CN1264596A - Polypeptide medicine as oral spray - Google Patents
Polypeptide medicine as oral spray Download PDFInfo
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- CN1264596A CN1264596A CN 00114318 CN00114318A CN1264596A CN 1264596 A CN1264596 A CN 1264596A CN 00114318 CN00114318 CN 00114318 CN 00114318 A CN00114318 A CN 00114318A CN 1264596 A CN1264596 A CN 1264596A
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- insulin
- soybean lecithin
- spray
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- promoter
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Abstract
A polypeptide-type medicine as absorbent of oral mucosa contains polypeptide medicine, promoter, cosolvent, flavouring, bacterial inhibitor and buffering solution of phosphate (pH=6.8-7.8). Its oray spray of insulin is suitable for diabetics with high safety.
Description
The invention provides the prescription and the preparation method of preparation polypeptide drug such as insulin oral spray.
Polypeptide drug is very easily degraded by gastric acid and multiple digestive enzyme in gastrointestinal tract, can not be directly oral, and can only drug administration by injection.Must be as insulin in injection half an hour before the meal, could blood sugar control, and want lifelong administration, the patient inconvenience that agonizes.Therefore study the non-injection administration preparation of safe, convenient and effective polypeptide drug, especially insulin, will greatly make things convenient for the disease patient.Insulin non-injection administration approach this century the seventies obtained bigger progress since just beginning to become the hot subject that countries in the world pharmacy circle is competitively studied, particularly the nineties.
Present alternative insulin administration approach has multiple.For example imbed the approach of insulin pump at intraperitoneal, be proved to be safety and metabolism is effective, be used for clinically abroad, but cost an arm and a leg, not general patient can bear.Also have the result to show that the method by bronchial mucosa absorption insulin has tempting application prospect, but this method also have some difficulties to capture.By embedding insulins such as liposome or polymer, making oral agents then uses, insulin is absorbed by small intestinal cell and enters the effect that blood reaches blood sugar lowering, but the bioavailability of medicament is low and medicament to be disposed fast from medicine-feeding part easily be the significant obstacle of oral insulin success.The relatively large research work that is just carrying out at present concentrates on the route of administration by the mucosa absorption of nose, eye, lung, mouth.The work of this respect obtains some progress through the exploration of more than ten years, but still there are some problems in the clinical practice of these approach, mainly is that bioavailability is low.
Because the polypeptide drug molecular weight is generally bigger, oral mucosa is difficult to absorb, therefore select suitable low toxicity absorption enhancer efficiently, and increase absorption area, and be the key that improves the polypeptide drug bioavailability.
The objective of the invention is to propose a kind of novel polypeptide drug oral mucosa and absorb spray.
With the insulin is example, and technical scheme of the present invention is as follows:
The component of polypeptide drug oral spray is: as polypeptide drug is insulin; As promoter is soybean lecithin; As cosolvent is propylene glycol and ethanol; As correctives is Borneolum Syntheticum; As antibacterial is phenol; As buffer solution is the phosphate buffered solution of pH=6.8～7.8.Its prescription is (per 1000 milliliters):
Insulin 5 000U-80 000U
Soybean lecithin 5-45g
Propylene glycol 5-45g
Borneolum Syntheticum 0-10g
Ethanol 0-15ml
Phenol 0-8g
Phosphate buffered solution (pH=6.8～7.8) is diluted to 1000ml
The preparation of insulin oral spray:
Get soybean lecithin by prescription, add the alcoholic solution of propylene glycol and Borneolum Syntheticum, slowly be stirred to soybean lecithin and dissolve fully; Insulin is dissolved in and is about total amount 2/3, in the phosphate buffer that contains phenol of pH=6.8～7.8.Constantly stirring under (400 ± 100 rev/mins), the phosphate buffered solution of insulin is slowly being joined in the propylene glycol solution of soybean lecithin, adding the back and continued stir about 10～30 minutes, adding phosphate buffer again to full dose.
This medicament spraying agent is a kind of Emulsion, and is moisture and oily, but need not to add in addition surfactant.As the soybean lecithin (oil) of medicine mucosa promoter of the present invention simultaneously also in this medicament as surfactant.
This preparation is packed in a kind of Packaging Bottle that has a quantitative atomizing pump, it can spray into the oral cavity as mist with insulin, on the mucosa of insulin attached to oral cavity and throat, can enter blood circulation rapidly by mucosa, this is a kind of increase medicament absorption area, improve infiltration rate, make things convenient for patient's novel non-injection administration mode.Yet there are no at present the report of similar insulin spray both at home and abroad.
In the insulin oral spray, insulin is a principal agent, but the permeability of its oral transmucosal administration is poor, must select suitable absorption enhancer for use for improving its blood sugar lowering rate.It is as a kind of nontoxic, safe and effective promoter that the present invention uses soybean lecithin.Because the poorly water-soluble of soybean lecithin needs to select suitable cosolvent.The present invention is an index with the blood sugar reducing function, has studied the solubilization-aid effect of propylene glycol.Experimental result shows that propylene glycol can increase soybean lecithin and promote the Absorption of oral mucosa to insulin, has determined their best proportioning by orthogonal experiment.
Insulin oral spray safety of the present invention, nontoxic.The long term toxicity test of insulin oral spray rat topical, dosage group are 4.5,9.0,18.0Ukg
-1, and normal saline matched group and excipient matched group.Carry out after 6 months, the part of each administration treated animal and overall condition and normal saline matched group are not relatively all found obviously unusual.
Insulin oral spray of the present invention has high bioavailability.The present invention is model with the normal rabbits, adopts euzymelinked immunosorbent assay (ELISA) to measure insulin content in its body, has studied the pharmacokinetics of insulin oral spray and has calculated its pharmacokinetic parameter.The result shows that behind normal rabbits mouth mucosa drug administration (1.5U/kg body weight), its serum insulin concentration raises rapidly, and peak time is 64 minutes, and peak concentration is 141.6 ± 6.4 μ U/ml, is reduced to the preceding foundation level of medication after 4 hours gradually.Compare with vehicle group, the serum insulin concentration of insulin mouth mucosa drug administration group and subcutaneous injection of insulin matched group rabbit all had significant difference (P＜0.05) in 30～120 minutes.Under this dosage, with subcutaneous injection of insulin matched group (0.5Ukg
-1) compare, the peak concentration and the peak time of serum insulin are basic identical, there was no significant difference (P＞0.1), and the average bioavailability of insulin oral spray is 29.2%.
That the insulin oral spray has is big with the oral mucosa contact area, absorb fast, blood sugar lowering rate characteristics higher, safe in utilization, therefore the invention of insulin oral spray will bring medication convenient to diabetics, alleviate the misery of drug administration by injection, thereby the present invention have bigger social benefit and economic interests.
The insulin oral spray of making according to technique scheme has good hypoglycemic effect.For example, the hyperglycemia animal and the intact animal's models such as (rat and rabbit) that adopt chemical reagent to bring out are leading indicator with the blood sugar lowering rate of insulin oral spray, and the main pharmacodynamics of insulin oral spray is studied.In zoopery, animal is anaesthetized with pentobarbital sodium, ligation esophagus to the administration 10 minutes; Behind the mouth mucosa drug administration, measured animal blood glucose with electronic induction blood glucose meter and electronic induction test strips, continue to measure 4～6 hours every 30 minutes.Establish subcutaneous injection of insulin (positive control) group and normal saline (negative control) group simultaneously.The result shows: 1. the oral administration dosage of the diabetes rat that brings out with streptozotocin mycin be 1,3,9Ukg-1, the blood sugar lowering rate is respectively 21.6%, 46.3%, 54.4%.2. with the oral administration dosage of the diabetic rabbit of model induced by alloxan be 0.5,1.5,4.5Ukg
-1, the blood sugar lowering rate is respectively: 26.2%, 50.8%, 55.8%.3. normal rat oral administration dosage be respectively 1,3,9Ukg
-1The time, the blood sugar lowering rate is respectively 30.7%, 51.6%, 58.4%.4. the oral administration dosage of normal rabbits be 0.5,1.5,4.5Ukg
-1, the blood sugar lowering rate is respectively 31.2%, 54.8%, 59.1%.5. the 3U/kg dosed administration is pressed in normal rat carbohydrate tolerance test, and the blood sugar lowering rate is 48.3%.
Claims (4)
1. polypeptide drug oral mucosa spray that absorbs the drug, form by polypeptide drug, promoter, cosolvent, correctives, antibacterial and buffer preparation, the prescription that it is characterized in that medicament is to be insulin 5 as polypeptide drug in every 1000ml, 000U-80,000U, as promoter is soybean lecithin 5-50g, as cosolvent is propylene glycol 2-45g, ethanol 0-15ml, as correctives is Borneolum Syntheticum 0-10g, as antibacterial be phenol 0-8g, as buffer solution is the phosphate buffered solution of pH=6.8～7.8.
2. it is characterized in that soybean lecithin according to the said medicament spraying agent of claim 1 as medicine spray promoter, soybean lecithin also in this medicament as surfactant.
3. polypeptide drug oral mucosa spray that absorbs the drug, form by polypeptide drug, promoter, cosolvent, correctives, antibacterial and buffer preparation, its compound method is, get soybean lecithin by prescription, add the alcoholic solution of propylene glycol and Borneolum Syntheticum, slowly be stirred to soybean lecithin and dissolve fully; Insulin is dissolved in and is about total amount 2/3, pH=6.8～7.8 contain phenol phosphate buffer in; Constantly stirring under (400 ± 100 rev/mins), the phosphate buffered solution of insulin is slowly being joined in the propylene glycol solution of soybean lecithin, adding the back and continued stir about 10～30 minutes, adding phosphate buffer again to full dose.
4. polypeptide drug oral mucosa spray that absorbs the drug is formed by polypeptide drug, promoter, cosolvent, correctives, antibacterial and buffer preparation, it is characterized in that this kind medicament is used for the spray of patient's mouth mucosa absorption.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB001143182A CN1163263C (en) | 2000-01-07 | 2000-01-07 | Polypeptide medicine as oral spray |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB001143182A CN1163263C (en) | 2000-01-07 | 2000-01-07 | Polypeptide medicine as oral spray |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1264596A true CN1264596A (en) | 2000-08-30 |
| CN1163263C CN1163263C (en) | 2004-08-25 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB001143182A Expired - Lifetime CN1163263C (en) | 2000-01-07 | 2000-01-07 | Polypeptide medicine as oral spray |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003013589A1 (en) * | 2001-08-08 | 2003-02-20 | Huazhong University Of Science & Technology | Isulin-containing oral spray and the preparation method thereof |
| WO2006026922A1 (en) * | 2004-09-08 | 2006-03-16 | The Chinese University Of Hong Kong | Method of enhancing absorptions of transmucosal administration formulations |
| US10543169B2 (en) | 2013-11-07 | 2020-01-28 | Generon (Shanghai) Corporation Ltd. | Use of IL-22 dimer in manufacture of a medicament for intravenous administration |
| CN110801515A (en) * | 2019-10-22 | 2020-02-18 | 王晶 | Insulin oral spray and preparation process method thereof |
| US10786551B2 (en) | 2007-08-06 | 2020-09-29 | Generon (Shanghai) Corporation Ltd. | Use of interleukin-22 in the treatment of fatty liver disease |
| US11510966B2 (en) | 2016-04-15 | 2022-11-29 | Evive Biotechnology (Shanghai) Ltd | Use of IL-22 in treating necrotizing enterocolitis |
-
2000
- 2000-01-07 CN CNB001143182A patent/CN1163263C/en not_active Expired - Lifetime
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003013589A1 (en) * | 2001-08-08 | 2003-02-20 | Huazhong University Of Science & Technology | Isulin-containing oral spray and the preparation method thereof |
| WO2006026922A1 (en) * | 2004-09-08 | 2006-03-16 | The Chinese University Of Hong Kong | Method of enhancing absorptions of transmucosal administration formulations |
| AU2005282135B2 (en) * | 2004-09-08 | 2009-01-22 | The Chinese University Of Hong Kong | Method of enhancing absorptions of transmucosal administration formulations |
| US10786551B2 (en) | 2007-08-06 | 2020-09-29 | Generon (Shanghai) Corporation Ltd. | Use of interleukin-22 in the treatment of fatty liver disease |
| US10543169B2 (en) | 2013-11-07 | 2020-01-28 | Generon (Shanghai) Corporation Ltd. | Use of IL-22 dimer in manufacture of a medicament for intravenous administration |
| US11654104B2 (en) | 2013-11-07 | 2023-05-23 | Evive Biotechnology (Shanghai) Ltd | Use of IL-22 dimer in manufacture of a medicament for intravenous administration |
| US11510966B2 (en) | 2016-04-15 | 2022-11-29 | Evive Biotechnology (Shanghai) Ltd | Use of IL-22 in treating necrotizing enterocolitis |
| CN110801515A (en) * | 2019-10-22 | 2020-02-18 | 王晶 | Insulin oral spray and preparation process method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1163263C (en) | 2004-08-25 |
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