CN104856947A - Alprostadil hydroxypropyl-alpha-cyclodextrin inclusion compound injection - Google Patents
Alprostadil hydroxypropyl-alpha-cyclodextrin inclusion compound injection Download PDFInfo
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- alprostadil
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Abstract
The invention provides an alprostadil hydroxypropyl-alpha-cyclodextrin inclusion compound injection. The inclusion compound injection is prepared through inclusion of alprostadil with hydroxypropyl-alpha-cyclodextrin, and the solubility of the alprostadil and the stability of the injection are greatly improved.
Description
Technical field
The present invention relates to a kind of pharmaceutical preparation of Alprostadil, be specifically related to a kind of Hydroxyproply-α-cyclodextrin clathrate injection of Alprostadil, belong to medical art.
Background technology
Alprostadil, also known as PGE1, is the one in natural prostaglandins class material.Prostaglandin is present in most of mammalian tissues, and basic structure is 20 carbon fatty acids containing a Pentamethylene. and two aliphatic side chainses.Can several types be divided into according to position of double bond on Pentamethylene. and substituent difference, wherein mainly contain four classes such as E/F/A/B.Each class has different hypotypes, has biological effect widely.
Alprostadil is a kind of efficient bio-active material, and chemical name is 11a, the anti-prostenoic acid of 15 (S)-dihydroxy-9-carbonyl-13-, molecular formula C
20h
34o
5, molecular weight 354.48, structural formula is:
Alprostadil has the generation of anticoagulant, thromboxane A2, tremulous pulse medicated porridge sample Lipid Plaque is formed and the effect of immune complex, and can expand periphery and arteria coronaria blood vessel.This strain Exogenous prostaglandins E1 (PGE1) is a kind of vasodilation and anticoagulant agent.PGE1, by adenyl cyclase in active cell, makes the cyclic adenosine monophosphate of platelet and vascular smooth intramuscular (cAMP) level increase exponentially, causes and produces inertia platelet and vasodilation.It is all low to the reaction of general induced polymerization inhibitor that patient injects the platelet in vitro tests after this product.After the quiet note of Alprostadil, be faintly combined with plasma protein, T1/2 is 5 ~ 10 minutes.Metabolism is complete in vivo, and 68% of dosage to reach a standard effect metabolism, with metabolite form through renal excretion through liver head.The Patients with Lung of serious respiratory failure removes the decline of this product, and Alprostadil plasma concentration can be made to raise.
Up to the present, Alprostadil experienced by three generations's dosage form altogether and develops, and first on behalf of sterile powder injection, due to the aqueous solution extremely unstable of Alprostadil, therefore needs to make injectable powder type and is easy to storage and transport.This dosage form manufacturer is many, side effect is reported for work also a lot, the side effect of having reported for work mainly contains intravenous drip bright sample swelling pain in various degree or pruritus more, " red line " is there is in some patients along vein skin, generally can tolerate, when instiling too fast, pain increases the weight of, and pain and " red line " disappear after stopping injection, but have then there is nonseptic phlebitis; Second on behalf of cyclodextrin clathrate, and commercially available prod is Alprostadil-alpha-cyclodextrin clathrate, and it utilizes the cavity of cyclodextrin to be entered by Alprostadil enclose, but stability is not good and toxic and side effects still exists; The third generation is liplid emulsions, also has commercially available prod at present, but the current technique of this dosage form is not very ripe, and technics comparing is complicated, and suitability for industrialized production degree is lower.
Clathrate refers to that a kind of drug molecular structure is wholly or partly enclose and enters the complex forming unique forms in the molecule chamber of another kind of material.Clathrate is very active in pharmaceutical preparation research field, the 1950's research worker have realized that the character of clathrate medicine has impact, as clathrate increase drug solubility and stability, affect medicine absorption in vivo, distribution, onset time etc.
Prior art is known, and cyclodextrin has α, β and γ tri-kinds, is made up of respectively 6,7 and 8 glucoses.Prove through X-ray diffraction and nuclear magnetic resonance research, the stereochemical structure of cyclodextrin is circular hollow cylindrical shape that is wide at the top and narrow at the bottom, both ends open, entered in cylinder by enclose material molecule, form clathrate, not only dissolubility can be increased, can also bad smell be improved, improve stability and bioavailability.At present, beta-schardinger dextrin-and derivant thereof are most widely used, and alpha-cyclodextrin and derivant thereof, owing to yielding poorly and unstability reason, do not become the conventional excipients of cyclodextrin clathrate.For a long time, do not use α and γ cyclodextrin to prepare common recognition and the convention that clathrate has become this area at pharmaceutical field.
Chinese patent CN02126054.0 discloses a kind of aseptic freeze-dried prostaglandin preparation and its production and use, and it is made up of Alprostadil, alpha-cyclodextrin, HP-β-CD or gamma-cyclodextrin, thymosin, dextran.Chinese patent CN201210190612.2 discloses a kind of Alprostadil freeze-dried injectable powder and preparation method thereof, and its component is Alprostadil, HP-β-CD and Dextran 40.Chinese patent CN200310102253.1 discloses a kind of injection containing Alprostadil, is made up of Alprostadil, dehydrated alcohol, PEG400, dimethyl acetylamide, 2-HP-BETA-CD, cysteine, sterilized water for injection.
In prior art, beta-schardinger dextrin-or HP-β-CD is normally adopted to carry out enclose to Alprostadil.But, by studying discovery further, the stability of the Alprostadil clathrate that beta-schardinger dextrin-and analog thereof obtain and bioavailability over time, become, still Shortcomings.Clinically for storing the pharmaceutical formulation still after certain hour with the Alprostadil that good biological utilizes, have in the urgent need to.
Summary of the invention
The object of this invention is to provide a kind of Alprostadil pharmaceutical formulation still after storing certain hour with good bioavailability.
The present inventor overcomes in prior art and does not use α and γ cyclodextrin to prepare the technology prejudice of clathrate, be have been surprisingly found that by research, the stability of the Alprostadil clathrate using Hydroxyproply-α-cyclodextrin to prepare and bioavailability are far superior to the Alprostadil product that in prior art, other cyclodextrin existing comprise.
The object of the present invention is to provide a kind of clathrate containing Alprostadil and Hydroxyproply-α-cyclodextrin.
The object of the present invention is to provide a kind of injection prepared by the clathrate of Alprostadil and Hydroxyproply-α-cyclodextrin, first Alprostadil Hydroxyproply-α-cyclodextrin is carried out enclose, then add the injection that Alprostadil Hydroxyproply-α-cyclodextrin clathrate made by pharmaceutically acceptable excipient.
A kind of pharmaceutical composition of the present invention, comprises Alprostadil, Hydroxyproply-α-cyclodextrin and pharmaceutically acceptable excipient.
Pharmaceutical composition of the present invention, wherein, described Alprostadil and Hydroxyproply-α-cyclodextrin are present in pharmaceutical composition with the form of clathrate, and the excipient pharmaceutically accepted is preferred for the excipient preparing injection.
One or more in mannitol, lactose, dextran, xylitol, sorbitol, glucose, sodium chloride are comprised for the preparation of the excipient of injection in the present invention.
The purity of Alprostadil of the present invention is 80% ~ 110%, preferably 90% ~ 100%.
In the clathrate of Alprostadil of the present invention and Hydroxyproply-α-cyclodextrin, wherein the part by weight of Alprostadil and Hydroxyproply-α-cyclodextrin is 1:3 ~ 3000, preferred 1:50 ~ 1500.
The injection of the clathrate of Alprostadil of the present invention and Hydroxyproply-α-cyclodextrin, the part by weight shared in whole preparation of the excipient wherein pharmaceutically accepted is 0.1 ~ 90%, preferably 0.3 ~ 60%.
As the preferred embodiment of the invention, pharmaceutical composition of the present invention comprises, based on parts by weight, and row ground that 1 part, Hydroxyproply-α-cyclodextrin 3 ~ 3000 parts, excipient 5 ~ 2000 parts.
As further preferred embodiment, pharmaceutical composition of the present invention comprises, based on parts by weight, and row ground that 1 part, Hydroxyproply-α-cyclodextrin 50 ~ 1500 parts, excipient 100 ~ 1300 parts.
Present invention also offers the preparation method of the injection of the clathrate of a kind of Alprostadil and Hydroxyproply-α-cyclodextrin, specific as follows:
(1) take the Hydroxyproply-α-cyclodextrin of recipe quantity, add water for injection, stirring and dissolving is complete, obtained solution A;
(2) take the Alprostadil of recipe quantity, add ethanol and make dissolving complete, obtained solution B;
(3) solution A and solution B are merged, regulate pH to 4.0 ~ 7.0 by pH adjusting agent, stir 3 ~ 5 hours, to dissolving completely, in clear and bright uniform solution;
(4) take the pharmaceutic adjuvant of recipe quantity, be stirred to dissolve completely, concentrating under reduced pressure, removing ethanol and part water;
(5) charcoal absorption, filtering decarbonization, aseptic filtration;
(6) fill;
(7) lyophilization, obtained injection Alprostadil Hydroxyproply-α-cyclodextrin clathrate injectable powder; Or, sterilizing, obtained Alprostadil Hydroxyproply-α-cyclodextrin inclusion complexes injection.
As the present invention one preferred embodiment, in above-mentioned steps (1), the ratio of Hydroxyproply-α-cyclodextrin and water for injection is 1:3 ~ 100, preferred 1:5 ~ 80.
As the present invention one preferred embodiment, in above-mentioned steps (2), the ratio of Alprostadil and ethanol is 1:30 ~ 3000, preferred 1:60 ~ 2000.
As the present invention one preferred embodiment, in above-mentioned steps (3), pH adjusting agent is selected from one or more in citric acid, sodium citrate, sodium hydrogen phosphate, sodium dihydrogen phosphate, hydrochloric acid, sodium hydroxide, preferably phosphoric acid sodium dihydrogen and sodium hydrogen phosphate combination.
As the present invention one preferred embodiment, 40 ~ 50 DEG C of concentrating under reduced pressure in above-mentioned steps (4), preferably 45 DEG C of concentrating under reduced pressure.
As the present invention one preferred embodiment, in above-mentioned steps (5), add the active carbon of overall solution volume 0.02 ~ 0.2% (w/v), stirring and adsorbing 5 ~ 50 minutes, filtering decarbonization; Preferably add the active carbon of overall solution volume 0.05% (w/v), stirring and adsorbing 20 ~ 30 minutes, filtering decarbonization.
As the present invention one preferred embodiment, in above-mentioned steps (7), freeze drying process is :-40 ~-50 DEG C are incubated 3 ~ 5 hours; Be warming up to-15 DEG C with 5 ~ 8 hours, be incubated to ice crystal and disappear; Be warming up to 30 DEG C with 4 hours again, be incubated 3 ~ 6 hours, to sample drying.
As the present invention one preferred embodiment, sterilization process is in above-mentioned steps (7): 121 DEG C of moist heat sterilizations 15 minutes.
Alprostadil Hydroxyproply-α-cyclodextrin clathrate injection of the present invention, technique is simple, workable, is suitable for suitability for industrialized production.Meanwhile, this product, compared to current commercially available prod, has carried out enclose owing to have employed Hydroxyproply-α-cyclodextrin to Alprostadil, and make stability better, bioavailability is higher, and toxicity is less.
Detailed description of the invention
Embodiment 1 injection Alprostadil Hydroxyproply-α-cyclodextrin clathrate
Prescription:
Preparation process
(1) take 20g Hydroxyproply-α-cyclodextrin, add 1500g water for injection, stirring and dissolving is complete, obtained solution A;
(2) take 20mg Alprostadil, add 20g ethanol and make dissolving complete, obtained solution B;
(3) solution A and solution B being merged, with sodium hydrogen phosphate and the sodium dihydrogen phosphate buffer adjustment pH to 4.9 of pH5.0, stirring 5 hours, to dissolving completely, in clear and bright uniform solution;
(4) take 20g dextran, be stirred to dissolve completely, 45 DEG C of concentrating under reduced pressure, removing ethanol and part water;
(5) 0.75g active carbon stirring and adsorbing is added 20 minutes, filtering decarbonization, aseptic filtration;
(6) fill; 1.5g/ bottle.
(7) lyophilization :-40 ~-50 DEG C are incubated 3 ~ 5 hours; Be warming up to-15 DEG C with 5 ~ 8 hours, be incubated to ice crystal and disappear; Be warming up to 30 DEG C with 4 hours again, be incubated 3 ~ 6 hours, to sample drying.
Embodiment 2 injection Alprostadil Hydroxyproply-α-cyclodextrin clathrate
Prescription:
Preparation process
(1) take 80g Hydroxyproply-α-cyclodextrin, add 2400g water for injection, stirring and dissolving is complete, obtained solution A;
(2) take 100mg Alprostadil, add 50g ethanol and make dissolving complete, obtained solution B;
(3) solution A and solution B being merged, with sodium hydrogen phosphate and the sodium dihydrogen phosphate buffer adjustment pH to 4.8 of pH5.0, stirring 3 hours, to dissolving completely, in clear and bright uniform solution;
(4) take 32g lactose, be stirred to dissolve completely, 40 DEG C of concentrating under reduced pressure, removing ethanol and part water;
(5) 1.2g active carbon stirring and adsorbing is added 30 minutes, filtering decarbonization, aseptic filtration;
(6) fill; 2.4g/ bottle.
(7) lyophilization :-40 ~-50 DEG C are incubated 3 ~ 5 hours; Be warming up to-15 DEG C with 5 ~ 8 hours, be incubated to ice crystal and disappear; Be warming up to 30 DEG C with 4 hours again, be incubated 3 ~ 6 hours, to sample drying.
Embodiment 3 injection Alprostadil Hydroxyproply-α-cyclodextrin clathrate
Prescription:
Preparation process
(1) take 300g Hydroxyproply-α-cyclodextrin, add 6000g water for injection, stirring and dissolving is complete, obtained solution A;
(2) take 200mg Alprostadil, add 150g ethanol and make dissolving complete, obtained solution B;
(3) solution A and solution B being merged, with sodium hydrogen phosphate and the sodium dihydrogen phosphate buffer adjustment pH to 5.1 of pH5.0, stirring 4 hours, to dissolving completely, in clear and bright uniform solution;
(4) take 100g mannitol, be stirred to dissolve completely, 50 DEG C of concentrating under reduced pressure, removing ethanol and part water;
(5) 3g active carbon stirring and adsorbing is added 25 minutes, filtering decarbonization, aseptic filtration;
(6) fill; 6g/ bottle.
(7) lyophilization :-40 ~-50 DEG C are incubated 3 ~ 5 hours; Be warming up to-15 DEG C with 5 ~ 8 hours, be incubated to ice crystal and disappear; Be warming up to 30 DEG C with 4 hours again, be incubated 3 ~ 6 hours, to sample drying.
Embodiment 4 Alprostadil Hydroxyproply-α-cyclodextrin inclusion complexes injection
Prescription:
Preparation process
(1) take 20g Hydroxyproply-α-cyclodextrin, add 1500g water for injection, stirring and dissolving is complete, obtained solution A;
(2) take 20mg Alprostadil, add 20g ethanol and make dissolving complete, obtained solution B;
(3) solution A and solution B being merged, with sodium hydrogen phosphate and the sodium dihydrogen phosphate buffer adjustment pH to 5.0 of pH5.0, stirring 5 hours, to dissolving completely, in clear and bright uniform solution;
(4) take 13.5g sodium chloride, be stirred to dissolve completely, 45 DEG C of concentrating under reduced pressure, removing ethanol and part water;
(5) 0.75g active carbon stirring and adsorbing is added 20 minutes, filtering decarbonization, aseptic filtration;
(6) fill; 1.5ml/ bottle.
(7) sterilizing: 121 DEG C of moist heat sterilizations 15 minutes.
Embodiment 5 Alprostadil Hydroxyproply-α-cyclodextrin inclusion complexes injection
Prescription:
Preparation process
(1) take 80g Hydroxyproply-α-cyclodextrin, add 2400g water for injection, stirring and dissolving is complete, obtained solution A;
(2) take 100mg Alprostadil, add 50g ethanol and make dissolving complete, obtained solution B;
(3) solution A and solution B being merged, with sodium hydrogen phosphate and the sodium dihydrogen phosphate buffer adjustment pH to 4.9 of pH5.0, stirring 3 hours, to dissolving completely, in clear and bright uniform solution;
(4) take 120g glucose, be stirred to dissolve completely, 40 DEG C of concentrating under reduced pressure, removing ethanol and part water;
(5) 1.2g active carbon stirring and adsorbing is added 30 minutes, filtering decarbonization, aseptic filtration;
(6) fill; 2.4ml/ bottle.
(7) sterilizing: 121 DEG C of moist heat sterilizations 15 minutes.
Embodiment 6 Alprostadil Hydroxyproply-α-cyclodextrin inclusion complexes injection
Prescription:
Preparation process
(1) take 300g Hydroxyproply-α-cyclodextrin, add 6000g water for injection, stirring and dissolving is complete, obtained solution A;
(2) take 200mg Alprostadil, add 150g ethanol and make dissolving complete, obtained solution B;
(3) solution A and solution B being merged, with sodium hydrogen phosphate and the sodium dihydrogen phosphate buffer adjustment pH to 5.0 of pH5.0, stirring 4 hours, to dissolving completely, in clear and bright uniform solution;
(4) take 54g sodium chloride, be stirred to dissolve completely, 50 DEG C of concentrating under reduced pressure, removing ethanol and part water;
(5) 3g active carbon stirring and adsorbing is added 25 minutes, filtering decarbonization, aseptic filtration;
(6) fill; 6ml/ bottle.
(7) sterilizing: 121 DEG C of moist heat sterilizations 15 minutes.
Comparative example
| Supplementary material | Comparative example 1 | Comparative example 2 | Comparative example 3 | Comparative example 4 | Comparative example 5 | The present invention |
| Alprostadil | 20mg | 20mg | 20mg | 20mg | 20mg | 20mg |
| Hydroxyproply-α-cyclodextrin | / | / | / | / | / | 20g |
| HP-β-CD | 20g | / | / | / | / | / |
| Hydropropyl-y-cyclodextrin | / | 20g | / | / | / | / |
| Alpha-cyclodextrin | / | / | 20g | / | / | / |
| Beta-schardinger dextrin- | / | / | / | 20g | / | / |
| Gamma-cyclodextrin | / | / | / | / | 20g | / |
Each comparative example in upper table adopts different cyclodextrin to carry out enclose respectively, and preparation technology, with embodiment 1, obtains the cyclodextrin clathrate of Alprostadil.
Embodiment 7 inclusion rate measures
By ether elution method, the clathrate that the invention process 1 and comparative example 1-5 adopt different cyclodextrin to prepare is carried out to the mensuration of inclusion rate, method is as follows: precision takes clathrate 0.2g, put in suitable measuring bottle, add 50ml ether jolting 10 minutes, filter, get filtrate evaporate to dryness, use dissolve with methanol residue, the concentration of the Alprostadil dissociated with Syrups by HPLC, calculates inclusion rate.Result is as follows.
Table 1 inclusion rate measurement result
| Embodiment | Comparative example 1 | Comparative example 2 | Comparative example 3 | Comparative example 4 | Comparative example 5 | Embodiment 1 |
| Inclusion rate | 48.6％ | 51.1％ | 49.3％ | 55.7％ | 53.4％ | 88.5％ |
Conclusion, from above-mentioned result of the test, the sample inclusion rate of the embodiment 1 adopting Hydroxyproply-α-cyclodextrin of the present invention to prepare, far away higher than the sample of the comparative example 1-5 adopting other cyclodextrin to prepare, has absolutely proved that Alprostadil of the present invention adopts the superiority of Hydroxyproply-α-cyclodextrin enclose.
Embodiment 8 study on the stability
Sample prepared by the embodiment of the present invention 1 and comparative example 1 ~ 5 is carried out study on the stability compare, the condition of investigation is (1) high temperature 60 DEG C 10 days; (2) intense light irradiation 4500Lx 10 days; (3) high temperature 40 DEG C 6 months, Testing index is character, content, pH and related substance.Result is as follows:
Table 20 day result
Table 3 high temperature 60 DEG C of 10 days results
Table semi-finals illumination 4500Lx 10 days results
Table 5 high temperature 40 DEG C of 6 months results
Conclusion: from above result of the test, sample stability prepared by the embodiment of the present invention 1 is better than product prepared by comparative example 1 ~ 5 far away, absolutely prove that the present invention adopts Hydroxyproply-α-cyclodextrin to carry out the useful effect of enclose, substantially increase the stability of Alprostadil, ensure that product quality.
Embodiment 9 bioavailability study
The product of comparative example 1-5 is adopted excipient respectively: dextran a, mannitol b, lactose c, sodium chloride d and glucose e, freeze-dried powder and injection is made according to the technique of the embodiment of the present invention 1 and embodiment 4 and excipient, after storing a period of time, the sample prepared with the embodiment of the present invention 1 and embodiment 4 carries out comparing of bioavailability.
Method: 30 Beagle dogs are divided into 6 groups at random, often organizes 5.Intravenous injection Alprostadil 40 μ g/ only, before administration (0 hour) and after taking medicine 10min, 20min, 30min, 45min, 1h, 1.5h, 2h, 3h, 4h and 6h get blood from dog hind leg vein and be about 1ml.Put in heparinization EP pipe, then add derivatization reagent, vibration, frozen centrifugation separated plasma.HPLC-MS/MS method is adopted to detect the content of Alprostadil in dog plasma sample.Blood concentration-time data, through DAS3.2 process, by the pharmacokinetic parameter of test preparation, must calculate relative bioavailability according to by test preparation AUC.
Result is as follows:
The bioavailability comparative result (dextran) of table 6 lyophilized formulations
| Freeze-dried powder | Embodiment 1a | Comparative example 1a | Comparative example 2a | Comparative example 3a | Comparative example 4a | Comparative example 5a |
| 10 days | 73.6％ | 58.3％ | 55.7％ | 59.6％ | 53.4％ | 54.4％ |
| 30 days | 73.8％ | 55.1％ | 53.8％ | 56.4％ | 49.6％ | 51.2％ |
| 2 months | 73.4％ | 50.2％ | 49.6％ | 52.2％ | 47.7％ | 47.0％ |
| 3 months | 73.5％ | 44.7％ | 45.5％ | 46.1％ | 40.5％ | 41.5％ |
| 4 months | 73.2％ | 37.6％ | 38.3％ | 39.6％ | 33.4％ | 32.5％ |
| 5 months | 73.0％ | 32.3％ | 30.0％ | 34.7％ | 29.5％ | 30.1％ |
| 6 months | 73.3％ | 30.4％ | 27.5％ | 31.1％ | 25.2％ | 27.6％ |
The bioavailability comparative result (mannitol) of table 7 lyophilized formulations
| Freeze-dried powder | Embodiment 1b | Comparative example 1b | Comparative example 2b | Comparative example 3b | Comparative example 4b | Comparative example 5b |
| 10 days | 74.1％ | 59.4％ | 58.7％ | 56.3％ | 58.0％ | 55.7％ |
| 30 days | 74.0％ | 56.3％ | 55.5％ | 53.7％ | 54.2％ | 52.0％ |
| 2 months | 73.8％ | 52.2％ | 50.9％ | 49.2％ | 51.3％ | 48.7％ |
| 3 months | 73.6％ | 48.4％ | 46.7％ | 44.9％ | 45.7％ | 42.2％ |
| 4 months | 73.5％ | 41.7％ | 40.5％ | 37.1％ | 41.8％ | 36.4％ |
| 5 months | 73.3％ | 35.8％ | 34.2％ | 32.0％ | 33.9％ | 31.0％ |
| 6 months | 73.2％ | 32.2％ | 31.9％ | 30.1％ | 32.6％ | 26.3％ |
The bioavailability comparative result (lactose) of table 8 lyophilized formulations
| Freeze-dried powder | Embodiment 1c | Comparative example 1c | Comparative example 2c | Comparative example 3c | Comparative example 4c | Comparative example 5c |
| 10 days | 75.3％ | 57.3％ | 56.3％ | 56.9％ | 54.8％ | 55.5％ |
| 30 days | 75.1％ | 53.5％ | 53.0％ | 53.3％ | 50.4％ | 50.7％ |
| 2 months | 75.0％ | 48.6％ | 48.9％ | 49.7％ | 46.1％ | 44.9％ |
| 3 months | 75.0％ | 43.2％ | 44.6％ | 44.0％ | 42.2％ | 40.4％ |
| 4 months | 74.8％ | 38.7％ | 39.5％ | 37.5％ | 36.1％ | 35.8％ |
| 5 months | 74.7％ | 34.1％ | 35.2％ | 33.3％ | 31.0％ | 32.3％ |
| 6 months | 74.5％ | 31.9％ | 32.3％ | 32.0％ | 28.4％ | 29.0％ |
The bioavailability comparative result (sodium chloride) of table 9 injection
| Injection | Embodiment 4d | Comparative example 1d | Comparative example 2d | Comparative example 3d | Comparative example 4d | Comparative example 5d |
| 10 days | 72.6％ | 60.4％ | 56.3％ | 57.7％ | 55.0％ | 53.7％ |
| 30 days | 72.2％ | 57.3％ | 53.0％ | 54.2％ | 50.5％ | 50.8％ |
| 2 months | 72.4％ | 52.2％ | 47.5％ | 51.3％ | 48.3％ | 46.5％ |
| 3 months | 72.0％ | 45.4％ | 43.9％ | 47.8％ | 43.2％ | 39.7％ |
| 4 months | 72.2％ | 38.1％ | 39.6％ | 40.1％ | 36.9％ | 33.3％ |
| 5 months | 71.4％ | 33.6％ | 31.4％ | 36.8％ | 32.8％ | 31.5％ |
| 6 months | 70.7％ | 31.8％ | 26.2％ | 30.9％ | 27.4％ | 28.6％ |
The bioavailability comparative result (glucose) of table 10 injection
| Freeze-dried powder | Embodiment 4e | Comparative example 1e | Comparative example 2e | Comparative example 3e | Comparative example 4e | Comparative example 5e |
| 10 days | 73.3％ | 59.6％ | 58.0％ | 56.8％ | 57.4％ | 58.2％ |
| 30 days | 73.3％ | 56.2％ | 54.4％ | 52.7％ | 53.2％ | 55.1％ |
| 2 months | 73.1％ | 52.7％ | 50.9％ | 48.5％ | 49.8％ | 51.4％ |
| 3 months | 73.0％ | 48.3％ | 45.5％ | 43.2％ | 45.1％ | 46.7％ |
| 4 months | 72.9％ | 43.5％ | 41.3％ | 37.1％ | 42.0％ | 41.9％ |
| 5 months | 72.7％ | 36.8％ | 36.9％ | 32.9％ | 37.5％ | 36.6％ |
| 6 months | 72.5％ | 32.7％ | 33.7％ | 28.7％ | 31.6％ | 30.3％ |
Conclusion: from above result of the test, after storing a period of time, the bioavailability of the embodiment of the present invention 1 is far superior to comparative example 1 ~ 5 and obtains freeze-dried powder with mannitol, lactose, dextran; And the sample bioavailability prepared of embodiment 4 is far superior to comparative example 1 ~ 5 and sodium chloride and glucose and obtains sample prepared by injection, describe the superiority of the present invention in guarantee bioavailability.
Claims (6)
1. a pharmaceutical composition, is characterized in that comprising Alprostadil, Hydroxyproply-α-cyclodextrin and pharmaceutically acceptable excipient.
2. pharmaceutical composition according to claim 1, it is characterized in that described Alprostadil and Hydroxyproply-α-cyclodextrin are present in pharmaceutical composition with the form of clathrate, pharmaceutically acceptable excipient is preferred for the excipient preparing injection.
3. pharmaceutical composition according to claim 1 and 2, is characterized in that in the clathrate of described Alprostadil and Hydroxyproply-α-cyclodextrin, and wherein the part by weight of Alprostadil and Hydroxyproply-α-cyclodextrin is 1:3 ~ 3000, preferred 1:50 ~ 1500.
4. pharmaceutical composition according to claim 1, is characterized in that it is injection.
5. pharmaceutical composition according to claim 4, it is characterized in that the injection of the clathrate of described Alprostadil and Hydroxyproply-α-cyclodextrin, the part by weight shared in whole preparation of the excipient wherein pharmaceutically accepted is 0.1 ~ 90%, preferably 0.3 ~ 60%.
6. according to claim 1
-pharmaceutical composition described in 4 any one, is characterized in that described pharmaceutically acceptable excipient is selected from as one or more in mannitol, lactose, dextran, xylitol, sorbitol, glucose, sodium chloride.
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| CN201510267786.8A CN104856947A (en) | 2015-05-18 | 2015-05-18 | Alprostadil hydroxypropyl-alpha-cyclodextrin inclusion compound injection |
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| CN201510267786.8A CN104856947A (en) | 2015-05-18 | 2015-05-18 | Alprostadil hydroxypropyl-alpha-cyclodextrin inclusion compound injection |
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| CN104856947A true CN104856947A (en) | 2015-08-26 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN201510267786.8A Pending CN104856947A (en) | 2015-05-18 | 2015-05-18 | Alprostadil hydroxypropyl-alpha-cyclodextrin inclusion compound injection |
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003101476A1 (en) * | 2002-05-29 | 2003-12-11 | New River Pharmaceuticals Inc. | Active agent delivery systems and methods for protecting and administering active agents |
| WO2005046699A1 (en) * | 2003-11-13 | 2005-05-26 | Ono Pharmaceutical Co., Ltd. | Freeze-dried article containing prostaglandin |
| CN1726921A (en) * | 2004-07-27 | 2006-02-01 | 中国人民解放军军事医学科学院毒物药物研究所 | Prostaglandin E 1Oral preparation |
| CN1726920A (en) * | 2004-07-27 | 2006-02-01 | 中国人民解放军军事医学科学院毒物药物研究所 | Prostaglandin E 1Nasal powder |
| CN104069114A (en) * | 2014-07-10 | 2014-10-01 | 韩彬 | Alprostadil oral preparation |
-
2015
- 2015-05-18 CN CN201510267786.8A patent/CN104856947A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003101476A1 (en) * | 2002-05-29 | 2003-12-11 | New River Pharmaceuticals Inc. | Active agent delivery systems and methods for protecting and administering active agents |
| WO2005046699A1 (en) * | 2003-11-13 | 2005-05-26 | Ono Pharmaceutical Co., Ltd. | Freeze-dried article containing prostaglandin |
| CN1726921A (en) * | 2004-07-27 | 2006-02-01 | 中国人民解放军军事医学科学院毒物药物研究所 | Prostaglandin E 1Oral preparation |
| CN1726920A (en) * | 2004-07-27 | 2006-02-01 | 中国人民解放军军事医学科学院毒物药物研究所 | Prostaglandin E 1Nasal powder |
| CN104069114A (en) * | 2014-07-10 | 2014-10-01 | 韩彬 | Alprostadil oral preparation |
Non-Patent Citations (1)
| Title |
|---|
| WILHELM HAMMES,ET. AL.: "Quantitative determination of α-cyclodextrin in human plasma by liquid chromatography/positive ion electrospray mass spectrometry", 《JOURNAL OF MASS SPECTROMETRY》 * |
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