CN101057972A - Alcohol-free transdermal analgesic composition and processes for manufacture and use thereof - Google Patents
Alcohol-free transdermal analgesic composition and processes for manufacture and use thereof Download PDFInfo
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- CN101057972A CN101057972A CNA2006101453752A CN200610145375A CN101057972A CN 101057972 A CN101057972 A CN 101057972A CN A2006101453752 A CNA2006101453752 A CN A2006101453752A CN 200610145375 A CN200610145375 A CN 200610145375A CN 101057972 A CN101057972 A CN 101057972A
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Abstract
The instant invention is directed toward a dermal delivery system composition comprising an aqueous base vehicle including Emu oil, at least one fatty acid alkyl ester, polyethylene glycol, and at least one gelling/emulsifying agent, in combination with at least one analgesic composition, such as ibuprofen, and to processes for the manufacture and use thereof.
Description
The cross reference of related application
The application is the partial continuous application of U.S. Patent application 10/412,637 co-pending when submitting on April 11st, 2003, and its content is hereby incorporated by.
Technical field
The present invention relates to be used for percutaneous drug delivery system bonded analgesic composition and the methods for making and using same thereof pure of percutaneous dosing with nothing.
Background technology
Insulin is a kind of hormone of natural generation, by the β emiocytosis on Langerhans in the pancreas (Langerhans) island, replys the glucose level that raises in the blood.The metabolism of this hormonal regulation glucose and with fat, process that carbohydrate is relevant with the protein intermediate supersession.Insulin reduces blood glucose levels and promotes glucose to the transhipment of muscle cell and other tissue with enter.Because the chemical property of insulin molecule, for the glycosuria patient of daily requirement number dose insulin, traditional insulin administration approach is Intradermal or subcutaneous injection.
The percutaneous insulin delivery system that prior art is devoted to develop a kind of non-injection carries out treatment of diabetes, but not success so far.Although the topical of the excipient by containing insulin can with the insulin system be transferred to the patient, the verified system's blood levels by the attainable insulin of this medication is not enough to satisfy glycosuria patient's needs usually.
Developed the percutaneous dosing that the whole bag of tricks is used to improve insulin, comprised that the infiltrative passive diffusion carrier of improved raising epidermis, ultrasound wave import method, iontophoresis and ion ultrasonic (ionosonic) introductory technique.Be successfully used to the transmission of low-molecular-weight lipophilic drugs by the passive diffusion of skin outer layer, as scopolamine, estradiol and nitroglycerine, but for the percutaneous dosing of lipophilic peptide, for example insulin, because the low dermal osmosis power of these peptides, not success to a great extent.Therefore, use mechanical vibrational energy and/or iontophoresis improve dermal osmosis power and promote the percutaneous insulin administration.Sibalis etc. are at U.S. Patent number 4,940, disclose a kind of apparatus and method that are used for the insulin percutaneous dosing of iontophoresis mediation in 456.Henley is at U.S. Patent number 5,667, discloses a kind of being applicable in 487 and 5,658,247 and will treat the ultrasonic ion unit of reagent by the skin conveying by ultrasonic ion method mediation.Insulin has the trend that forms dimer and six aggressiveness in pharmaceutical composition, it is excessive that these polymers are considered to volume for percutaneous dosing.Brange is at U.S. Patent number 5,597, proposed chemically modified insulin in 796 producing insulin analog, and this analog can be resisted the intermolecular interrelated and conveying that improved iontophoresis.Jang etc. are at U.S. Patent number 5,681, disclose a kind of paster that contains insulin in 580, and this insulin is mixed with gel, and this paster is used for the percutaneous dosing of the insulin that iontophoresis drives.Although there is the progress of above-mentioned insulin percutaneous dosing method, up to now also can not be with insulin capacity percutaneous dosing in the glycosuria blood samples of patients, to reach treatment level.
Percutaneous dosing application clinically is limited, because few medicine at least only by passive diffusion, can produce the efficient system drug level with enough speed skin permeations in patient's body.The skin of skin, horny layer are low-molecular-weight and (particularly) high molecular medicine advance blood by skin diffusion main barriers.Insulin is the medicine that a kind of quilt is explored effective transdermal delivery system for a long time, is a kind of be used to control I type (juvenile form) and II type (adult) treatment of diabetes reagent.Insulin is regretted, and becomes an example that can't diffuse through cuticular molecule with the treatment effective speed easily.
Although existing in the prior art trial exploitation contains the percutaneous " paster " of specified quantitative insulin, wherein insulin can be transported by special speed, and these pasters exist a large amount of limitations.Special limitation is that the insulin user must often be adjusted the related request that their body movement and carbohydrate are taken in.In addition, there is dissimilar insulins, for example long lasting and fugitive, the necessary developing ability of patient, the insulin that mixes variety classes and consumption is to control their blood sugar level fully.Use with multiple paster of different dose intensities and insulin replies feature has problems thus.
Still need for a long time thus a kind of insulin the percutaneous drug delivery system make things convenient for form, example gel or cream, this form can be made prescription with the insulin compounds with different release characteristics, dosage can be defined as the function of employed volume thus.
Prior art
United States Patent (USP) 6,416,772 have instructed the local skin anaesthetic composition that eases the pain, and said composition contains the alcohol of about 57-91wt%; The glycerol of about 1-12wt%; The analgesic of about 2-28wt%, this analgesic comprises salicylic derivant; The dimethyl sulfone (MSM) of about 0.02-5wt%; And Dromaius novaehollandiae (Emu) oil of about 0.01-3wt%.This component produces percutaneous pain when analgesic is applied directly to afflicted areas.
Alcohol, preferred alcohol or isopropyl alcohol according to announcement, are effectively to dissolve analgesic that it can be absorbed by skin is necessary.Secondly, need the stabilizing agent of glycerol, thus the sale effect duration that alcohol can the appreciable impact component as aspirin, triethanolamine Salicylate or other analgesic.It is essential that glycerol also is considered to abundant dispersion analgesic, so needn't rock or stir component before use the part.Introduce dimethyl sulfone (MSM) and fat of Oromaius norvaehollandeae and be considered to help to quicken the absorption of skin component, and because the feature that eases the pain of itself, they make analgesic more effective, have improved the effect of component.
The compositions that this patent can effectively ease the pain when instruction is not used for the regional tip of various trigger point, uncomfortable real sensation.In addition, ' 772 patent need be used alcohol when percutaneous dosing, and alcohol causes the degraded of analgesic, needs glycerol to stop the alcohol degraded as stabilizing agent thus.
United States Patent (USP) 6,346,278 have instructed lipid-soluble extract with blue or green limit mussel (Perna canaliculus) or Mytilus edulis (Mytilus edulis) as the active component in the compositions that is applicable to percutaneous dosing, said composition comprises ointment or lotion base material or excipient, can comprise that skin penetration enhancer is to assist the administration of active component.Suitable base material or excipient are oil, as olive oil or fat of Oromaius norvaehollandeae, and can be separately or with penetrating agent such as eucalyptole or limonene administration.
United States Patent (USP) 6,444,234 have instructed a kind of pharmaceutical composition that contains alcohol, carry out the percutaneous dosing of medicine or other active agent by the topical to the skin of people or other animal.The method of preparing these components is based on transdermal delivery system (TDS), this system's Chinese medicine modified and specific solvent and solvent and solute dressing agent and skin combination of stabilizers formation mixture true solution, this method makes medicine by fast Absorption, shift and, simultaneously skin irritation and/or immunoreation are minimized by skin arrival fatty tissue or vascular system.Analgesic such as ibuprofen and analog thereof, MSM and fat of Oromaius norvaehollandeae are considered to and can be used in combination with transdermal delivery system.
United States Patent (USP) 6,528,040 has instructed the prescription based on fat of Oromaius norvaehollandeae as analgesic, anesthetis and pruritus.Prescription contains 0.01 to 13wt% Arrcostab; And 20 to 70wt% fat of Oromaius norvaehollandeae; 10 to 33wt% benzyl alcohol; 10 to 33% Benzoinum; 0.2 allantoin to 2wt%; 0.25 to the nipagin of 1.25wt% and 0.01 to 0.30wt% propyl parabene.This prescription can be made into spraying or percutaneous prescription, can be used to treat chronic skin ulcer and burn wound.
United States Patent (USP) 5,885,597 have instructed a kind of local prescription that is used to alleviate the patient suffering, and this prescription basic composition is the combination of at least a corticoid class analgesic of effective dose, at least a aromatic acid class analgesic and at least a para-aminobenzoic acid ester type local anesthetic; With the capsaicin compositions of the raising pain relief effect of effective dose, and at least a phospholipid of its skin turn-over capacity of the raising of effective dose and at least a polyoxyethylene polyoxypropylene copolymer.
U.S. Patent application 20030031724 has been instructed from Dromaius novaehollandiae, the cost-effective component that Dromiceiusnovaehollandiae derives or prepares, and this component can be used as the intravital antiinflammatory of patient.This application is not imagined MSM or analgesic in the percutaneous dosing environmental applications.
U.S. Patent application 20010033838 has been instructed fat of Oromaius norvaehollandeae and various fraction thereof the carrier as antifungal, antibacterium and antiviral drugs and preparation.This application has instructed being used in combination of MSM and fat of Oromaius norvaehollandeae, but when the needs percutaneous dosing, fat of Oromaius norvaehollandeae is substituted by liposome component or oiliness percutaneous composition.
United States Patent (USP) 6,024,975 disclose a kind of by polymer skin reinforcing agent and pharmaceutical actives are used in patient skin and the macromolecule medicine of percutaneous dosing.Medicine can be incapsulated or drug solution is partly incapsulated part and dissociate.The skin reinforcing agent that needs is a polyvinylpyrrolidone (PVP) and it is with 7-35% and medicament mixed.Optionally add volume and reach 20% gellant.Chemical system preferably carries out administration by the combination of multiple dose transdermal drug paster, and this combination comprises the non-property of the medicine that is pressed into a series of cells holder.Every cell is between the storage of the active medicine that is designed to percutaneous dosing of unit dose.This holder adhesion is fixed on the patient skin.Provide independent device can be encapsulated into medicine again in making between each stores.This individual packages device can be removed and discharge unit dose and contact with patient skin, and the percutaneous that can accurately control pharmaceutical actives absorbs.The patent disclosure major part makes up about transdermal drug, and the combination about forming between being stored by a plurality of unit dose more specifically has between wherein each stores and independently opens and discharge the device that can heavily seal thing, with initialization with control Drug therapy.But according to proposal, medicine also can be with the cream administration.All prescriptions all need polyvinylpyrrolidone.
U.S. Patent number 6,444,240 disclose preparation is used for the compositions that contains insulin of topical and the method that said composition is used for the wrinkle beauty therapeutic.
Summary of the invention
The invention discloses a kind of percutaneous drug delivery set of systems compound that comprises water base excipient, comprise at least a fatty acid alkyl esters, Polyethylene Glycol-8 (PEG-8), fat of Oromaius norvaehollandeae and gellant with 13 to 30 six carbon atoms.In order to improve dermal osmosis power, can in said composition, add dimethyl sulfone (MSM).One or more biologically active insulin compositions are added in this water base excipient.
The example of suitable fatty acid alkyl esters comprises, but be not limited to methyl laurate, methyl myristate, methyl hexadecanoate, methyl stearate, methyl behenate, ethyl oleate, Ethyl linoleate, butyl oleate, butyl stearate, isopropyl myristate, isopropyl palmitate, dodecyl acetate, sad tetradecane ester, cetyl palmitate and stearic stearolactone.
Above-mentioned fatty acid alkyl esters promotes chemical combination and can add in the prescription that its amount is the about 31.0wt% of about 0.001-of compositions, preferably approximately 3wt%.
Can be used for suitable gelling/emulsifying agent of the present invention and comprise guar gum, xanthan gum, carrageenan (carrageenan), cellulose, hydroxy alkyl cellulose, carboxycellulose sodium, SEPIGEL 305, gelatin, agar, starch or analog.SEPIGEL 305 is trade marks, and (Fairfield NJ) makes by Seppic company.SEPIGEL 305 is a kind of gelling/emulsifying agents, comprises about 40% polyacrylamide, about 15% C
13-C
14Isoparaffin and about 5% laureth-7 and suitable quantity of water.
Add gelling/emulsifying agent reaching required viscosity in this prescription, its amount can be about 0.001 to about 31.0wt%, preferably approximately 3wt%.
The preferred Polyethylene Glycol that uses among the present invention is that (trade mark PROTACHEM400 is by Protameen Chemical, Inc. for PEG-8, Totawa, NJ makes), its addition in this prescription be compositions about 0.001 to approximately to about 31.0wt%, preferably approximately 3wt%.In this prescription, add fat of Oromaius norvaehollandeae and promote the absorption of said composition in skin.Fat of Oromaius norvaehollandeae the amount in the present invention prescription of can adding is about 0.001 to about 31.0wt%.
In a preferred implementation, the present invention openly comprises the percutaneous drug delivery set of systems compound of water base excipient, comprise fat of Oromaius norvaehollandeae (U.S.), isopropyl palmitate (trade mark PROTACHEMIPP, by Protameen Chemical, Inc., Totawa, NJ makes), PEG-8 and SEPIGEL305 (selling) by Seppic company.Also can comprise dimethyl sulfone (MSM) and promote the absorption of said composition in skin.
With one or more biologically active insulin compositions, add in this excipient as HUMALOG.
Opposite with the use of insulin injection, local cream of the present invention has the strong point that does not require that patient or caretaker inject; The patient also needn't carry and/or transport the essential tool that is used to inject in order to inject.
Percutaneous drug delivery system in this explanation does not contain alcohol, does not therefore have the problem of the effect duration shortening relevant with the prior art formula that contains alcohol.Because do not use alcohol, the existence of glycerol is optional equally.Therefore, provide a kind of percutaneous drug delivery system of no alcohol of uniqueness, this system has improved the penetration to skin, become thus replace capsule and tablet safer, effect rapidly and the method that is easy to realize.
Therefore, the purpose of this invention is to provide a kind of alcohol that do not have, be used for effectively treating the cream fast skin drug-supplying system of the analgesic composition transdermal dosage of diabetes.
Another object of the present invention provides a kind of method for preparing described percutaneous drug delivery system.
In conjunction with appended accompanying drawing, by illustration of the present invention and embodiment, specific implementations, other purpose of the present invention and benefit are conspicuous according to following explanation.
The specific embodiment
The percutaneous drug delivery system that can improve dermal osmosis power in order to simplify the operation is necessary to understand the parameter that influences this phenomenon.
Influence the various factors of dermal osmosis power:
1) oil-soluble (J Pharm Sci " Linear relationships between lipophiliccharacter and biological activity of drugs. " 1972 Jan; 61 (1): 1-19) oil-soluble of material (lipotropy) is good more, and dermal osmosis power is strong more;
2) molecular weight (molecule is more little, easy more infiltration);
3) penetration of cream, gel and liquid is better than solid;
4) penetration enhancers improves local absorption (Targeted drug delivery tothe skin and deeper tissues:role of physiology, the solute structure and disease of lipophilic substance; Clin Exp Pharmacol Physiol 1997 Nov; 24 (11): 874-9).
Embodiment 1
This paper provides indefiniteness explanation embodiment; Following just embodiment and can not independently represent notion of the present invention disclosed herein.
According to preferred implementation of the present invention, the batching of excipient base material has following composition:
| Component | Amount (wt%) |
| U.S. fat of Oromaius norvaehollandeae isopropyl palmitate PEG-8 SEPIGEL 305 dimethyl sulfone water (deionized water) | ～3％ ～3％ ～4％ ～3％ *～0.75% surplus |
(
*Gelling if desired additionally increases by 1%)
Preparation steps:
In order to prepare aforesaid insulin transdermal delivery system/compositions, carry out following operation:
1, active component is weighed, and per 1 gram cream adds about 1 HUMALOG of unit insulin;
2, measure U.S.'s fat of Oromaius norvaehollandeae of 3%, add high-speed mixing device;
3, active component is added fat of Oromaius norvaehollandeae.Mixing enters oil until all powder.Mixture will be very dry;
4, measure isopropyl palmitate and PEG-8, add in the fat of Oromaius norvaehollandeae mixture;
5, mix half an hour;
6, add sterilized water, mixed 5 minutes, scraping mixes vessel wall once in a while;
7, the SEPICEL 305 of adding 3% mixed 5 minutes; If the denseness of also not realizing ideal, the SEPIGEL 305 of increase by 1% is until obtaining ideal denseness.
In order to prepare insulin transdermal delivery system/compositions, abide by above step and carry out the effect that this transdermal delivery system is determined in subsequently experiment:
The application of the percutaneous cream of the insulin of institute's dose
1, measures about 1 gram mixture;
2, use it for the inboard friction of carpal joint until the dermal sensation drying;
3, measure glucose level in per 10 minutes and write down reading;
4, glucose level is reduced to below 50 in 30 to 40 minutes;
5, take in the reduction that 2 tablets of glucose tablets and 2 Hershey rods stop blood sugar level;
6, under 3 kinds of different occasions, repeat this experiment and confirm that thus insulin enters the variation that blood circulation influences sugar level in the health thus with treatment effective dose percutaneous.
According to the present invention, be to be understood that analgesic composition refers to be used for any insulin that is used alone or in combination for the treatment of diabetes, to produce any ideal effect.Such compositions by but be not limited to each para-insulin and be illustrated, as the mixing of short-acting insulin; Protamine zine insulin; Guarantee the insulin of basic concentration level and the fugitive control of additional generation that can be by second kind of prescription between more long-term, and their various combinations.
All patents and the publication mentioned among the present invention have illustrative to those skilled in the art in the invention.Quoted by reference with same degree in these all patents and publication, illustrated by reference respectively specially as each publication and quote.
Illustrated that particular form of the present invention, the present invention are not limited in the particular form of this description and demonstration or the arrangement of each several part although be understood that.In the case without departing from the scope of the present invention, it is apparent to one skilled in the art to carry out various modifications, and should not think that the present invention is subjected in the description showing and the restriction of the content of explanation.
One of ordinary skill in the art will readily recognize that the present invention is very suitable for realizing goal of the invention, obtain to mention and itself inherent result and benefit.Any chemical compound, method, step and technology in this explanation are the representatives of current preferred specific embodiments, be intended to the explanation and scope is not limited.That those skilled in the art will carry out that spirit of the present invention comprised and by variation and other application of the scope definition of claims.Although the present invention is illustrated in conjunction with specific preferred specific embodiments, be understood that the present invention who declares should not be subjected to the improper restriction of these specific specific embodiments.In fact, conspicuous to those skilled in the art should be within the scope of the appended claims to carrying out various modifications that described pattern of the present invention carries out.
Claims (7)
1, a kind of analgesic composition that is effective to the no alcohol of percutaneous dosing basic composition is:
At least a insulin of the gellant of at least a fatty acid alkyl esters of the fat of Oromaius norvaehollandeae of effective dose, effective dose, the Polyethylene Glycol of effective dose, gelling effective dose, treatment effective dose and the sterilized water of enough supplying 100%.
2. analgesic composition as claimed in claim 1, wherein said fatty acid alkyl esters comprise that at least one is selected from the composition in methyl laurate, methyl myristate, methyl hexadecanoate, methyl stearate, methyl behenate, ethyl oleate, Ethyl linoleate, butyl oleate, butyl stearate, isopropyl myristate, isopropyl palmitate, dodecyl acetate, sad tetradecane ester, cetyl palmitate and the stearic stearolactone.
3. analgesic composition as claimed in claim 1, wherein said gellant comprise that at least one is selected from the composition of guar gum, xanthan gum, carrageenan, cellulose, hydroxy alkyl cellulose, carboxycellulose sodium, SEPIGEL 305, gelatin, agar, starch or analog.
4. analgesic composition as claimed in claim 1, wherein said Polyethylene Glycol are Polyethylene Glycol-8.
5. analgesic composition as claimed in claim 1 also comprises the dimethyl sulfone of effective dose.
6, a kind of preparation is effective to the method for analgesic composition of the no alcohol of percutaneous dosing, comprising:
At least a insulin of treatment effective dose is provided;
The fat of Oromaius norvaehollandeae of effective dose is provided in high-speed mixing device;
Described insulin is added the component of also mixing in the described fat of Oromaius norvaehollandeae until the formation mix homogeneously;
In described homogeneous mixture, add the Polyethylene Glycol of the fatty acid alkyl esters of effective dose and effective dose and mix the sufficiently long time;
Add sterilized water and be mixed to even;
At least a gellant that adds effective dose is mixed to evenly and is gel-like consistency; With
If desired, add extra gellant, until the gel consistency of realizing ideal.
7. by the product of the described method of claim 6 preparation.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US11/407,379 US20060263439A1 (en) | 2003-04-11 | 2006-04-18 | Alcohol-free transdermal analgesic composition and processes for manufacture and use thereof |
| US11/407,379 | 2006-04-18 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101057972A true CN101057972A (en) | 2007-10-24 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2006101453752A Pending CN101057972A (en) | 2006-04-18 | 2006-11-24 | Alcohol-free transdermal analgesic composition and processes for manufacture and use thereof |
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| Country | Link |
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| CN (1) | CN101057972A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2486915A1 (en) * | 2011-02-14 | 2012-08-15 | Sanovel Ilaç Sanayi Ve Ticaret Anonim Sirketi | Topical pharmaceutical compositions comprising flurbiprofen and methylsulfonylmethane |
| CN108465105A (en) * | 2018-04-25 | 2018-08-31 | 福州大学 | A kind of percutaneous sustained release preparation of nanometer and preparation method thereof based on PAMAM dendrimer load insulins |
-
2006
- 2006-11-24 CN CNA2006101453752A patent/CN101057972A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2486915A1 (en) * | 2011-02-14 | 2012-08-15 | Sanovel Ilaç Sanayi Ve Ticaret Anonim Sirketi | Topical pharmaceutical compositions comprising flurbiprofen and methylsulfonylmethane |
| TR201101374A1 (en) * | 2011-02-14 | 2012-09-21 | Sanovel İlaç Sanayi̇ Ve Ti̇caret Anoni̇m Şi̇rketi̇ | Topical pharmaceutical compositions of flurbiprofen and methylsulfonylmethane. |
| CN108465105A (en) * | 2018-04-25 | 2018-08-31 | 福州大学 | A kind of percutaneous sustained release preparation of nanometer and preparation method thereof based on PAMAM dendrimer load insulins |
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