CN101919799B - Novel sustained-release transdermal medicament delivery system - Google Patents
Novel sustained-release transdermal medicament delivery system Download PDFInfo
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- CN101919799B CN101919799B CN2009102598659A CN200910259865A CN101919799B CN 101919799 B CN101919799 B CN 101919799B CN 2009102598659 A CN2009102598659 A CN 2009102598659A CN 200910259865 A CN200910259865 A CN 200910259865A CN 101919799 B CN101919799 B CN 101919799B
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Abstract
The invention discloses a novel sustained-release transdermal medicament delivery system for treating ulcer and wound surface. The system contains an auxiliary material with a biological adhesion effect. The system is a dry gel preparation prepared by blending the auxiliary material and an active medicament and then performing freeze drying on the mixture. After being hydrated on the ulcer and the wound surface, the preparation tightly contacts the ulcer and the wound surface, so that the residence time of the medicament on the ulcer and the wound surface is obviously prolonged and the treatment effect of the medicament is fully brought into full play; at the same time, the preparation has good elasticity and flexibility, so that the preparation inosculates with the biological curve of the ulcer or the wound surface; and after being hydrated, the preparation is formed into a gel and the active medicament dispersed in the gel is slowly released onto an action part, so that the action time of the medicament is prolonged. At the same time, the gel formed after the medicament is hydrated plays a role in isolating and protecting the wound surface and can quicken the concrescence of the wound surface. The preparation is small and light, has no foreign body sensation and peculiar smell and is suitable for all patients.
Description
Technical field
This invention belongs to the research of newtype drug medicine-releasing system; Relate to the application of a kind of novel sustained-release transdermal medicament delivery system in field of medicaments, relate in particular to macromolecular material that a kind of utilization has a bio-adhesive effect as carrier and use the sustained-release transdermal medicament delivery system of freeze drying process preparation.
Background technology
Oral ulcer is a kind of very common clinically disease of cari oris mucosa, claims aphtha again, and pain is very obvious during outbreak, but untreated and spontaneous recovery.The outbreak repeatedly that also has is called recurrent oral ulceration, and patient's work and life caused very big influence.Oral ulcer prevalence in the crowd it is generally acknowledged at 10-30%, can betide men and women, old and young, sees at most with the young and the middle aged.Oral ulcer can betide any position of oral mucosa, sees with lip, cheek, tongue more, and severe patient can involve pharyngeal mucosa.Much patients are along with the prolongation of the course of disease, and the ulcer area increases, and number increases, and pain increases the weight of, and healing stage prolongs, and shorten interval etc., and influence is taken food and spoken.
The concrete pathogenic factor of oral ulcer does not still have final conclusion so far, and most of doctors think that oral ulcer is relevant with following factor:
Digestive system disease and dysfunction: like situation such as abdominal distention, diarrhoea or constipation.
Hormonal change: some female patient often takes place in menstrual phase, possibly descend relevant with body inner estrogen amount.
Nervous and Mental Factors: the patient who has falls ill under the not good situation of psychentonia, anxious state of mind, sleep state, maybe be relevant with autonomic nervous dysfunction.
Inherited genetic factors: when all suffering from recurrent oral ulceration like father and mother both sides, its children have 80-90% ill approximately, and when suffering from this disease as if one of parents, its children have 50-60% ill approximately.
Other factors: as lacking trace element zinc, ferrum, folic acid, vitamin B12 etc., can reduce immunologic function, increase the probability of recurrent oral ulceration morbidity.
The treatment oral ulcer mainly contains Western medicine and two kinds of Therapeutic Method of Chinese medicine at present; Oral medicine or vitamin during western medical treatment with antiinflammation, like vitamin B, C, E, folic acid, chlortetracycline, hibitane, dexamethasone acetate, metronidazole etc.Its advantage is that the patient takes like a shot, but its shortcoming onset is slow, and the toxic and side effects of medicine is big.The method of Chinese traditional treatment is to adopt decoction or local application, the advantage of decoction to be that utilization is dialectical to execute that to control comprehensive function obvious; But this kind Therapeutic Method produce effects is slow, and because the decoction taste is bitter, thereby not easy for patients to accept.Local application is sprinkling upon the Chinese medicine powder BINGPENG SAN on the ulcer surface, though this local application instant effect causes that patient's oral ulcer surface produces violent pain, particularly infant and is difficult to medication.
See from therapeutic effect; Topical can yet be regarded as and treated the best route of administration of oral ulcer, but it seems that from the modern medicines galenic pharmacy its dosage form is often not too reasonable; Bioavailability is low; Be difficult to bring into play best therapeutic effect, adopt powder, unguentum or cream like current common dosage forms, more like nourishing yin shengjisan, BINGPENG SAN, watermelon crystal, ulcer ointment.Experiment confirm, because ulcer occurs in these privileged sites of oral cavity, the continuous motion of facial muscle, after patient's medication, the medicine tack is poor, and is short in the wound surface time of staying, thereby causes drug effect low, and treatment cycle is long.Simultaneously, the continuous secretion of salivary gland, and saliva washes away powder, and dilution makes medicine be difficult to lastingly in partial effect, and the concentration reduction makes drug effect fail to give full play to.Mouth paster is a kind of novel paster, and it can be attached on ulcer or wound surface, but because it can not flexural deformation, because of hold this and not for a long time wound surface stick.Mouth paster density is bigger simultaneously, and this makes the processing of its asepticize that very big obstacle arranged.In addition, the traditional Chinese medicines prescription is complicated, and poor stability is difficult to control effectively drug quality.Therefore, adopt modern preparation means, can develop in conjunction with Chinese traditional traditional Chinese medical science and have high bioavailability, good effect, the convenient new formulation that uses.This invention is made efforts in this regard, and has obtained result preferably.
Summary of the invention
The objective of the invention is to overcome existing pharmaceutical preparation wound surface and adhere to the time weak point, bioavailability is low, and weak curative effect provides a kind of brand-new dosage form.Thereby this novel form can combine with wound surface for a long time and can slowly discharge medicine in site of action, and the whippy construction features of this system, make its own curve in oral cavity that can coincide, thereby healing acceleration speed shortens treatment time.
Another object of the present invention provides a kind of novel sustained-release transdermal medicament delivery system, and this system can be used as a kind of drug release platform.Behind the various active compatibility of drugs, process compound preparation, thereby overcome the low problem of therapeutic effect in the single preparations of ephedrine.For example, to the strong shortcoming of pain during the existing preparation for treating, add local anesthetic easily, the pain during the remissive treatment; In this dosage form, can add chemical synthetic drug with antiinflammatory action, process compound preparation, to improve curative effect, shorten the course of treatment.
Another object of the present invention provides a kind of pharmaceutical preparation that does not have antiseptic, and this new formulation can be used ultra violet lamp easily, and is xeothermic, and gas or lonizing radiation carry out disinfection.So just avoided the stimulation of antiseptic to ulcer or wound surface.
Another object of the present invention provides a kind of new sustained release preparation, and said preparation can delay the release of medicine, keeps certain drug level for a long time in ulcer or surgical wound surface, thereby reaches the purpose of long-time onset.
Another object of the present invention provides a kind of new formulation, and said preparation can be protected ulcer or wound surface, and simultaneously the adjuvant of preparation can be by biodegradation, and does not have toxic and side effects.
Another object of the present invention provides a kind of new formulation, and the said preparation volume is little, and tack is high, and free from extraneous odour does not have tangible foreign body sensation simultaneously.Patient's compliance is high in therapeutic process, is particularly useful for infant.
Another object of the present invention provides a kind of new formulation, and said preparation can be used as a kind of wound dressing.According to the size of wound, said preparation can be prepared into the dressing that varies in size; Simultaneously, can also select for use different materials, like substratum for waterproofing, to satisfy the requirement of different clinical as bottom substrate.Promptly can be prepared into different sizes and shape, be prepared on anti-water-based or the hydrophilic substrate, can attach to oral ulcer or wound surface, and stick the time and be no less than 10 minutes, said ulcer or wound surface are oral ulcer, postoperative wound surface or trauma wounds.
More particularly, the object of the present invention is to provide a kind of new formulation through the lyophilization preparation, it comprises and conforms with the pharmaceutic adjuvant (high molecular polymer, antiseptic, excipient etc.) that pharmacopeia requires, and has the active medicine of therapeutic efficiency.Simultaneously in said preparation, other active medicine auxiliary treatment can also be optionally added, one or more the ancillary drug that is selected from following group can be comprised: local anesthetic, vitamin, freshener and spice.
Sustained-release transdermal medicament delivery system of the present invention is processed solution by high molecular polymer and active medicine, is prepared from through lyophilization, contains active medicine 0.1-5000 milligram in the per unit dosage particles, has the high molecular polymer 5-5000 milligram of the effect of sticking.In this kind new formulation, high molecular polymer is as skeleton, and active medicine disperses wherein to form a kind of preparation structure that is similar to solid dispersion.When said preparation is applied in the oral cavity, after the high molecular polymer aquation, form gel and ulcer or postoperative wound surface and combine closely, thereby ulcer or wound surface are played a protective role, reduce stimulation to ulcer or wound surface, sense obviously eases the pain.The same with matrix tablet controlled release principle, after the high molecular polymer aquation, form gel, through the dissolving of gel and the infiltration of active medicine, active medicine is discharged into site of action slowly, brings into play its biological action for a long time.
In further specific embodiments, new formulation provided by the invention, it is to process macromolecular solution with the high molecular polymer with biological agent, other active Chinese medicine extract of compatibility are prepared from through lyophilization again.
High molecular polymer can be selected for use but be not limited to one or more following polymer;
1, polyvidone
2, hydroxyethyl-cellulose
3, hydroxypropyl methylcellulose
4, polyoxyethylene
5, sodium alginate
6, hydroxypropyl cellulose
7, carbopol
8, sodium carboxymethyl cellulose
In this new formulation, can optionally add active medicine; Active medicine is the medicine that has the chemicals of antibiotic and/or antiviral activity or have the plant origin of antibiotic and/or antiviral activity, and the active medicine that can add includes but not limited to following:
1, antibiotic medicine is like metronidazole
2, antiviral drugs
3, antibiotic
In specific embodiment of the present invention, active medicine, high molecular polymer and other raw materials all adopt the commercially available prod.Its concrete method for preparing is: get an amount of high molecular polymer water-soluble after, add active medicine and adjuvant therapy medicaments.Through this new formulation of Freeze Drying Technique preparation.
In further specific embodiments, the present invention provides bioavailability to continue the new formulation of discharge type, and it comprises high molecular polymer, active medicine, suitable dosage form adjuvant.In order to satisfy the requirement of drug release, the viscosity of the high molecular polymer of being selected for use can not be too low.Last dosage form satisfies the requirement of medicine stripping in should be able to the physiological environment in the oral cavity.
Embodiment 1
1.0 gram polyvidones and 0.5 gram hydroxyethyl-cellulose are dissolved in the 75 gram pure water.0.05 general slave's caine of gram and 0.05 gram metronidazole are dissolved in the 25 gram pure water, use activated carbon decolorizing.After the filtration, add 0.005 gram sodium benzoate.Mix with macromolecule polymer solution, with the pH value of 0.1NNaOH solution regulator solution in 6.5.The solution of preparation is transferred in the pallet and is let the height of solution be about 1 centimetre.Through after the lyophilization, can obtain cotton shape xerogel (concrete prescription is seen form 1).Obtain the lyophilization thing and can cut into different sizes and shape to satisfy different treatment requirements.
Form 1
Embodiment 2
Similar with the method for embodiment 1, there is not antiseptic in the prescription of instance two.The purpose that adds antiseptic is in order to prolong the storage period of preparation.Because said preparation is a kind of xerogel of low density porous shape and has extraordinary elasticity, can carry out disinfection through ultra violet lamp or radiation exposure easily.Therefore in optimizing prescription, do not add antiseptic (concrete prescription is seen form 2).
Form 2
Embodiment 3
1.0 gram polyvidones and 0.5 gram hydroxyethyl-cellulose are dissolved in the 75 gram pure water.0.10 gram Flos Lonicerae extract is dissolved in the 25 gram pure water, uses activated carbon decolorizing.After the filtration, add 0.005 gram sodium benzoate, 0.005 gram procaine and 0.005 gram metronidazole.Mix with macromolecule polymer solution, with the pH value of 0.1N NaOH solution regulator solution in 6.5.The solution of preparation is transferred in the pallet and is let the height of solution be about 1 centimetre.Through after the lyophilization, can obtain cotton shape xerogel (concrete prescription is seen form 3).In this embodiment, added local anesthetic (procaine) to alleviate patient's pain.Antibiotic medicine (metronidazole) is used for heightening the effect of a treatment, and shortens the course of treatment.
Form 3
Embodiment 4
Similar with the method for embodiment 1, the prescription of embodiment 4 has adopted metronidazole, and high molecular polymer has been selected carbopol and hydroxypropyl cellulose for use simultaneously.Experiment proof metronidazole has affinity preferably with the high molecular polymer of being selected for use, and this prescription can successfully prepare the high cotton shape xerogel of biological adhesiveness (concrete prescription is seen form 4).
Form 4
Embodiment 5
Similar with the method for embodiment 1, the prescription of embodiment 5 has adopted Flos Lonicerae extract, and high molecular polymer has been selected polyoxyethylene for use simultaneously.Benzocaine and gentamycin have been added simultaneously as active pharmaceutical ingredient (concrete prescription is seen form 5).
Form 5
Embodiment 6
Similar with the method for preparing of embodiment 1, the prescription of embodiment 6 has adopted metronidazole, and high molecular polymer has been selected sodium alginate and hydroxyethyl-cellulose for use simultaneously.In order to improve the mouthfeel of preparation, added Radix Glycyrrhizae extract; Added sodium benzoate simultaneously as the storage life (concrete prescription see form 6) of antiseptic to prolong preparation.
Form 6
The preliminary clinical trial of embodiment 7 oral ulcer
1, experimental subject
Select light-duty oral ulcer patient's 28 examples as the object of observation at random, by random assortment test group (first group), matched group (second group) is evenly distributed at sex, age, severity extent between two groups.Male's 16 examples wherein, women's 12 examples, age 12-55 year, average 31 years old, course of disease 1d-1, average February.
2, usage
Gargle with eliminating cold for resuscitation water earlier, a little is affixed on the affected part after with a small amount of saliva moistening to get the oral cavity dry gels, 2～3 times/day, is coated with taboo water and fasting afterwards 1.5～2.0 hours.
3, efficacy determination
Cure: medication is after 1～2 day, and oral mucosa damaged area pain and redness go down or disappear, and ulcer is recovered.Effectively: after 4 days, oral mucosa damaged area pain and redness alleviate, and the ulcer surface pseudomembrane disappears, and ulcer surface dwindles, shoals.Invalid: after 5 days, oral mucosa damaged area pain is alleviated to some extent, and ulcer does not heal yet.
4, therapeutic outcome
Through clinical practice 28 examples, cure 25 examples, cure rate 89.2%; Effective 2 examples, effective percentage 7.14%; Invalid 1 example, total effective rate 96.4%.
The preliminary clinical trial of embodiment 8 stomatitis type oral ulcer
1, experimental subject
Select stomatitis type oral ulcer patient 31 examples as the object of observation immediately.Male's 20 examples wherein, women's 11 examples, age 15-66 year, average 46.3 years old, course of disease 1-3, the average 7-9 month.
2, usage
Gargle with eliminating cold for resuscitation water earlier, the reuse normal saline is gargled, and a little is affixed on the affected part after with a small amount of saliva moistening to get the oral cavity dry gels, 2～5 times/day, is coated with taboo water and fasting afterwards 1.5～2.0 hours.
3, efficacy determination
Cure: medication is after 1～2 day, and oral mucosa damaged area pain and redness go down or disappear, and ulcer is recovered.Effectively: after 4 days, oral mucosa damaged area pain and redness alleviate, and the ulcer surface pseudomembrane disappears, and ulcer surface dwindles, shoals.Invalid: after 7 days, oral mucosa damaged area pain is alleviated to some extent, and ulcer does not heal yet.
4, therapeutic outcome
Through clinical practice 31 examples, cure 20 examples, cure rate 64.5%; Effective 9 examples, effective percentage 29.0%; Invalid 2 examples, total effective rate 93.5%.
Claims (9)
1. sustained-release transdermal medicament delivery system that is used to treat ulcer or wound surface; It is characterized in that containing in the per unit dosage particles active medicine 0.1-5000 milligram; High molecular polymer 5-5000 milligram with the effect of sticking, wherein said polymer are to be selected from following group one or more: polyvidone, hydroxyethyl-cellulose, hydroxypropyl emthylcellulose, carbopol, sodium alginate, hydroxypropyl cellulose, POLYOX, sodium carboxymethyl cellulose;
This drug-supplying system is processed through following method: high molecular polymer and active component are processed solution, carry out lyophilization then.
2. drug-supplying system according to claim 1, wherein said active medicine are the medicine that has the chemicals of antibiotic and/or antiviral activity or have the plant origin of antibiotic and/or antiviral activity.
3. drug-supplying system according to claim 2, wherein said active medicine are metronidazole.
4. drug-supplying system according to claim 1, it also comprises one or more the ancillary drug that is selected from following group: local anesthetic, vitamin, freshener and spice.
5. drug-supplying system according to claim 1, it also comprises antiseptic.
6. drug-supplying system according to claim 1, it can attach to oral ulcer or wound surface, and sticks the time and be no less than 10 minutes.
7. drug-supplying system according to claim 1, it is prepared into different sizes and shape, makes its ulcer that can be fit to vary in size or wound surface.
8. drug-supplying system according to claim 7, wherein said ulcer or wound surface are oral ulcer, postoperative wound surface or trauma wounds.
9. drug-supplying system according to claim 1, it is prepared on anti-water-based or the hydrophilic substrate.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101156846A (en) * | 2007-08-08 | 2008-04-09 | 北京协和建昊医药技术开发有限责任公司 | A buccal pellicle for treating gingivitis and oral mucosa canker as well as its preparation method |
| CN101461832A (en) * | 2007-12-18 | 2009-06-24 | 丁月芳 | Bioadhesive paster for treating mouth ulcer |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101156846A (en) * | 2007-08-08 | 2008-04-09 | 北京协和建昊医药技术开发有限责任公司 | A buccal pellicle for treating gingivitis and oral mucosa canker as well as its preparation method |
| CN101461832A (en) * | 2007-12-18 | 2009-06-24 | 丁月芳 | Bioadhesive paster for treating mouth ulcer |
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