CN100457186C - Application of saturated fatty polyol or alcoholic acid as cross-linking agent in filming gel composition - Google Patents
Application of saturated fatty polyol or alcoholic acid as cross-linking agent in filming gel composition Download PDFInfo
- Publication number
- CN100457186C CN100457186C CNB2005100272257A CN200510027225A CN100457186C CN 100457186 C CN100457186 C CN 100457186C CN B2005100272257 A CNB2005100272257 A CN B2005100272257A CN 200510027225 A CN200510027225 A CN 200510027225A CN 100457186 C CN100457186 C CN 100457186C
- Authority
- CN
- China
- Prior art keywords
- film
- gel composition
- saturated fatty
- cross
- linking agent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Images
Abstract
The present invention discloses the application of saturated fatty polyol and/or alcoholic acid as cross-linking agent in filming gel composition. The saturated fatty polyol and alcoholic acid have the chemical general expression of CnH2n+2-m-l(OH)m(COOH)l, where n, m and l are integral number. The filming gel composition may be coated onto skin or oral mucosa to form one smooth, tough, antiwear and hydrophobic protecting film, and the film may be retained for over 5 hr in oral mucosa or 8 hr in skin.
Description
Technical field
The present invention relates to the application in film forming gel composition of a kind of saturated fatty polyol or alkyd or its mixture as cross-linking agent.
Background technology
Human body skin, oral mucosa because hurt, damage that scratch, otch and scald etc. cause; The inflammation that caused by antibacterial, fungus or viral infection; The pain of the local organization that ulcer that a variety of causes causes and a variety of causes cause etc. is the commonly encountered diseases in people's daily life.The topical pharmaceutical formulations that is used for the treatment of the skin and the disease of cari oris mucosa clinically is generally ointment, ointment, gel, tincture, paste, gargarism spray etc.; when above these preparations when tissue or oral mucosa carry out topical therapeutic; because the normal activity of affected part and surrounding tissue thereof; as friction; the secretion of perspiration, saliva and flushing; can make these medicament dissolvings and/or corrosion, be shifted, come off; medicament and affected part retention time are shorter; make curative effect obviously reduce, and need repeatedly medication every day.
Film forming gel composition is particularly suitable for treating the disease and the damage of various skins and mucosal tissue, as lip chap, herpes labialis, scald, incised wound and scratch; The inflammation that antibacterial, fungus, viral infection cause; The ulcer that not bright reason causes; And the pain of the local organization that causes of a variety of causes etc., so can claim that again this gellike agent is the bioadhesive film forming gel composition.About the example of these film-forming compositions open by Rencher (USP5192802,5314915), Tinnell (USP4381296 and 4285934), Promerantz (USP5081158), Epstein (USP5906814), Tapolsky (USP6103266).
Wherein a class partial film forming gel composition normally forms cellulose esters with the reaction of hydroxy alkyl cellulose and esterifying agent, and it is crosslinked to pass through cross-linking agent again, with the product of gained as filmogen.Because the structure of the cross-linking agent that adopts and character is different, this class film forming gel composition forms physical property such as pliability, the adhesion of sticking film, resistance to wear and film widely different holding time of affected part.USP 5081158 disclosed partial film forming gel compositions are composed of the following components: nontoxic easy volatile solvent 1) hydroxypropyl cellulose, 2), as ethanol or water, 3) esterifying agent, as salicylic acid and tannic acid (claiming tannin again), 4) cross-linking agent, as boric acid, 5) medicine, as hydrocortisone etc.Salicylic acid and tannic acid can form ester with the hydroxyl generation esterification on the hydroxypropyl cellulose as esterifying agent, can produce following effect after its esterification products and boric acid are crosslinked:, this two tunic can be combined after having added cross-linking agent 1. if do not add cross-linking agent and can not form two tunics; 2. can form comparatively tough and tensile, blocky film after crosslinked.According to the report of USP 5906814 and we research to this patent working example, it is thicker and fragile that discovery is made the formed film of cross-linking agent with boric acid, after being applied to the affected part, can be caused film rupture, come off that its holdup time on oral mucosa has only 4～5 hours by body fluid or saliva corrosion.USP 5906814 thinks that the reason that causes this phenomenon may be relevant with the structural property of boric acid, three hydroxyls on the boric acid can be crosslinked with three sites on the hydroxypropyl cellulose ester, because three hydroxyl spacings on the boric acid are very near, three crosslinked sites just separated by the space of boron atom, the result causes the product after crosslinked to be strapped in tightly together, formed rigidity, fragile opaque coating.And boric acid has zest to the skin and the mucosa of a lot of individualities.
Therefore, USP 5906814 discloses a kind of partial film forming gel composition, is with lauric acid monoglyceride substituted boracic acid that with the difference of USP 5081158 as cross-linking agent, other component remains unchanged substantially.Behind hydroxypropyl cellulose and esterifying agent reaction formation hydroxypropyl cellulose ester (one of its reactive mode as shown in Figure 1), comparatively flexible film (its crosslinking method as shown in Figure 2) can be formed with glycerol monolaurate after crosslinked, the fragility of USP5081158 film can be improved.But we find the partial film forming gel composition made as cross-linking agent with the lauric acid monoglyceride, though the pliability of its film strengthens to some extent, but the time that is attached on body tissue or the mucosa is then shorter, as the film that on oral mucosa, forms easily by body fluid or saliva corrosion/dissolving, make film break prematurely, come off, so that disappear, its effective holdup time on oral mucosa has only 3～4 hours.The reason of weak point may be relevant with following reason to cause this film holdup time: have only two crosslinked hydroxyl can be provided on (1) glycerol monolaurate, crosslinkable site is less; (2) long carbon-chain structure (the alkane chains of 12 carbon) may shield partial cross-linked site in the lauric acid list glyceride molecule, and long lauric acid carbochain also is unfavorable for the tight arrangement of gel combination inside.More than these factors weakened the adhesion of gel combination inside, thereby cause that this film more easily breaks, dissolving and/or corrosion, so that very fast the disappearance.
Summary of the invention
The technical problem to be solved in the present invention promptly is to be the film forming gel composition of cross-linking agent preparation with boric acid or lauric acid monoglyceride in the above-mentioned prior art, the film that forms be rigidity, fragility or easily come off, effective short problem of holdup time, seek a kind of material and be used as new cross-linking agent.
Therefore, the purpose of this invention is to provide the application in film forming gel composition of a kind of saturated fatty polyol or alkyd or its mixture as cross-linking agent.
Saturated fatty polyol of the present invention or alkyd are meant and contain the hydroxyl that adds up to 4～8 or the C of hydroxyl and carboxyl
4～C
8Alkane, its chemical general formula are C
nH
2n+2-m-l(OH)
m(COOH)
l, wherein, this n, m, l are integer, n 〉=m 〉=2, and l 〉=0, m+l is 4～8, n+l is 4～8.
According to the present invention, be preferably as n+l in the above-mentioned general formula of the saturated fatty polyol of cross-linking agent or alkyd and be no more than 6.
M+l generally also is no more than 6, promptly in 4～6 scopes.
As seen, saturated fatty polyol of the present invention or alkyd can be C
4～C
6Saturated fatty polyol is as daily some used sugar alcohols; Or contain the C of two above hydroxyls
4～C
6Saturated fat alkyd.
For example, n=m=l=2 in the above-mentioned molecular formula, as tartaric acid, its structural formula is as follows:
N=m is 5～6 in the molecular formula of another preferred embodiment of the present invention, and as xylitol, mannitol or sorbitol, its structural formula is as follows:
C
5H
12O
5Molecular weight is 152.15
The molecular weight of saturated fatty polyol of the present invention or alkyd is preferably 122～250, more preferably between 150～183.
According to the present invention, said film forming gel composition is meant by hydroxy alkyl cellulose and esterifying agent esterification and forms the hydroxy alkyl cellulose ester, again the gel combination that is cross-linked to form by cross-linking agent.When it is applied to body surface, can form smooth, tough and tensile, wear-resisting, the hydrophobic protecting film of one deck when particularly body tissue is surperficial, so one of advantageous characteristic that bioadhesive is it to have.It can contain or not contain the medicine active component, can be used to treat the damage and the disease of skin or mucosa.
Wherein, do not contain the film forming gel composition useful as drug carrier of medicine active component or be applied directly to the wound of skin, mucosa (for example oral mucosa); thereby form layer protecting film to isolate or the shielding wound; prevent that effectively extraneous foreign body from contacting wound once more and causing pain or infection, and promoted the healing of wound.Said wound is meant the interruption that body tissue connects, accompany or do not accompany the disappearance of material, the cell damage that causes by machinery or physical cause, can be the damage that mechanical wound, thermal burn mouth, chemical wound and radiation wound etc. are caused by extrinsic factor, for example hurt, abrade, stab, lacerated wound, bite, scratch, cold injury and scald etc., and the wound of disease associations such as congested relevant wound, injection place or operative incision, diabetic wounds, oral ulcer.
And the film forming gel composition that contains the medicine active component can be described as the medicine film forming gel composition.Active constituents of medicine of the present invention can be a various kinds of drug, as local anesthetic (as benzocaine, lignocaine, dyclonine etc.), analgesic agent (diclofenac diethylammonium, ibuprofen, indomethacin etc.), antibiotic [comprises antibacterium medicine (erythromycin, clindamycin, chloromycetin, neomycin etc.), antifungal agent is (as econazole nitrate, clotrimazole, miconazole, itraconazole, interferon, nystatin etc.) and antiviral agents (virazole, idoxuridine, acyclovir, cytosine arabinoside etc.)], hemorrhage (YUNNAN BAIYAO, aminomethylbenzoic acid etc.), vasoconstrictor (as pseudoephedrine etc.), hormone (hydrocortisone, dexamethasone, triamcinolone acetonide etc.), disinfectant (chlorhexidine acetate, benzalkonium bromide etc.), (peace accounts for promise in other local application, isotretinoin, silver sulfadiazine, povidone iodine, podophyllotoxin, cantharidin etc.); Certain described various kinds of drug also comprises various active ingredient of Chinese herbs, as Oleum Curcumae, ZHENGHONGHUA YOU, asiaticoside, Bulbus Allii wet goods.It also has the effect of the various medicines of adding except the effect of said medicine carrier film forming gel composition.
The said hydroxy alkyl cellulose of the present invention is meant the cellulose that contains 1 above propoxyl on the side chain of its trunk at least, and as hydroxypropyl cellulose etc., preferred molar average molecular weight preferably is 80～1,000,000 daltonian hydroxypropyl celluloses.And esterifying agent is meant that the hydroxyl on energy and the above-mentioned hydroxy alkyl cellulose side chain plays the material of esterification, as organic carboxylic acid, comprises salicylic acid, tannin etc.This film forming gel composition also contains the solvent of the above-mentioned various components of dissolving and esterification products and cross-linking products usually.Certainly, as required, also can in gel combination, add other additives such as reinforcing agents such as alkylcellulose and/or penetration enhancer.
The preparation method of film forming gel composition of the present invention is: the esterifying agent stirring and dissolving in an amount of solvent, is slowly added hydroxy alkyl cellulose under stirring, make it to dissolve fully/swelling, continue stirring and make formation even gel shape; Add cross-linking agent (can add reinforcing agent when needing) then, continue to be stirred to fully evenly, replenish the solvent of surplus, stir, the degassing, promptly; As contain active constituents of medicine, medicine can be dissolved stirring together with esterifying agent.
Generally speaking, except that cross-linking agent by saturated fatty polyol of the present invention or alkyd or its mixture replacing, the concrete composition or the content of other components such as all the other hydroxy alkyl celluloses, esterifying agent all can be with reference to prior aries, the used solvent of the present invention can be the volatilizable alcoholic solvent that falls, as ethanol, isopropyl alcohol any or its mixture, or alcoholic solvent and water.
Saturated fatty polyol of the present invention or alkyd or its mixture in film forming gel composition as cross-linking agent, have following distinct advantages: the used cross-linker molecules amount of (1) the present invention is less, as xylitol, mannitol, sorbitol, tartaric molecular weight between 150～183, for containing the C that hydroxyl or hydroxyl and carboxyl add up to 4～8
4～C
8Carbon alkane, because that the crosslinkable hydroxyl of cross-linking agent does not have substantially is sterically hindered, its hydrogen bond with the crosslinked back formation of hydroxy alkyl cellulose ester is keeping suitable spacing (one of its reactive mode as shown in Figure 3), makes the film of formation have pliability preferably.(2) the used cross-linking agent of the present invention is the saturated fatty polyol that contains at least 4 hydroxyls, or contain at least 2 hydroxyls, and hydroxyl and carboxyl sum are at least 4 saturated fat alkyd, contain two hydroxyls and two carboxyls as tartaric acid, sorbitol, mannitol and xylitol all contain 5～6 hydroxyls, because these cross-linking agent have more hydroxyl can be crosslinked together effectively with a plurality of hydroxy alkyl cellulose ester molecules, it is stronger to form internal bond strength, the network-like complex that quality is bigger, make whole product after crosslinked keep stable, thereby avoided effectively with boric acid or lauric acid monoglyceride as above-mentioned defective that cross-linking agent produced.(3) the present invention selects saturated fatty polyol or the alkyd as cross-linking agent for use, is pharmaceutic adjuvant or food additive as tartaric acid, sorbitol, mannitol and xylitol etc., good biocompatibility, and raw material is easy to get.
Saturated fatty polyol of the present invention or alkyd or its mixture have more tenacity, wearability, persistency and hydrophobicity as the formed film of partial film forming gel composition of cross-linking agent preparation, experimental results show that this film forming gel composition can effectively keep more than 5 hours in the oral mucosa affected part, effectively keep more than 8 hours in the skin affected part.
Description of drawings
Fig. 1 is that hydroxypropyl cellulose (I) with salicylic acid (II) sketch map that esterification generates hydroxypropyl cellulose ester (III) and water (IV) takes place.
Fig. 2 is cross-linked to form the sketch map (dotted line is represented hydrogen bond) of membrane complex (VI) for hydroxypropyl cellulose ester (III) and cross-linking agent lauric acid monoglyceride (V).
Fig. 3 is cross-linked to form the sketch map (dotted line is represented hydrogen bond) of membrane complex (VIII) for hydroxypropyl cellulose ester of the present invention (III) and cross-linking agent xylitol (VII).
The specific embodiment
Following examples are used to describe the present invention, but not as limitation of the present invention.Wherein the percentage ratio of specified otherwise all is not weight percentage.
Embodiment 1～10 and comparative example
Table 1
Respectively with the esterifying agent stirring and dissolving among embodiment 1-10 and the comparative example in the table 1 in the solvent of recipe quantity, stir down and slowly add hydroxypropyl cellulose, make fully dissolving/swelling after, continue to stir and make formation even gel shape; Add cross-linking agent (comparative example does not add cross-linking agent) then, continue stirring and make fully evenly; Replenish the volatilizable solvent that falls, make to reach recipe quantity, stir, the degassing promptly makes the film forming gel compositions various of the present invention that are 100 grams.
Embodiment 11～15
Table 2
With benzocaine (Benzocaine), triamcinolone acetonide (Triamcinolone Acetonide), econazole nitrate (Econazole Nitrate), amlexanox (Amlexanox) and chlorhexidine acetate (Chlorhexidine Acetate) as model drug, component in the table 2 is made medicine film forming gel composition 100 grams respectively by the preparation method among the embodiment 1, wherein, medicine adds in the solvent with esterifying agent.
The medicine film forming gel composition that makes in the table 2 all can on skin or mucosa, form one deck smooth, tough and tensile, wear-resisting, stick persistent hydrophobic membrane.
Various component raw material in the foregoing description are conventional commercially available prod.
Effect embodiment 1
The film forming gel composition that the foregoing description 1 and comparative example are made carries out external comparison of sticking performance, corrosion phenomenon and holdup time respectively.The mould circle of getting internal diameter 16mm, thick 0.6mm is fixed on the microscope slide, respectively gel combination is applied in the mould circle, wipes off with dull and stereotyped, takes out the mould circle behind natural drying under the room temperature, forms a skim on the microscope slide.Above microscope slide is fixed on the bottom of digestion instrument container with 45, presses Chinese Pharmacopoeia dissolution method (second method) operation, 900mL distilled water, rotating speed 200rpm.That observes film on the microscope slide sticks performance, corrosion phenomenon, the situations such as holdup time on microscope slide.
Result of the test shows: embodiment 1 can form one deck and stick film on microscope slide; In water, soak after 2 hours, have only the minute quantity tiny solid to be shed in the water, but whole film is kept perfectly by corrosion; Caudacoria still was attached on microscope slide tightly in 10 hours, did not see breakage, and whole film is kept perfectly.The comparative example can form one deck and stick film on microscope slide; But soak in water after about 20 minutes, the corrosion from the film of the solid of part splits away off, membrane portions corrosion and begin breakage after 1 hour, and the film of whole breakage is peeled off and is shed to the water from microscope slide after 2 hours.
Film forming gel composition with the preparation of the prescription of the foregoing description 2～10 carries out the comparison that external oral mucosa sticks performance, corrosion phenomenon and holdup time.Get 3 * 4cm size, fresh beagel dog oral mucosa, prune away the blood vessel and the connective tissue of mucosa inboard, with normal saline soak, washing, dry; The mould circle of internal diameter 16mm, thick 0.6mm is put on the mucosa, respectively sample is applied in the mould circle, wipe off, after natural drying film forming under the room temperature, take out the mould circle, this mucosa is fixed on the microscope slide with dull and stereotyped.Above microscope slide is fixed on the bottom of digestion instrument container with 45, presses Chinese Pharmacopoeia dissolution method (second method) operation, 900mL distilled water, rotating speed 200rpm.Observe the situation of film on the microscope slide, result of the test sees Table 3.
Table 3
| Stick performance | The corrosion situation | | |
| Embodiment | |||
| 2 | Rough surface, adhesion are good | Slightly attenuation behind the 5hr, but still be kept perfectly, the 10hr film still is kept perfectly, and tightly is attached on the mucosa | ＞10hr |
| Embodiment 3 | Slightly wrinkle in the surface, adhesion is good | The 1hr rear surface has the part solid to come off; Slightly attenuation behind the 3hr, but still be kept perfectly, the 6hr film begins slowly to break, and has fragment to come off | ＞6hr |
| Embodiment 4 | Smooth smooth, adhesion good | Slightly attenuation behind the 5hr, but still be kept perfectly, the 10hr film still is kept perfectly, and tightly is attached on the mucosa | ＞10hr |
| Embodiment 5 | Smooth smooth, adhesion good | Slightly attenuation behind the 5hr, but still be kept perfectly, the 10hr film still is kept perfectly, and tightly is attached on the mucosa | ＞10hr |
| Embodiment 6 | Smooth smooth, adhesion good | Slightly attenuation behind the 5hr, but still be kept perfectly, the 10hr film still is kept perfectly, and tightly is attached on the mucosa | ＞10hr |
| Embodiment 7 | Smooth smooth, adhesion good | Slightly attenuation behind the 5hr, but still be kept perfectly, the 10hr film still is kept perfectly, and tightly is attached on the mucosa | ＞10hr |
| Embodiment 8 | The surface is slightly rough, adhesion is good | Slightly attenuation behind the 5hr, but still be kept perfectly, the 10hr film still is kept perfectly, and tightly is attached on the mucosa | ＞10hr |
| Embodiment 9 | Smooth smooth, adhesion good | The 1hr rear surface has the part solid to come off; The attenuation of 5hr caudacoria has a small amount of insoluble solid in the solution, slightly mix, and behind the 10hr, film still tightly is attached on the mucosa | ＞ |
| Embodiment | |||
| 10 | Rough surface, adhesion are good | The 1hr rear surface has the part solid to come off; The attenuation of 3hr caudacoria has a small amount of insoluble solid in the solution, slightly mix, and behind the 10hr, film still tightly is attached on the mucosa | ＞10hr |
The result of table 3 shows that embodiment 2-10 all can form one deck and stick film on mucosa, and except that embodiment 3, all the other embodiment place more than 10 hours in water, and film is kept perfectly substantially and still tightly is attached on the mucosa.
Effect embodiment 3
Get the Benzocaine film-formed gel composition that embodiment 11 makes, the triamcinolone acetonide film forming gel composition that embodiment 12 makes, the amlexanox film forming gel composition that embodiment 14 makes, commercially available Zilactin-B film forming gel composition (USP5081158 patented product) (U.S. Zila ParmacuticalsInc., prescription: benzocaine 10%, hydroxypropyl cellulose, salicylic acid, tannic acid, boric acid, ethanol etc.), the sample of pressing the embodiment preparation of U.S. Pat P5906814 (is called for short USP Gel, prescription: benzocaine 10%, hydroxypropyl cellulose, salicylic acid, tannic acid, the lauric acid monoglyceride, ethanol etc.) carry out external oral mucosa and stick performance, the comparison of corrosion phenomenon and holdup time.Get 3 * 4cm size, fresh beagel dog oral mucosa, prune away the blood vessel and the connective tissue of mucosa inboard, with normal saline soak, washing, dry; The mould circle of internal diameter 16mm, thick 0.6mm is put on the mucosa, respectively above 5 samples are applied in the mould circle, wipe off, after natural drying film forming under the room temperature, take out the mould circle, this mucosa is fixed on the microscope slide with dull and stereotyped.Above microscope slide is fixed on the bottom of digestion instrument container with 45, presses Chinese Pharmacopoeia dissolution method (second method) operation, 900mL distilled water, rotating speed 200rpm.Observe the situation of film on the microscope slide, the results are shown in Table 4.
The external comparison of sticking performance, corrosion time and holdup time of table 4
| Sample | Zilactin-B | USP Gel | Embodiment 11/12/14 |
| Stick performance | Smooth smooth, adhesion good | Smooth smooth, adhesion good | Smooth smooth, adhesion good |
| The corrosion situation | The 4hr caudacoria begins the part corrosion; Damaged gradually behind the 5hr; The 6hr membrane portions comes off, and the 8hr film comes off from mucosa with the fragment shape | The 1hr caudacoria begins corrosion; Attenuation of 3hr caudacoria and part are damaged; Membrane portions comes off behind the 4hr, 5 hours films disappear substantially | Slightly attenuation behind the 5hr, but still be kept perfectly, the 10hr film still is kept perfectly, and tightly is attached on the mucosa |
| Holdup time | 6～8hr | 4～5hr | ＞10hr |
Above result shows that Zilactin-B and USP Gel all can form one deck and stick film on mucosa, but can be by corrosion, breakage in water.The film that Benzocaine film-formed gel composition of the present invention, triamcinolone acetonide film forming gel composition, amlexanox film forming gel composition form all has extremely strong bioadhesive and hydrophobicity, even place more than 10 hours in water, film is kept perfectly substantially and still tightly is attached on the mucosa.
Effect embodiment 4
The sample of getting above-mentioned effect embodiment 3 carries out sticking in the rabbit oral mucosa body comparison of performance, corrosion situation and holdup time.
With 15 experimental rabbits, be divided into 5 groups at random, every group 3, with mouth-gag the rabbit oral cavity is fixed, dried the moisture of oral cavity dimple mucomembranous surface, be coated in 5 samples on the oral mucosa of having handled in the mode that is coated with thin layer respectively with clean gauze, dehisce eupnea after 1～2 minute, 5 samples all can form one deck and stick film, take off mouth-gag subsequently, and laboratory animal can freely be drunk water between probation.Observe stick performance, corrosion situation and the holdup time on mucosa (the disappearing 1/2) of film, the results are shown in Table 5 in membrane area.
Table 5. rabbit mucosa sticks the comparison of performance, corrosion phenomenon and holdup time
| Sample | Zilactin-B | USP Gel | Embodiment 11 | Embodiment 12 | Embodiment 14 |
| Stick performance | Smooth smooth, adhesion good | Smooth smooth, adhesion good | Smooth smooth, adhesion good | Smooth smooth, adhesion good | Smooth smooth, adhesion good |
| The corrosion situation | Begin corrosion behind the 3hr, break, come off with the fragment shape behind the 4hr, film is imperfect, during 4.5hr approximately surplus about 1/2 | 1 hour caudacoria begins film rupture behind corrosion, the 2hr, and area dwindles gradually, during 3hr approximately surplus about 1/2 | Begin slowly corrosion, attenuation behind the 3hr, but film is still complete; The edge of 4hr caudacoria is damaged gradually; Surplus about 1/2 during 5hr | Begin slowly corrosion, attenuation behind the 3hr, but film is still complete; The edge of 4hr caudacoria is damaged gradually; Surplus about 1/2 during 5hr | Begin slowly corrosion, attenuation behind the 3hr, but film is still complete; The edge of 4hr caudacoria is damaged gradually; Surplus about 1/2 during 5hr |
| Holdup time | About 4.5hr | About 3hr | About 5hr | About 5hr | About 5hr |
Result of the test shows that 5 samples all can form one deck and stick film on the rabbit oral mucosa, and the formed film of Zilactin-B shows slightly tight, may be relatively poor relevant with this film flexibility, and the film of USP Gel is easily dissolved, and existing about 1/2 film disappears after 3 hours.No matter the film that Benzocaine film-formed gel composition of the present invention, triamcinolone acetonide film forming gel composition, amlexanox film forming gel composition form obviously is better than two control samples in the corrosion situation with on the holdup time.
Effect embodiment 5
Get triamcinolone acetonide/econazole nitrate film forming gel composition of embodiment 13, the chlorhexidine acetate film forming gel composition of embodiment 15, commercially available Zilactin-B film forming gel composition, USP Gel and carry out the comparison that vitro skin sticks performance, corrosion phenomenon and holdup time.Get 3 * 4cm size, fresh rat back skin, prune away the blood vessel and the connective tissue of mucosa inboard, with normal saline soak, washing, dry; The mould circle of internal diameter 16mm, thick 0.6mm is put on the mucosa, respectively above 4 samples are applied in the mould circle, wipe off, after natural drying film forming under the room temperature, take out the mould circle, this skin is fixed on the microscope slide with dull and stereotyped.Above microscope slide is fixed on the bottom of digestion instrument container with 45, presses Chinese Pharmacopoeia dissolution method (second method) operation, 900mL distilled water, rotating speed 200rpm.Observe the situation of film on the microscope slide, the results are shown in Table 6.
Table 6. vitro skin sticks the comparison of performance, corrosion time and holdup time
| Sample | Zilactin-B | USP Gel | Embodiment 13/15 |
| Stick performance | Smooth smooth, adhesion good | Smooth smooth, adhesion good | Smooth smooth, adhesion good |
| The corrosion situation | 3 hours caudacorias begin to come off from mucosa with the fragment shape gradually behind corrosion, the 4hr, and 5hr left and right sides film comes off from mucosa fully | The 1hr caudacoria begins corrosion, and membrane portions breakage after 2 hours, comes off at the breakage of 3hr caudacoria, and the 4hr film disappears substantially | Slightly attenuation behind the 5hr, but still be kept perfectly, the 10hr film still is kept perfectly, and tightly is attached on the mucosa |
| Holdup time | About 5hr | 4hr | ＞10hr |
Above result shows that Zilactin-B and USP Gel all can form one deck and stick film on skin, but can be by corrosion, breakage in water.The film that triamcinolone acetonide/econazole nitrate film forming gel composition of the present invention and chlorhexidine acetate film forming gel composition form has extremely strong bioadhesive and hydrophobicity, even place more than 10 hours in water, film is kept perfectly substantially and still tightly is attached on the skin.
Effect embodiment 6
The sample of getting above-mentioned effect embodiment 5 carries out the comparison that rat skin sticks performance, corrosion situation and holdup time.
With 16 experimental rats, be divided into 4 groups at random, 4 every group, cut the Mao Bingyong shaver of rat back and scrape the fine, soft fur on most surface, disinfect in alcohol, after the drying, respectively 4 samples are coated in the mode that is coated with thin layer on the skin of having handled, 4 samples all can form one deck and stick film.Observe stick performance, corrosion situation and the holdup time on skin (the disappearing 1/2) of film, the results are shown in Table 7 in membrane area.
Table 7. skin sticks the comparison of performance, corrosion phenomenon and holdup time
| Sample | Zilactin-B | USP Gel | Embodiment 13/15 |
| Stick performance | Smooth smooth, adhesion good | Smooth smooth, adhesion good | Smooth smooth, adhesion good |
| The corrosion situation | Begin behind the 4hr to break, film is imperfect; Disappear more than 1/2 during 6hr | Film rupture after 3 hours, area dwindles gradually, disappears more than 1/2 during 5hr | Begin slowly attenuation behind the 6hr, but film is still complete; The 8hr caudacoria damaged gradually, come off, surplus more than 1/2 approximately |
| Holdup time | ＜6hr | ＜5hr | About 8hr |
Result of the test shows, 4 samples all can form one deck and stick film on skin, but the holdup time on skin, of the present invention triamcinolone acetonide/econazole nitrate film forming gel composition and chlorhexidine acetate film forming gel composition obviously are better than Zilactin-B and USP Gel.
Effect embodiment 7
The analgesic activity of the pain that the Benzocaine film-formed gel composition of observing embodiment 11 preparations causes oral ulcer.
The herpetic stomatitis patient that 8 others are all healthy is divided into test group and blank group, every group 4 people.Every patient sucked orange juice 15 seconds, and two groups patient stimulates ulcer place, back pain to strengthen greatly at orange juice.Patient's water of test group is gargled and is blotted the ulcer place with clean gauze and reaches the moisture of mucosa on every side subsequently, Benzocaine film-formed gel composition is coated to ulcer spot in the mode of filming, and the eupnea of dehiscing has formed the film of one deck white around the ulcer surface reaches after 1 minute.
Result of the test shows: test group patient forms back pain soon by slightly to weakening significantly at film.Stimulate with orange juice once more after 3 hours, blank group patient still has an intense pain, and the test group patient do not feel tangible pain.
Claims (9)
1, as the application of cross-linking agent, the chemical general formula that it is characterized in that this saturated fatty polyol or alkyd is C in film forming gel composition for a kind of saturated fatty polyol or alkyd or its mixture
nH
2n+2-m-l(OH)
m(COOH)
l, wherein, this n, m, l are integer, n 〉=m 〉=2, and l 〉=0, m+l is 4～8, n+l is 4～8.
2, application according to claim 1 is characterized in that said n+l is no more than 6.
3, application according to claim 1 is characterized in that above-mentioned m+l is no more than 6.
4, application according to claim 3 is characterized in that said n=m=l=2.
5, application according to claim 4 is characterized in that this saturated fatty polyol or alkyd are tartaric acid.
6, application according to claim 3 is characterized in that said n=m is 5～6.
7, application according to claim 6 is characterized in that this saturated fatty polyol or alkyd are xylitol, mannitol or sorbitol.
8, according to each described application of claim 1～7, the molecular weight that it is characterized in that this saturated fatty polyol or alkyd is between 122～250.
9, each described application according to Claim 8, the molecular weight that it is characterized in that this saturated fatty polyol or alkyd is between 150～183.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2005100272257A CN100457186C (en) | 2005-06-29 | 2005-06-29 | Application of saturated fatty polyol or alcoholic acid as cross-linking agent in filming gel composition |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2005100272257A CN100457186C (en) | 2005-06-29 | 2005-06-29 | Application of saturated fatty polyol or alcoholic acid as cross-linking agent in filming gel composition |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1887280A CN1887280A (en) | 2007-01-03 |
| CN100457186C true CN100457186C (en) | 2009-02-04 |
Family
ID=37576560
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2005100272257A Active CN100457186C (en) | 2005-06-29 | 2005-06-29 | Application of saturated fatty polyol or alcoholic acid as cross-linking agent in filming gel composition |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN100457186C (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104997723A (en) * | 2014-04-16 | 2015-10-28 | 上海现代药物制剂工程研究中心有限公司 | Film-forming gel composition and uses thereof, and pharmaceutical film-forming gel composition |
| CN105012960A (en) * | 2014-04-16 | 2015-11-04 | 上海现代药物制剂工程研究中心有限公司 | Film-forming gel composition, application and wound protecting material |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1240454A (en) * | 1996-12-18 | 2000-01-05 | 科尔加特·帕尔莫利弗公司 | Process for the preparation of cross-linked maleic anhydride copolymers |
-
2005
- 2005-06-29 CN CNB2005100272257A patent/CN100457186C/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1240454A (en) * | 1996-12-18 | 2000-01-05 | 科尔加特·帕尔莫利弗公司 | Process for the preparation of cross-linked maleic anhydride copolymers |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1887280A (en) | 2007-01-03 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US5081158A (en) | Compositions and in situ methods for forming films on body tissue | |
| US6329343B1 (en) | Bioadhesive antibacterial wound healing composition | |
| CN105012960A (en) | Film-forming gel composition, application and wound protecting material | |
| IE902096A1 (en) | Compositions and in situ methods for forming films of body¹tissue | |
| RU2673342C2 (en) | Methods and compositions for improvement of external view and formation of scar tissue | |
| CN114904046A (en) | Recombinant III-type humanized collagen composition and preparation method and application thereof | |
| CN100457186C (en) | Application of saturated fatty polyol or alcoholic acid as cross-linking agent in filming gel composition | |
| US9808429B2 (en) | Topical drug patch including microspheres | |
| CN100594908C (en) | Triamcinolone benetonide local film forming gel composition | |
| CN100500747C (en) | Filming gel composition and its use | |
| CN110200988A (en) | A kind of scar repair agent and preparation method thereof | |
| CN101138543B (en) | Centella asiatica partial film forming gel composition and uses thereof | |
| CN104997723A (en) | Film-forming gel composition and uses thereof, and pharmaceutical film-forming gel composition | |
| CN101138556B (en) | Terbinafine or its salt film forming gel composition and uses thereof | |
| CN101190177B (en) | Dectancyl partial film forming gel composition and uses thereof | |
| CN101190178B (en) | Antiviral partial film forming gel composition | |
| CN106562953A (en) | Application of hydroxysafflor yellow A in preparing medicine for treating diabetic foot ulceration, medicine and medicine preparation method | |
| CN100571679C (en) | Lidocaine hydrochloride partial film forming gel composition and the application in pharmacy thereof | |
| CN101138541B (en) | Amlexanox partial film forming gel composition and uses thereof | |
| CN1891300B (en) | Benzocaine film-formed gel composition and its use | |
| CN100446814C (en) | Compound econazole nitrate film forming gel composition and its use | |
| CN101138557B (en) | Chlorhexidine acetate partial film forming gel composition and uses thereof | |
| WO2024051687A1 (en) | Topical formulation containing pirfenidone and use thereof | |
| CN109498598B (en) | Temperature-sensitive traditional Chinese medicine liquid band-aid and preparation method thereof | |
| CN101138544B (en) | Diclofenac or the salt partial film forming gel composition and uses thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20201012 Address after: 1111 Halley Road, China (Shanghai) pilot Free Trade Zone, Pudong New Area, Shanghai, 201203 Patentee after: SHANGHAI MODERN PHARMACEUTICAL ENGINEERING RESEARCH CENTER Co.,Ltd. Address before: 200040 No. 1320 West Beijing Road, Shanghai Patentee before: SHANGHAI INSTITUTE OF PHARMACEUTICAL INDUSTRY |