oral polypeptide drug often need provide the dosage bigger than injection, daily dose as folk prescription bone peptide injection type (5mg/ml) is a 10mg (national drug Western medicine standard, standard numbering: WS1-XG-035-2000), but the daily dose of its peroral dosage form (40mg/ sheet) is that (national drug Western medicine standard, the standard numbering: WS1-XG-008-2002), two kinds of dosage form daily doses differ 12～24 times to 120～240mg.The difference of two kinds of bone peptide dosage form dosages has reflected the difference of bone peptide product oral and non-oral efficient.It is significant to improve oral medication efficient.
Development and application at present cyclodextrin inclusion technique has faster had the research report in polypeptide drug, the several amino acids side chain (or group) of polypeptide drugs molecule can produce (enclose) effect with cyclodextrin and form complicated clathrate, the clathrate that the interaction of this peptide species/cyclodextrin (enclose) forms can prevent the formation of self assembling of peptide molecule and prevention enzyme-substrate (polypeptide) complex, the effect of cyclodextrin can strengthen the biological and chemical stability of polypeptide, increase film surface polypeptide drugs concentration, or the membrane permeability of raising polypeptide drug, improve the purpose that polypeptide drugs absorb the raising bioavailability thereby reach.But the research of adopting cyclodextrin inclusion technique to carry out the bone peptide product at present yet there are no report.
Summary of the invention
The complex bone peptide product that the purpose of this invention is to provide a kind of higher oral efficient.
Technical scheme of the present invention is: adopt cyclodextrin inclusion compound complex bone peptide extract, strong, the well behaved solid clathrates of pharmaceutics of preparation stability adopts practice of pharmacy commonly used to prepare orally active compound recipe bone-peptide preparation product with clathrate.
Concrete technical scheme: oral administered compound bone peptide pharmaceutical composition, it consists of,
The complex bone peptide extract quality is than 1 part
3～11 parts of cyclodextrin mass ratioes.
Complex bone peptide extract described in the above scheme is meant: described complex bone peptide extract is meant: with the health pig of 3 parts of quality or the Scorpio of fetal bovine limb bone and 1 part of mass ratio is raw material, extracts the thickness paste product that obtains.
Described cyclodextrin can be: beta-schardinger dextrin-or HP-or sulphur butyl-beta-schardinger dextrin-.
The prioritization scheme of above-described oral administered compound bone peptide pharmaceutical composition is: the mass ratio of complex bone peptide extract and cyclodextrin is 1: 4～7.
The further qualification of above-mentioned composition, described oral administered compound bone peptide pharmaceutical composition is the compositions for preparing by the following method:
With beta-schardinger dextrin-, or the complex bone peptide extract of HP-or sulphur butyl-beta-schardinger dextrin-and 1/3～1/11 mass ratio adds the abundant stirred for several of water hour of 1～6 times of quality, and drying under reduced pressure gets the light yellow solid clathrate under 60 ℃ of temperature being lower than.
Solid clathrates compatibility common medicinal supplementary material be prepared into can be oral dosage form such as preparations such as tablet, capsule, granule, slow releasing tablet or dispersible tablet.Above-mentioned solid clathrates is made solid preparation, and the adjuvant that needs to add can be selected for use from following material: beta-schardinger dextrin-, microcrystalline Cellulose, starch, citric acid, Pulvis Talci, carboxymethylstach sodium, stearic acid, pregelatinized Starch, lactose, mannitol, polyvinylpolypyrrolidone, Pulvis Talci, PEG4000 (Macrogol 4000), low-substituted hydroxypropyl cellulose, micropowder silica gel, carboxymethylstach sodium, PEG6000 (polyethylene glycol 6000).
The consumption of adjuvant is by existing technical specification.
The preparation of solid clathrates is a key problem in technology among the present invention.
Oral administered compound bone peptide preparation of drug combination method of the present invention is as follows:
The pure water of cyclodextrin with 1～6 times of quality mixed, make suspension or solution, add the complex bone peptide extract of 1/3～1/11 mass ratio, fully mix, stirred 1～10 hour, system evenly promptly gets solid clathrates in 45 ℃ of-60 ℃ of following drying under reduced pressure behind the thing in the pasty state.
Clathrate of the present invention prepares preferred following scheme:
Beta-schardinger dextrin-or HP-or sulphur butyl-beta-schardinger dextrin-are mixed with the pure water of 1～5 times of quality, make into suspension or solution; The complex bone peptide extract that adds 1/4～1/7 mass ratio fully mixes, stirred 5～6 hours, gets solid clathrates in 50 ℃ of following drying under reduced pressure.
By the oral formulations of enclose preparation of compositions of the present invention, can reach the identical or close activity of drug administration by injection to the complex bone peptide for injection quality than administration with 2～3 times.The common oral preparation (not adopting inclusion technique) of complex bone peptide extract preparation then need just have the identical or close activity of drug administration by injection more than the dosage more than 3 times.
The technology of the present invention characteristics below are described.
The enclose feasibility: the complex bone peptide extract be the ethanol extraction of the ethanol extraction of Os Sus domestica or Os Bovis seu Bubali and Scorpio Scorpio with the certain proportion product of mixing, for buff toughening oil paste, be dissolved in ethanol, certain solubility is arranged in water.In the water-soluble filter, the complex bone peptide extract has more weak uv absorption in 232nm～272nm interval, add the cyclodextrin of self no uv absorption after, complex bone peptide extract uv absorption presents the regular (see figure 1) that strengthens with the increase of cyclodextrin concentration.The complex bone peptide extract contains multiple composition, according to document (CHINA JOURNAL OF CHINESE MATERIA MEDICA, 2004,29 (8): method 12-15), can measure the blended apparent enclose constant of extract multicomponent by the quantitative relationship of cyclodextrin concentration and complex bone peptide extract uv absorption Strength Changes, the apparent enclose constant (257nm) of measuring beta-schardinger dextrin-, HP-, sulphur butyl-beta-schardinger dextrin-and complex bone peptide the results are shown in Table 1.
Table 1: the enclose constant (Ka) of different rings dextrin and complex bone peptide
| Cyclodextrin | Ka(M -1) |
| Beta-schardinger dextrin-HP-sulphur butyl-beta-schardinger dextrin- | 903 752 819 |
Bigger apparent enclose constant shows, there are strong clathration in beta-schardinger dextrin-, HP-, sulphur butyl-beta-schardinger dextrin-and complex bone peptide, can form stable clathrate, this to improve polypeptide stability, improving extract medicament, to learn character very favourable.
Differential thermal analysis verification experimental verification clathrate: adopt beta-schardinger dextrin-and complex bone peptide clathrate (complex bone peptide extract: solid sample contrast cyclodextrin mass ratio 1: 5), the differential thermal analysis result of the test is seen accompanying drawing 2,75 ℃～80 ℃ is beta-schardinger dextrin-typical dehydrated endothermic peak (remove enclose water) among the beta-schardinger dextrin-figure, 220 ℃～230 ℃ have a feature phase transformation (heat absorption), 280 ℃ of solid beta-schardinger dextrin-s beginning decalescence, exothermic decomposition fast after 315 ℃.45 ℃～100 ℃ endothermic peaks broaden and intensity obviously weakens among the clathrate figure, show that sample contains micro-enclose water and removes a small amount of low-molecular-weight component, 220 ℃～230 ℃ beta-schardinger dextrin-feature decalescence peak disappears, 280 ℃ of beginning phase transformation heat releases to 305 ℃～315 ℃ are changed to decalescence, its differential thermal analysis curve significantly is different from beta-schardinger dextrin-, and sample is the new thing phase (clathrate) that is different from beta-schardinger dextrin-.
Sample stability test: complex bone peptide clathrate and simulated gastric fluid (1000ml) are mixed with the solution that contains extract 1mg/ml, 37 ℃ of constant temperature stir, get solution 20 μ L high performance liquid chromatograph sample introductions respectively at 1,2,4,6 and 8 hour, detect with ultraviolet 240nm wavelength; The 1ml/min flow velocity; PH4.5 acetic acid-sodium acetate buffer the solution (0.015mol/L) that contains benzyltrimethylammonium chloride (5mmol/L) is mobile phase, gets sample high performance liquid chromatogram fingerprint chromatogram.The own control result of the test, each characteristic peak no change of sample (component does not have obvious degradation, decomposition), each feature peak height and peak area constant substantially (stable content) show that clathrate tool in simulated gastric fluid is enough stable.Solid clathrates accelerated test and long-term reserved sample observing are not seen variation yet.
The oral test of pesticide effectiveness: the extract of complex bone peptide clathrate and non-enclose is prepared into complex bone peptide containing plate (abbreviation containing plate) and two kinds of peroral dosage forms of complex bone peptide ordinary tablet (abbreviation ordinary tablet) respectively, with the contrast of commercially available folk prescription bone peptide tablet (oral administration) and complex bone peptide injection (drug administration by injection), carry out the mouse writhing method analgesic test, rat paw carrageenin (Carraeenin) causes swollen method and the scorching method antiinflammatory test of mouse ear caused by dimethylbenzene xylene.Result of the test shows: the oral administered compound bone peptide has tangible analgesia, antiinflammatory action, and general effect is better than the bone peptide sheet.Containing plate is than a little less than acting on dosage complex bone peptide for injection (drug administration by injection), but the containing plate drug effect obviously is better than not having the conventional tablet of cyclodextrin.The complex bone peptide oral formulations that shows cyclodextrin inclusion compound has higher oral efficient.Test of pesticide effectiveness methods and results is as follows:
1, mouse writhing test
Be subjected to the reagent thing: containing plate, ordinary tablet, bone peptide sheet (oral positive control drug), complex bone peptide for injection (injection positive control drug)
Animal subject: Kunming mouse, male and female half and half, body weight 20 ± 2g, the The 2nd Army Medical College Experimental Animal Center provides, credit number SCXK (Shanghai) 2002-0006, body weight 18～22g.The male and female dual-purpose.
The raising condition: laboratory animal occupancy permit number is the 2003-0012 of SY-XK-Soviet Union.(cage tool volume is 32 * 21.5 * 17cm) to animal subject, and every cage is raised the same sex and only do not moved thing 5 in order to support.Normal feedstuff is the experimental mouse full-valence pellet feed, is provided by Jiangpu, Jiangsu Province laboratory animal feed factory.Freely drink water.Cage heelpiece material is the wood shavings wood flour, and the drying sterilization is changed weekly 2 times.18～25 ℃ of laboratory temperatures, humidity 50～70%.Has exhaust ventilation equipment.
Experiment group and dosage setting: animal random packet, 10 every group.Test divides blank group, test group, positive drug control group.Test group dosage is respectively 25,50 and 100mg/kg, and positive controls bone peptide sheet is 50mg/kg, and the blank group is irritated stomach with the distilled water isometric(al).Be administered once totally 7 days every day before the modeling.
Medication: each is organized administering mode and is single gastric infusion (complex bone peptide for injection is a drug administration by injection).Administration time is preceding 10 minutes of acetic acid lumbar injection.Each dosage group equal-volume (0.1ml/10g) administration.
Observation index: observe not phase mouse writhing number of times simultaneously.
Operating procedure: every mouse peritoneal is injected 0.6% acetic acid 0.2ml, and what the different periods (20 and 40 minutes) were counted mice respectively after administration turns round the body number of times.
Date processing:
Ec: matched group not simultaneously phase turn round the body number of times; Et: each experimental group not simultaneously phase turn round body number of times statistical method: data are represented with X ± SD, turn round the body number of times and check with Mann-Whitney.
The result: acetic acid causes the mouse writhing result of the test and shows (table 2),
Table 2 sample Dichlorodiphenyl Acetate causes the influence of mouse writhing reaction
| Group | Medicine-feeding way | Dosage mg/kg | Not simultaneously phase (minute) rat writhing response number of times | |
| 20 | 40 | |||
| The matched group containing plate | Irritate stomach and irritate stomach filling stomach | 0 25 50 | 14.1±8.2 8.7±2.6 6.0±4.6 * | 16.8±4.5 7.7±3.2 ** 5.1±4.0 ** |
| Sheet bone peptide sheet complex bone peptide | Irritate stomach and irritate |
100 50 50 15 | 3.3±2.7 ** 10.4±5.5 11.4±9.1 9.5±8.1 * | 4.0±6.1 ** 8.2±7.0 * 7.4±6.6 ** 9.6±1.7 * |
N=10, X ± SD,
*P＜0.05
*P＜0.01 and matched group are turned round body number of times Mann-Whitney
Containing plate can obviously suppress acetic acid and cause the mouse writhing reaction, reduces and turns round the body number of times.The effect of containing plate obviously is better than bone peptide sheet matched group.But a little less than the effect of drug administration by injection mode matched group complex bone peptide for injection.Cyclodextrin inclusion compound sheet drug effect is better than conventional tablet.
2. carrageenin causes the rat paw edema test
Test material: animal: the SD rat, male, body weight 163 ± 18g, the The 2nd Army Medical College Experimental Animal Center provides, credit number SCXK (Shanghai) 2002-0006, body weight 18～22g.The male and female dual-purpose.The raising condition: laboratory animal occupancy permit number is the 2003-0012 of SY-XK-Soviet Union.(cage tool volume is 32 * 21.5 * 17cm) to animal subject, and every cage is raised the same sex and only do not moved thing 5 in order to support.Normal feedstuff is the experimental mouse full-valence pellet feed.Freely drink water.Cage heelpiece material is the wood shavings wood flour, and the drying sterilization is changed weekly 2 times.Laboratory temperature 18～25, humidity 50～70%.Has exhaust ventilation equipment.
Reagent and compound method: carrageenin (Carrageenin, Sigma): 1% carrageenin normal saline suspension: quantitatively take by weighing carrageenin, in grinding alms bowl with the injection normal saline grind be mixed even, experiment existing preparation on the same day.
Instrument: volumetric measurement instrument (it is customized to press Xu Shuyun, Bian Rulian, Chen Xiu chief editor " pharmacological experiment methodology " p716).
Experiment group and dosage setting: the animal random packet, 8 every group, test divides blank group, test group, positive drug control group.Test group dosage is respectively 12.5,25 and 50mg/kg, and positive controls bone peptide sheet is respectively 25mg/kg, and the blank group is that the equal-volume distilled water is irritated stomach.Be administered once totally 7 days every day before the modeling.
Medication: each is organized administering mode and is single gastric infusion (complex bone peptide for injection is a drug administration by injection).Administration time is that carrageenin causes scorching preceding 10 minutes.Equal-volume between each dosage group (1ml/100g body weight).
Observation index when observing mutually: animal is in not surveying right sufficient volume simultaneously mutually.Respectively at cause scorching before and cause scorching back and surveyed volume in 1,2,4 and 6 hour.
Operating procedure: press document capillary tube amplifying method and measure.With the marking pen line, measure right back sufficient sole of the foot volume around the rat right hind leg ankle joint, after the administration 10 minutes with No. 7 syringe needles at the subcutaneous injection 1% carrageenin normal saline suspension 0.05ml of the sufficient sole of the foot, measure and cause simultaneously mutually insufficient sole of the foot change in volume after the inflammation.
Date processing:
In the formula: L
Tn: cause after the inflammation not the sufficient sole of the foot volume of phase simultaneously; L
T0: cause scorching preceding sufficient sole of the foot volume;
In the formula: Ec: the matched group foot sole of the foot is the rate of phase swelling simultaneously not; Et: each experimental group foot sole of the foot is the rate of phase swelling simultaneously not;
Data is represented with X ± SD, Student-t check between the row group.
The result: containing plate has the obvious suppression effect to rat paw edema, drug effect tool dosage compliance, the fastest 1 hour of onset time, at least 6 hours persistent period.Dosage such as containing plate and bone peptide sheet and simultaneously mutually the swelling degree compare, significant difference is arranged, prompting containing plate drug effect obviously is better than the bone peptide sheet.But a little less than complex bone peptide for injection (drug administration by injection) effect.Cyclodextrin inclusion compound sheet drug effect is better than ordinary tablet.
Table 3. sample is to causing the influence of rat
| Group | Dosage mg/kg | Administration not simultaneously phase (hour) (%) | |||
| 1 | 2 | 4 | 6 | ||
| Control group containing plate sheet bone peptide sheet complex bone peptide | 0 25 50 100 50 50 15 | 22.6±8.1 16.7±3.8 10.5±4.1 ** 10.3±3.3 ** 12.5±4.3 * 16.8±4.3 113±5.4 * | 27.6±8.2 18.5±6.2 13.6±4.2 ** 12.6±4.7 ** 14.2±4.6 ** 19.7±6.5 13.8±5.2 ** | 23.0±10.1 16.0±5.9 12.4±5.3 * 12.5±6.2 * 14.6±7.3 19.8±7.0 13.6±3.2 * | 12.9±6.1 10.5±7.2 8.5±5.4 6.5±5.4 10.0±5.5 10.7±8.8 10.5±3.4 |
N=8, X ± SD,
*P＜0.05,
*P＜0.01 and matched group Student-t
3. mice caused by dimethylbenzene xylene auricle edema test
Animal: Kunming mouse, male and female half and half, body weight 20 ± 2g, the The 2nd Army Medical College Experimental Animal Center provides, credit number SCXK (Shanghai) 2002-0006, body weight 18～22g.The male and female dual-purpose.The raising condition: laboratory animal occupancy permit number is the 2003-0012 of SY-XK-Soviet Union.(cage tool volume is 32 * 21.5 * 17cm) to animal subject, and every cage is raised the same sex and only do not moved thing 5 in order to support.Normal feedstuff is the experimental mouse full-valence pellet feed.Freely drink water.Cage heelpiece material is the wood shavings wood flour, and the drying sterilization is changed weekly 2 times.Laboratory temperature 18～25, humidity 50～70%.Has exhaust ventilation equipment.
Reagent and compound method: dimethylbenzene (AR, Nanjing chemical reagent factory).
Instrument: card punch ( 8mm); Electronic balance.
Experiment group and dosage setting: the animal random packet, 10 every group, experiment divides blank group, test group and positive drug control group.The blank group is respectively 25,50 and 100mg/kg for equal-volume distilled water, test group dosage, and positive controls bone peptide sheet is 50mg/kg.
Medication: each is organized administering mode and is single gastric infusion (complex bone peptide for injection is a drug administration by injection).Administration time is scorching preceding 10 minutes of caused by dimethylbenzene xylene.Equal-volume between each dosage group (0.1ml/10g body weight) administration.Be administered once totally 7 days every day before the modeling.
Observation index: the weight of left and right sides auricle sheet.Its difference is increment.
Phase during observation: surveyed These parameters in scorching back 2 hours in caused by dimethylbenzene xylene.
Operating procedure: dripping 100% dimethylbenzene 0.02ml/ in the mouse right ear front only in 10 minutes behind each dosage group gastric infusion, is contrast with left ear.Take off after causing scorching 2 hours cervical vertebra put to death cut behind the mice about two ears, get garden shape auricle with the 8mm card punch in two ear same area, use scales/electronic balance weighing, with about the difference of two ear weight be the swelling degree, the calculating suppression ratio.
Date processing:
In the formula: Ec: matched group is phase measured value simultaneously not; Et: each experimental group is phase measured value simultaneously not;
Statistical method: measurement data is represented with X ± SD, Student-t check between the row group.
The result: mice caused by dimethylbenzene xylene auricle edema result of the test shows, when containing plate 25,50 and 100mg/kg dosage, calculates suppression ratio with left and right sides auricle weightening finish value, is respectively 35.7%, 54.3% and 60%, the suppression ratio 58.6% of bone peptide sheet 100mg/kg dosage; Calculate suppression ratio with the auricle rate of body weight gain, the suppression ratio of containing plate is respectively 26.7%, 44.7% and 52.3%, and dosage suppression ratio such as bone peptide sheet are 50.5%.Containing plate is compared there was no significant difference with dosage such as bone peptide sheets, and a little less than complex bone peptide for injection effect, but cyclodextrin inclusion compound sheet drug effect is better than ordinary tablet.
Table 4. sample is to causing the influence of mice
| Group | Dosage (mg/kg) | (g) | (％) | (Δ％) | (％) |
| Matched group containing plate sheet bone peptide sheet complex bone peptide | 0 25 50 100 50 100 15 | 7.0±2.83 4.5±2.76 3.2±1.55 ** 2.8±2.44 ** 4.0±2.12 2.9±1.71 ** 4.2±2.25 | 35.7 54.3 60.0 42.8 58.6 40.0 | 43.0±10.3 31.5±15.0 23.8±9.6 ** 20.5±14.1 ** 28.5±8.3 21.3±8.50 ** 26.5±7.77 | 26.7 44.7 52.3 33.7 50.5 38.4 |
N=10, X ± SD,
*P＜0.05,
*P＜0.01 with to group ratio, Student-t check.
3, advantage of the present invention
(1) the complex bone peptide extract oral is effective, and it is better that extract and cyclodextrin form the clathrate oral result, and the present invention provides complex bone peptide safer, route of administration and method easily for the patient.
(2) behind the cyclodextrin inclusion compound complex bone peptide extract, the solid-state liquid sample stable in properties of enclose state is suitable for various peroral dosage forms.
(3) clathrate of the present invention prepares under the pure water condition, does not use any organic solvent, and organic solvent-free is residual, helps improving drug safety.
(4) cyclodextrin clathrate stable in properties of the present invention, solid clathrates and other pharmaceutic adjuvant compatibilitys are good, are easy to compatibility agent processing, are convenient to the preparation of preparation, and be practical.
(5) preparation method is simple, easy and simple to handle, cost is low and non-environmental-pollution.Clathrate easily stores easily transportation, nonhazardous.
Description of drawings:
Fig. 1 is the variation that increases cyclodextrin concentration complex bone peptide extract uv absorption in the aqueous solution;
Fig. 2 is beta-schardinger dextrin-and complex bone peptide clathrate differential thermal analysis (DTA) figure contrast.
The specific embodiment:
Embodiment 1, oral administered compound bone peptide pharmaceutical composition: 1100 gram beta-schardinger dextrin-s are made into suspension with the mixing of 6600 ml pure waters, stir and add 100 gram paste complex bone peptide extracts down, mix fully back restir hour, system is thing in the pasty state evenly, promptly gets 1117 gram light yellow solid clathrates in 60 ℃ of following drying under reduced pressure.
It is standby that the gained solid clathrates is crossed 100 mesh sieves, getting 2/3 amount pharmaceutic adjuvant behind mixed microcrystalline cellulose 100 grams, starch 150 grams, carboxymethylstach sodium 200 grams, Pulvis Talci 20 grams, the abundant mixing of stearic acid 26 grams mixes with solid clathrates, fully behind the mixing with 70% ethanol moistening system soft material, crossing 14 mesh sieves granulates, add other 1/3 amount pharmaceutic adjuvant behind 50 ℃ of dryings, the granulate, fully measure the complex bone peptide extractive content behind the mixing, require tabletting to make complex bone peptide containing plate product according to dosage.
Embodiment 2: 900 gram beta-schardinger dextrin-s are mixed making into suspension with 2500 ml pure waters, stir and add 300 gram paste complex bone peptide extracts down, mix fully back restir hour, system is thing in the pasty state evenly, gets 1136 gram light yellow solid clathrates in 60 ℃ of following drying under reduced pressure.
It is standby that the gained solid clathrates is crossed 100 mesh sieves, getting 2/3 amount pharmaceutic adjuvant behind mixed microcrystalline cellulose 100 grams, starch 100 grams, carboxymethylstach sodium 250 grams, Pulvis Talci 20 grams, the abundant mixing of stearic acid 26 grams mixes with solid clathrates, fully behind the mixing with 70% ethanol moistening system soft material, crossing 14 mesh sieves granulates, add other 1/3 amount pharmaceutic adjuvant behind 50 ℃ of dryings, the granulate, fully measure content behind the mixing, tabletting makes the complex bone peptide containing plate.
Embodiment 3: 960 gram beta-schardinger dextrin-s are mixed making into suspension with 2000 ml pure waters, stir and add 240 gram paste complex bone peptide extracts down, mix fully back restir hour, system is thing in the pasty state evenly, gets 1126 gram light yellow solid clathrates in 60 ℃ of following drying under reduced pressure.
It is standby that the gained solid clathrates is crossed 100 mesh sieves, getting 2/3 amount pharmaceutic adjuvant behind mixed microcrystalline cellulose 100 grams, starch 100 grams, carboxymethylstach sodium 250 grams, Pulvis Talci 20 grams, the abundant mixing of stearic acid 26 grams mixes with solid clathrates, fully behind the mixing with 70% ethanol moistening system soft material, crossing 14 mesh sieves granulates, add other 1/3 amount pharmaceutic adjuvant behind 50 ℃ of dryings, the granulate, fully measure content behind the mixing, tabletting makes the complex bone peptide containing plate.
Embodiment 4: 1000 gram beta-schardinger dextrin-s are mixed making into suspension with 2000 ml pure waters, stir and add 200 gram paste complex bone peptide extracts down, mix fully back restir hour, system is thing in the pasty state evenly, gets 1121 gram light yellow solid clathrates in 60 ℃ of following drying under reduced pressure.
It is standby that the gained solid clathrates is crossed 100 mesh sieves, getting 2/3 amount pharmaceutic adjuvant behind mixed microcrystalline cellulose 100 grams, starch 100 grams, carboxymethylstach sodium 250 grams, Pulvis Talci 20 grams, the abundant mixing of stearic acid 26 grams mixes with solid clathrates, fully behind the mixing with 70% ethanol moistening system soft material, crossing 14 mesh sieves granulates, add other 1/3 amount pharmaceutic adjuvant behind 50 ℃ of dryings, the granulate, fully measure content behind the mixing, tabletting makes the complex bone peptide containing plate.
Embodiment 5: substantially the same manner as Example 1, but mix with 1100 ml pure waters with HP-; Add 157 gram paste complex bone peptide extracts.
Coating makes complex bone peptide cyclodextrin inclusion compound coated tablet behind granulation, the tabletting.
Embodiment 6: substantially the same manner as Example 3, but mix with 1000 ml pure waters with HP-.Coating makes cyclodextrin inclusion compound complex bone peptide coated tablet behind granulation, the tabletting.
Embodiment 7: substantially the same manner as Example 4, but mix with 1000 ml pure waters with HP-.Coating makes cyclodextrin inclusion compound complex bone peptide coated tablet behind granulation, the tabletting.
Embodiment 8: substantially the same manner as Example 1, but mix with 1100 ml pure waters with sulphur butyl-beta-schardinger dextrin-.Coating makes complex bone peptide cyclodextrin inclusion compound coated tablet behind granulation, the tabletting.
Embodiment 9: substantially the same manner as Example 3, but mix with 1000 ml pure waters with sulphur butyl-beta-schardinger dextrin-.Coating makes complex bone peptide cyclodextrin inclusion compound coated tablet behind granulation, the tabletting.
Embodiment 10: substantially the same manner as Example 4, but mix with 1000 ml pure waters with sulphur butyl-beta-schardinger dextrin-.Coating makes complex bone peptide cyclodextrin inclusion compound coated tablet behind granulation, the tabletting.
Claims (5)
1, a kind of oral administered compound bone peptide pharmaceutical composition, it consists of,
The complex bone peptide extract quality is than 1 part
3～11 parts of cyclodextrin mass ratioes.
2, according to the described oral administered compound bone peptide of claim 1 pharmaceutical composition, it is characterized in that, described complex bone peptide extract is meant: with the health pig of 3 parts of quality or the Scorpio of fetal bovine limb bone and 1 part of mass ratio is raw material, extracts the thickness paste product that obtains.
Described cyclodextrin is selected from: beta-schardinger dextrin-or HP-or sulphur butyl-beta-schardinger dextrin-;
The mass ratio of described complex bone peptide extract and cyclodextrin is 1: 4～7.
3, according to claim 1 or 2 described oral administered compound bone peptide pharmaceutical compositions, it is characterized in that described oral administered compound bone peptide pharmaceutical composition is the compositions for preparing by the following method:
With beta-schardinger dextrin-, or the complex bone peptide extract of HP-or sulphur butyl-beta-schardinger dextrin-and 1/3～1/11 mass ratio adds the abundant stirred for several of water hour of 1～6 times of quality, and drying under reduced pressure gets the light yellow solid clathrate under 60 ℃ of temperature being lower than.
4, the described oral administered compound bone peptide of a kind of claim 1 preparation of drug combination method, step is as follows:
The pure water of cyclodextrin with 1～6 times of quality mixed, make suspension or solution, add the complex bone peptide extract of 1/3～1/11 mass ratio, fully mix, stirred 1～10 hour, system evenly promptly gets solid clathrates in 45 ℃～60 ℃ following drying under reduced pressure behind the thing in the pasty state.
5, according to the described oral administered compound bone peptide of claim 4 preparation of drug combination method, it is characterized in that concrete steps are:
Beta-schardinger dextrin-or HP-or sulphur butyl-beta-schardinger dextrin-are mixed with the pure water of 1～5 times of quality, make into suspension or solution; The complex bone peptide extract that adds 1/4～1/7 mass ratio fully mixes, stirred 5～6 hours, gets solid clathrates in 50 ℃ of following drying under reduced pressure.
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