CN1726921A - Prostaglandin E 1Oral preparation - Google Patents
Prostaglandin E 1Oral preparation Download PDFInfo
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- CN1726921A CN1726921A CN 200410071032 CN200410071032A CN1726921A CN 1726921 A CN1726921 A CN 1726921A CN 200410071032 CN200410071032 CN 200410071032 CN 200410071032 A CN200410071032 A CN 200410071032A CN 1726921 A CN1726921 A CN 1726921A
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- pge
- cyclodextrin
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Abstract
The present invention relates to prostaglandin E
1Sublingual tablet, mouth paster or the buccal tablets of oral preparation, especially PGE1.
Description
Technical field:
The present invention relates to prostaglandin E
1Sublingual tablet, mouth paster or the buccal tablets of oral preparation, especially PGE1.
Technical background:
Prostaglandin E
1(PGE
1) have another name called Alprostadil (Alprostadil),
Its chemical name is: 11 α, and 15 (the S)-two hydroxyls-anti-prostenoic acid of 9-ketone-13-, structure is:
PGE
1Atomic water-soluble, its unstable chemcial property is to pH, wet, thermo-responsive.Contain beta-hydroxy ketone in its structure, easily dehydration generates PGA under acid, alkali condition
1, and under alkali condition, continue to take place rearrangement reaction generation PGB
1Thereby, lose the physiological and pharmacological activity.
PGE
1Be a kind of endogenous biological active substances, have multiple physiology, pharmacological action.Its expansible blood vessel, anticoagulant reduces gastric secretion, stimulates small intestinal, uterus wriggling.Can be used for prevention clinically and treat various cardiovascular and cerebrovascular diseases, male erectile dysfunction, serious peripheral blood vessel, adult respiratory distress syndrome etc., diseases such as adjuvant treating hepatitis, hyperlipidemia, diabetes, renal insufficiency, bronchial asthma, pancreatitis.
PGE
1In the gastrointestinal tract metabolism that easily is decomposed, therefore can not oral administration.Usually adopt drug administration by injection.The domestic and international at present PGE that has gone on the market
1Dosage form comprises: freeze-dried powder injection, injectable emulsion, topical cream agent, gel and urethral suppository etc.In process of clinical application, PGE
1There is tangible blood vessel irritation in injection, brings certain misery to the patient.In addition, existing PGE
1The preparation poor chemical stability needs stored refrigerated.Therefore, the clinical practice of this medicine has been subjected to very big restriction.
Summary of the invention:
For overcoming PGE in the prior art
1Defective that can not be oral, the inventor has now found that PGE
1Mix with cyclodextrin and and then mix with pharmaceutic adjuvant or carrier, obtain can oral administration PGE
1Preparation.Said preparation convenient drug administration, room temperature are down stable, are easy to store, and be rapid-action and good absorption arranged.
Therefore first aspect present invention relates to a kind of oral preparation, and it comprises PGE
1, cyclodextrin and pharmaceutic adjuvant or carrier.
Further aspect of the present invention relates to a kind of oral preparation, and it comprises the clathrate of PGE1 and cyclodextrin, pharmaceutical carrier or excipient.
According to the present invention, oral preparation of the present invention is preferably sublingual tablet, mouth paster or buccal tablet.
Among the present invention, Sublingual tablet means the tablet that places hypoglossis mucous membrane to use, and mouth paster means the tablet that adheres to oral cavity buccal mucosa use.
The cyclodextrin that uses among the present invention (CD) is said: the various soluble derivatives of α-CD, β-CD, γ-CD and above-mentioned cyclodextrin such as hydroxypropyl-α-CD, hydroxy propyl-Beta-CD, hydroxypropyl-γ-CD, carboxymethyl-β-CD, dimethyl-β-CD, sulfobutyl ether-β-CD etc. for example for suitable medicinal various cyclodextrin.
Pharmaceutic adjuvant that Sublingual tablet uses among the present invention or pharmaceutical carrier are adjuvant that uses in the pharmaceutical field or carrier, have said for example: diluent, disintegrating agent, lubricant, binding agent.PGE
1Cyclodextrin clathrate comprises any in the various soluble derivatives of α-CD, β-CD, γ-CD clathrate and above-mentioned cyclodextrin such as hydroxypropyl-α-CD, hydroxy propyl-Beta-CD, hydroxypropyl-γ-CD, carboxymethyl-β-CD, dimethyl-β-CD, the sulfobutyl ether-β-clathrates such as CD; Diluent is said for example: the mixture of monosaccharide such as mannitol, lactose, glucose, xylitol, sorbitol and Different Weight ratio thereof; Disintegrating agent has been said crospolyvinylpyrrolidone (PVPP), low-substituted hydroxypropyl cellulose (L-HPC), carboxymethyl starch sodium (CMS-Na), cross-linking sodium carboxymethyl cellulose (CCNa), corn starch etc. for example; Binding agent is said 2～5% hydroxypropyl emthylcellulose (HPMC) aqueous solution, 2～10% sodium carboxymethyl cellulose (CMC-Na), 5～10% polyvinylpyrrolidones (PVP) aqueous solution or ethanol solution etc. for example; Lubricant has been said stearic acid, Macrogol 4000 or 6000 etc. for example.
According to the present invention, in the clathrate of PGE1 cyclodextrin of the present invention, by weight, PGE
1Be 1.6～26.7%, cyclodextrin is 73.3～98.4%.
According to the present invention, oral preparation of the present invention such as Sublingual tablet comprise, in the oral preparation gross weight,
1.0～18%PGE
1Cyclodextrin clathrate,
80～90% diluent,
1～10% disintegrating agent,
0.5～1.0% lubricant,
0.5～1.0% binding agent.
According to the present invention, pharmaceutic adjuvant in mouth paster of the present invention or the adhesion tablet or carrier have been said bioadhesive material, lubricant, binding agent for example.PGE
1Cyclodextrin clathrate is said any in the various soluble derivatives of α-CD, β-CD, γ-CD clathrate and above-mentioned cyclodextrin such as hydroxypropyl-α-CD, hydroxy propyl-Beta-CD, hydroxypropyl-γ-CD, carboxymethyl-β-CD, dimethyl-β-CD, the sulfobutyl ether-β-clathrates such as CD for example; Bioadhesive material has been said carbopol (carbopol 934,940,941), sodium carboxymethyl cellulose (CMC-Na), hydroxypropyl cellulose (HPC), hyaluronic acid, poly-aspartic-acid, sulphuric acid dextran, chondroitin sulfate, polyvinyl sulfuric acid ester for example; Binding agent is said 2～5% hydroxypropyl emthylcellulose (HPMC) aqueous solution, 2～10% sodium carboxymethyl cellulose (CMC-Na), 5～10% polyvinylpyrrolidones (PVP) aqueous solution or ethanol solution etc. for example; Lubricant has been said stearic acid, Macrogol 4000 or 6000 etc. for example.The dosage specification of oral preparation of the present invention is 100～1000 μ g.
According to the present invention, in mouth paster of the present invention or the adhesion tablet preparation, with paster or the total restatement of adhesion tablet,
1.0%～18%PGE
1Cyclodextrin clathrate,
80～96% bioadhesive material,
0.1～1.0% binding agent,
0.5～1.0% lubricant.
The specific embodiment
The following examples are used for further specifying the present invention, but it does not mean that any limitation of the invention.
Embodiment 1 α-CD and PGE
1The preparation of clathrate:
Take by weighing PGE
150mg, with the 1ml anhydrous alcohol solution, α-CD 686mg mixes two liquid then with the 10ml dissolved in distilled water, and supersound process placed the freezer dryer lyophilization 24 hours after 10 minutes, and the dry thing of gained places vacuum desiccator to place 48 hours promptly.The moisture of last obtained freeze-drying thing should be controlled at below 1%.
Embodiment 2 HP-β-CD (substitution value=5.0) and PGE
1The preparation of clathrate:
Take by weighing PGE
150mg, with the 1ml anhydrous alcohol solution, HP-β-CD 1.9g mixes two liquid then with the 10ml dissolved in distilled water, and supersound process placed the freezer dryer lyophilization 24 hours after 5 minutes, and the dry thing of gained places vacuum desiccator to place 48 hours promptly.The moisture of obtained freeze-drying thing should be less than 1%.
Embodiment 3 β-CD and PGE
1The preparation of clathrate:
Take by weighing PGE
150mg, with the 1ml anhydrous alcohol solution, β-CD 1.6g mixes two liquid then with the 100ml dissolved in distilled water, and supersound process placed the freezer dryer lyophilization 24 hours after 5 minutes, and the dry thing of gained places vacuum desiccator to place 48 hours promptly.The moisture of obtained freeze-drying thing should be less than 1%.
Embodiment 4PGE
1The Sublingual tablet of-α-CD clathrate
Composition: PGE
1-α-CD clathrate 1.4mg (contains PGE
150 μ g)
Mannitol 96.6mg
Low-substituted hydroxypropyl cellulose (L-HPC) 11mg
Stearic acid 1mg
2% HPMC solution is an amount of
Preparation technology: get PGE
1-α-CD clathrate 1.4mg, mannitol 96.6mg, with equivalent progressively increase method with the two mixing after, add the L-HPC11.0mg mixing again, the HPMC solution with an amount of 2% is that binding agent prepares soft material, crossing 20 mesh sieves granulates, placed 50 ℃ of exsiccators 2 hours, after the sieve granulate of identical order number, mixing behind the adding stearic acid 1.0mg, compacting is 110mg heavily in flakes, contains 50 μ g PEG
1/ sheet.
Embodiment 5 PGE
1The Sublingual tablet of-beta-CD inclusion
Composition: PGE
1-beta-CD inclusion 3.3mg (contains PGE
1100 μ g)
Mannitol, lactose (9: 1 weight ratios) mixed powder 100.2mg
Crospolyvinylpyrrolidone (PVPP) 5.5mg
Macrogol 4000 (PEG4000) 1mg
10% CMC-Na solution is an amount of
Preparation technology: get PGE
1-beta-CD inclusion 3.3mg, progressively increase behind method and 100.2mg mannitol, the lactose mixed powder mixing with equivalent, add the 5.5mgPVPP mixing again, CMC-Na solution with 10% is that binding agent prepares soft material, crosses 20 mesh sieves and granulates, and places 50 ℃ of exsiccators 2 hours, sieve granulate after identical order number, mixing behind the adding 1.0mgPEG4000, compacting heavily is 110mg in flakes, hardness is at the tablet of 3～5kg.
Embodiment 6 PGE
1The preparation of-hydroxypropyl-beta-CD inclusion Sublingual tablet
Composition: PGE
1-HP-beta-CD inclusion 8mg (contains PGE
1200 μ g)
Lactose 90mg
L-HPC 11mg
Stearic acid 1mg
10% polyvinylpyrrolidone (PVP) solution is an amount of
Preparation technology: get PGE
1-HP-beta-CD inclusion 8.0mg, progressively increase behind method and the 90.0mg lactose mixing with equivalent, add the 11.0mgL-HPC mixing again, PVP solution with 10% is that binding agent prepares soft material, crosses 20 mesh sieves and granulates, and places 50 ℃ of exsiccators 2～3 hours, sieve granulate after identical order number, mixing behind the adding 1.0mg stearic acid, compacting heavily is 110mg in flakes, hardness is at the tablet of 3～5kg.
Embodiment 7 PGE
1The preparation of-sulfobutyl ether-beta-cyclodextrin inclusion compound Sublingual tablet
Composition: PGE
1-sulfobutyl ether-beta-cyclodextrin inclusion compound 16.3mg (contains PGE
1500 μ g)
Xylitol 81.7mg
Carboxymethyl starch sodium (CMS-Na) 11mg
Stearic acid 1mg
5% HPMC solution is an amount of
Preparation technology: get PGE
1-sulfobutyl ether-beta-cyclodextrin inclusion compound 16.3mg, progressively increase behind method and the 81.7mg xylitol mixing with equivalent, add carboxymethyl starch sodium 11.0mg mixing again, HPMC solution with 2% is that binding agent prepares soft material, crosses 20 mesh sieves and granulates, and places 50 ℃ of exsiccators dry 2～3 hours, sieve granulate after identical order number, mixing behind the adding 1.0mg stearic acid, compacting heavily is 110mg in flakes, hardness is the tablet of 3～5kg.
The made Sublingual tablet of the present invention, disintegration time are between 5～10 minutes, and the sublingual administration time is at 3～4 minutes, and stripping is more than 95% in external 15 minutes.Stability experiment is the result show, said preparation is at room temperature preserved, and has good stability.Human experimentation is the result show, said preparation nonirritant and bitterness, and mouthfeel is good, absorbs good.
The packing of the made Sublingual tablet of the present invention is drafted and is the single dose aluminium-plastic bubble plate packing.This Sublingual tablet should be preserved at shady and cool, lucifuge place.Instructions of taking is: each 1～2, place sublingual administration.
Embodiment 8 PGE
1-beta-CD inclusion oral cavity adhesion tablet
Composition: PGE
1-beta-CD inclusion 3.3mg (contains PGE
1100 μ g)
Carbopol 934 65mg
Hydroxypropyl cellulose (HPC) 30mg
Stearic acid 1mg
5% CMC-Na solution is an amount of
Preparation technology: get PGE
1-beta-CD inclusion 3.3mg, progressively increase behind method and hydroxypropyl cellulose (HPC) the 30.0mg mixing with equivalent, add 65.0mg Carbopol 934 mixings again, CMC-Na solution with 5% is that binding agent prepares soft material, crosses 20 mesh sieves and granulates, and places 50 ℃ of exsiccators dry 2 hours, sieve granulate after identical order number, mixing behind the adding 1.0mg stearic acid, compacting heavily is 100mg in flakes, hardness is at the tablet of 3～5kg.
Embodiment 9 PGE
1The oral cavity adhesion tablet of-hydroxypropyl-beta-CD inclusion
Composition: PGE
1-HP-beta-CD inclusion 8mg (contains PGE
1200 μ g)
Sodium carboxymethyl cellulose (CMC-Na) 40mg
Carbopol 940 50mg
Polyethylene glycol 6000 1mg
5% polyvinylpyrrolidone (PVP) alcoholic solution is an amount of
Preparation technology: get PGE
1-hydroxypropyl-beta-CD inclusion 8.0mg, progressively increase behind method and the sodium carboxymethyl cellulose 40.0mg mixing with equivalent, add 50.0mg Carbopol 940 mixings again, polyvinylpyrrolidone with 5% (PVP) solution is that binding agent prepares soft material, crosses 20 mesh sieves and granulates, and places 50 ℃ of exsiccators dry 2 hours, sieve granulate after identical order number, mixing behind the adding 1.0mg polyethylene glycol 6000, compacting heavily is 100mg in flakes, hardness is at the tablet of 3～5kg.
The made oral cavity adhesion tablet of the present invention is at room temperature preserved, and has good stability.Human experimentation is the result show, said preparation is to oral cavity cheek film good adhesion, nonirritant, and infiltration rate is fast.
Same Sublingual tablet is packed in drafting of this oral cavity adhesion tablet.Should preserve at shady and cool, lucifuge place.Using method is: each 1, adhere to a side oral cavity buccal mucosa.
The PGE of embodiment 10 embodiment of the invention 1-3
1The stability of clathrate
| Time (my god) | PGE 1Cyclodextrin clathrate content (%) | ||||
| PGE 1Former medicine | α-CD | β-CD | HP-β-CD (substitution value=2.5～3.0) | HP-β-CD (substitution value=5.0) | |
| 0 1 3 5 7 9 14 | 100 55.97 26.25 20.47 9.43 0 0 | 100 93.50 89.64 91.57 91.89 87.63 88.49 | 100 97.28 96.58 91.67 90.40 86.09 78.35 | 100 96.76 94.77 95.21 98.25 89.03 86.41 | 100 101.93 101.93 100.0 96.69 102.9 100 |
PGE
1Cyclodextrin clathrate results of stability (was 100% with 0 day content)
Embodiment 6PGE
1-HP-beta-CD inclusion Sublingual tablet room temperature reserved sample observing results of stability (3 months data)
| Lot number | 0 day labelled amount % | 90 days labelled amount % |
| 1 2 3 | 104.35 93.71 105.01 | 100.92 92.72 105.96 |
Get 3 batches of PGE1-HP-beta-CD inclusion Sublingual tablets, under the room temperature, measure their PGE in the Sublingual tablet in 90 days by embodiment 6 preparation
1Changes of contents, the result sees the above table.
PGE
1-HP-beta-CD inclusion Sublingual tablet pharmacodynamic study result:
Get 5 groups of rats, 10 every group, and every group be designated as A respectively, B, C, D and E.Will be by the PGE of embodiment 6 preparations
1The dissolving of-HP-beta-CD inclusion Sublingual tablet gives respectively to organize rat after disperseing to make even suspension through the Sublingual, observe PGE
1Blood pressure lowering, antiplatelet aggregation and anti-thrombosis function, to confirm the absorbing state of medicine.The results are shown in following table:
PGE
1-HP-beta-CD inclusion Sublingual tablet is to the influence (dosage is 500 μ g/kg) of rat blood pressure
| The drug effect peak time | Duration of efficacy | Area under the blood pressure drops %-time graph | ||
| Animal number | (min) | The maximum % of blood pressure drops | (min) | (AUC) |
| A B C D E average standard deviation | 35 60 30 15 40 36.0 16.4 | 8.63 9.23 7.1 10.97 7.46 8.68 1.54 | 70 85 70 70 90 77.0 9.7 | 362.59 305.77 315.48 460.97 473.88 383.74 79.49 |
PGE
1-HP-beta-CD inclusion Sublingual tablet is to the thrombotic influence of rat artery (dosage is 500 μ g/kg)
Get 3 groups of rats, 10 every group.3 groups are respectively intravenous injection, normal saline matched group and Sublingual tablet group.Wherein intravenous injection group vein gives 10 μ g PGE
1/ kg, normal saline matched group only give normal saline, and the Sublingual tablet group gives 500 μ g PGE through the Sublingual
1(pressing the preparation of embodiment 6 methods) the results are shown in following table.
| Group | Dosage (μ g/kg) | Wet weight of thrombus (mg) | Thrombosis suppresses (%) |
| Intravenous injection group normal saline matched group Sublingual tablet group | 10 0 500 | 15.1±1.3 28.4±3.9 14.2±1.5 | 46.8 0 50.0 |
Claims (10)
1, a kind of oral preparation, it comprises clathrate and the pharmaceutic adjuvant or the carrier of PEG1 and cyclodextrin.
2, the oral preparation of claim 1, it is a Sublingual tablet.
3, the oral preparation of claim 1, it is mouth paster or adhesion tablet.
4, the oral preparation of claim 2, it comprises
1.0～18%PGE
1Cyclodextrin clathrate,
80～90% diluent,
1～10% disintegrating agent,
0.5～1.0% lubricant,
0.5～1.0% binding agent.
5, the oral preparation of claim 3, it comprises
1.0%～18%PGE
1Cyclodextrin clathrate,
80～96% bioadhesive material,
0.1～1.0% binding agent,
0.5～1.0% lubricant.
6, the oral preparation of claim 4, wherein PGE in the Sublingual tablet
1Cyclodextrin in the cyclodextrin inclusion is selected from any among hydroxypropyl-α-CD, hydroxy propyl-Beta-CD, hydroxypropyl-γ-CD, carboxymethyl-β-CD, dimethyl-β-CD, the sulfobutyl ether-β-CD; Diluent is selected from the mixture of monosaccharide such as mannitol, lactose, glucose, xylitol, sorbitol and Different Weight ratio thereof; Disintegrating agent is selected from crospolyvinylpyrrolidone (PVPP), low-substituted hydroxypropyl cellulose (L-HPC), carboxymethyl starch sodium (CMS-Na), cross-linking sodium carboxymethyl cellulose (CCNa), corn starch; Binding agent is selected from 2～5% hydroxypropyl emthylcellulose (HPMC) aqueous solution, 2～10% sodium carboxymethyl cellulose (CMC-Na), 5～10% polyvinylpyrrolidones (PVP) aqueous solution or ethanol solution; Lubricant is selected from stearic acid or its magnesium salt, Macrogol 4000 or 6000.
7, the oral preparation of claim 5, PGE in mouth paster wherein of the present invention or the adhesion tablet
1Cyclodextrin is selected from any among hydroxypropyl-α-CD, hydroxy propyl-Beta-CD, hydroxypropyl-γ-CD, carboxymethyl-β-CD, dimethyl-β-CD, the sulfobutyl ether-β-CD in the cyclodextrin clathrate; Bioadhesive material is selected from carbopol (carbopol 934,940,941), sodium carboxymethyl cellulose (CMC-Na), hydroxypropyl cellulose (HPC), hyaluronic acid, poly-aspartic-acid, sulphuric acid dextran, chondroitin sulfate, polyvinyl sulfuric acid ester; Binding agent is selected from 2～5% hydroxypropyl emthylcellulose (HPMC) aqueous solution, 2～10% sodium carboxymethyl cellulose (CMC-Na), 5～10% polyvinylpyrrolidones (PVP) aqueous solution or ethanol solution etc.; Lubricant is selected from stearic acid, Macrogol 4000 or 6000.
8, claim 6 or 7 preparation, it comprises PGE
1-α-CD clathrate, mannitol, low-substituted hydroxypropyl cellulose and stearic acid.
9, claim 6 or 7 preparation, it comprises PGE
1-beta-CD inclusion, mannitol, lactose, crospolyvinylpyrrolidone, Macrogol 4000,10%CMC-Na.
10, claim 6 or 7 preparation, it comprises PGE
1-HP-beta-CD inclusion, lactose, low-substituted hydroxypropyl cellulose, stearic acid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2004100710327A CN100542537C (en) | 2004-07-27 | 2004-07-27 | Prostaglandin E 1Oral preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2004100710327A CN100542537C (en) | 2004-07-27 | 2004-07-27 | Prostaglandin E 1Oral preparation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1726921A true CN1726921A (en) | 2006-02-01 |
| CN100542537C CN100542537C (en) | 2009-09-23 |
Family
ID=35926560
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2004100710327A Expired - Fee Related CN100542537C (en) | 2004-07-27 | 2004-07-27 | Prostaglandin E 1Oral preparation |
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| Country | Link |
|---|---|
| CN (1) | CN100542537C (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104069114A (en) * | 2014-07-10 | 2014-10-01 | 韩彬 | Alprostadil oral preparation |
| CN104856947A (en) * | 2015-05-18 | 2015-08-26 | 海南圣欣医药科技有限公司 | Alprostadil hydroxypropyl-alpha-cyclodextrin inclusion compound injection |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS503362B1 (en) * | 1970-06-10 | 1975-02-04 | ||
| CN1155384C (en) * | 2000-09-21 | 2004-06-30 | 侯文阁 | Cyclodextrin encapsulated freeze-dried powder injection of prostaglandin E1 |
| CN1176658C (en) * | 2002-08-12 | 2004-11-24 | 蔡海德 | Aseptic freeze-dried prostaglandin injection and its preparing method and use |
-
2004
- 2004-07-27 CN CNB2004100710327A patent/CN100542537C/en not_active Expired - Fee Related
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104069114A (en) * | 2014-07-10 | 2014-10-01 | 韩彬 | Alprostadil oral preparation |
| CN104856947A (en) * | 2015-05-18 | 2015-08-26 | 海南圣欣医药科技有限公司 | Alprostadil hydroxypropyl-alpha-cyclodextrin inclusion compound injection |
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| Publication number | Publication date |
|---|---|
| CN100542537C (en) | 2009-09-23 |
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