CN100571679C - Lidocaine hydrochloride partial film forming gel composition and the application in pharmacy thereof - Google Patents
Lidocaine hydrochloride partial film forming gel composition and the application in pharmacy thereof Download PDFInfo
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- CN100571679C CN100571679C CNB200610030854XA CN200610030854A CN100571679C CN 100571679 C CN100571679 C CN 100571679C CN B200610030854X A CNB200610030854X A CN B200610030854XA CN 200610030854 A CN200610030854 A CN 200610030854A CN 100571679 C CN100571679 C CN 100571679C
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Abstract
The invention discloses a kind of lidocaine hydrochloride partial film forming gel composition, it comprises following components in weight percentage: hydroxy alkyl cellulose 0.5～7%, esterifying agent 1～10%, cross-linking agent 0.5～5%, solvent 75～90% and lidocaine hydrochloride 0.1～5%; Wherein, this cross-linking agent is saturated fatty polyol or alkyd, and its chemical general formula is C
nH
2n+2-m-l(OH)
m(COOH)
l, this n, m, l are integer, n 〉=m 〉=2, and l 〉=0, m+l is 4～8, n+l is 4～8.Lidocaine hydrochloride film forming gel composition of the present invention is used for the local analgesia of tissue such as mucosa/skin; can form smooth, tough and tensile, wear-resisting, the hydrophobic protecting film of one deck when being coated in skin or mucomembranous surface; compare with the various topical dosage forms of existing lidocaine hydrochloride that the formed film of this gel combination is difficult for breaking, dissolving and/or corrosion; and this film can effectively keep more than 5 hours on the oral mucosa surface, effectively keeps more than 8 hours at skin surface.
Description
Technical field
The present invention relates to the application in the local body tissue pain of a kind of lidocaine hydrochloride partial film forming gel composition and alleviation.
Background technology
The body local tissue because hurt, scratch, otch, scald, sprain, strain, pain that contusion and oral ulcer etc. cause is the commonly encountered diseases of often meeting in people's daily life.Usually carry out analgesia therapy with the topical pain relief medicine clinically, as local anesthetics such as lignocaine, benzocaine.The topical pharmaceutical formulations that is used to alleviate these diseases is generally mucilage, gel, paste etc.; when above these preparations when skin or mucosal tissue carry out topical therapeutic; because the normal activity of therapentic part and surrounding tissue; as friction; the secretion of perspiration, saliva and flushing can make these medicament dissolving and/or corrosions; be shifted, come off, so that disappear.The time of contact of these local application's agent and therapentic part is all shorter usually, generally can not surpass 15 minutes in the holdup time of oral mucosa, can not surpass 30 minutes at skin surface, makes curative effect obviously reduce.
People have studied some can be at skin or moist mucomembranous surface, and the partial film forming gel composition (film-forming gel agent) as oral mucosa surface formation one deck adhesion film can claim again that usually this gellike compositions is the bioadhesive film forming gel composition.The partial film forming gel composition of this class medicine carrying forms film and attaches to the body part, and a kind of mechanism of lasting release medicine can be provided, thereby improves curative effect.About the example of these film forming gel compositions disclosed by Rencher (USP5192802,5314915), Tinnell (USP4381296 and 4285934), Promerantz (USP5081158), Epstein (USP5906814), Tapolsky (USP6103266).
Wherein a class partial film forming compositions is normally used water-soluble material, make as Calculus Bovis from Northwest of China Millefolium carboxylic, arabic gum, xanthan gum, sodium alginate, sodium carboxymethyl cellulose, carbomer etc., for example the disclosed adhesion compositions of USP5192802 is made up of sodium carboxymethyl cellulose, xanthan gum, sodium alginate etc.But the adhesion material that this preparation adopted mostly is water-soluble substances greatly, and its holdup time in the affected part is very short, is easy to be eluted from medicine-feeding part by saliva or body fluid.
The another kind of partial film forming gel composition that is loaded with local anesthetic normally forms the hydroxy alkyl cellulose ester with hydroxy alkyl cellulose and esterifying agent reaction, crosslinked by cross-linking agent again, but form the film-forming gel of bioadhesive, be used for the pain relieving of local mucous membrane or skin histology.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: 1) hydroxypropyl cellulose; 2) nontoxic easy volatile solvent is as ethanol; 3) esterifying agent is as salicylic acid and tannin (claiming tannic acid, tannic acid again); 4) cross-linking agent is as boric acid; 5) medicine is as local anesthetic benzocaine etc.Salicylic acid and tannin can form the hydroxypropyl cellulose ester with the hydroxyl generation esterification on the hydroxypropyl cellulose as esterifying agent, can produce following effect after hydroxypropyl cellulose ester 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 USP 5081158 embodiment, 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.USP5906814 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.
USP 5906814 discloses another 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, can form comparatively flexible film after the usefulness glycerol monolaurate is crosslinked, can improve the fragility of USP5081158 film.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.
Wherein, lidocaine hydrochloride (Lidocaine) is a class local anesthetic, and its effective ingredient can reach afflicted areas by transdermal after the topical application, block nerves reflection and extenuate pain.If adopt the technology of above-mentioned existing film forming gel composition to prepare lidocaine hydrochloride partial film forming gel, can make the retention time in medicament and affected part shorter, therapeutic effect is lower.
Summary of the invention
Purpose of the present invention is intended to solve above-mentioned the problems of the prior art, and a kind of pliability, adhesion, abrasion resistance better and action time of longer lidocaine hydrochloride partial film forming gel composition is provided.
Above-mentioned purpose of the present invention realizes by following technical proposal: lidocaine hydrochloride partial film forming gel composition of the present invention comprises hydroxy alkyl cellulose, esterifying agent, cross-linking agent, solvent and lidocaine hydrochloride, wherein, this cross-linking agent is saturated fatty polyol or alkyd, and the chemical general formula of this saturated fatty polyol or alkyd is C
nH
2n+2-m-1(OH)
m(COOH)
l, this n, m, l are integer, n 〉=m 〉=2, and l 〉=0, m+l is 4～8, n+l is 4～8.
Each components contents all can be with reference to existing film forming gel composition technology in the lidocaine hydrochloride partial film forming gel composition of the present invention, as above-mentioned U.S. Pat P5081158 and the disclosed constituent content of USP5906814, but lidocaine hydrochloride partial film forming gel composition of the present invention can preferably be selected the content of following percentage by weight for use: hydroxy alkyl cellulose is preferred 0.5%～7%, more preferably 2%～5%; Esterifying agent is preferred 1%～10%, and more preferably 3%～8%; Cross-linking agent is preferred 0.5%～5%, and more preferably 1%～3%; Lidocaine hydrochloride is then got the treatment effective dose, should determine according to concrete feelings to be cured the disease, the patient's that receives treatment age and physiological situation, the degree that is in a bad way, course of treatment factor such as length and medicinal part, and is preferred 0.1%～5%, and more preferably 1%～3%; And solvent can be 75%～90%, and solvent complements to 100% and gets final product during practical operation, is generally 80%～90%.
Wherein, lidocaine hydrochloride partial film forming gel composition of the present invention can also comprise the reinforcing agent below 5%, preferably is 0.5%～5%, more preferably is 2%～3% reinforcing agent.
Lidocaine hydrochloride partial film forming gel composition of the present invention also preferably comprises penetration enhancer, as laurocapram (Azone), isopropyl myristate etc., the present invention preferred 1.0% laurocapram.
In the chemical formula of a preferred embodiment of the present invention, n+l preferably is no more than 6, and correspondingly m+l also is no more than 6 usually, promptly can be C
4～C
6Saturated fatty polyol is as daily some used sugar alcohols; Or contain two above hydroxyls, and hydroxyl and carboxyl number are 4～6 C
4～C
6Saturated fat alkyd.
As n=2, m=2, l=2 in the following formula, as tartaric acid, its structural formula is as follows:
Tartaric acid C
4H
6O
6Molecular weight is 150.09
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:
Mannitol C
6H
14O
6Molecular weight is 182.17
Sorbitol C
6H
14O
6Molecular weight is 182.17
Xylitol 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.
Hydroxy alkyl cellulose of the present invention is meant the cellulose that contains 1 above hydroxyl on the side chain of cellulose trunk at least, as hydroxypropyl emthylcellulose, hydroxypropyl cellulose etc., the preferred hydroxypropyl cellulose of the present invention.
Described esterifying agent is the material that can generate ester with the hydroxyl generation esterification on the hydroxy alkyl cellulose side chain, and as organic carboxylic acid, preferred salicylic acid, tannin or their mixture are the mixture of salicylic acid and tannin best.Salicylic acid and tannin can both be individually and hydroxypropyl cellulose generation esterification, wherein salicylic acid except can with hydroxy alkyl cellulose generation esterification, the hydroxyl on the salicylic acid also can be crosslinked with the form of hydrogen bond with the hydroxyl on the cross-linking agent.
The said reinforcing agent of the present invention is meant hydrophobicity, the wearability that can increase film and/or sticks persistent material.The insoluble alkylcellulose of preferred water of the present invention is as ethyl cellulose, cellulose acetate or their mixture etc.
Described solvent is meant the solvent of various components in the solubilized film forming gel composition and esterification products and cross-linking products.The used solvent of the present invention can be the volatilizable alcoholic solvent that falls, as ethanol, or the mixture of ethanol and water; It not only can dissolve and carry said components and help gel combination using the position to form film.
Certainly, as required, also can in gel combination, add various additives, as antioxidant: vitamin E, vitamin C, sodium sulfite, sodium thiosulfate, butylated hydroxyarisol etc.; Chelating agen: disodium EDTA, EDTA calcium complex disodium salt etc.; Antibacterial: sorbic acid and salt thereof, benzoic acid and salt thereof, methyl parahydroxybenzoate, ethylparaben, propyl p-hydroxybenzoate, chlorobutanol etc.; Pigment: solatene, lemon yellow, light blue, sunset yellow, beet red etc., and other additive commonly used on the medicament.
In a word, except that cross-linking agent by saturated fatty polyol of the present invention or alkyd or its mixture replacing, remaining each component of lidocaine hydrochloride partial film forming gel composition of the present invention: concrete composition or content as hydroxy alkyl cellulose, esterifying agent and solvent etc. all can be with reference to prior aries.
The present invention adopt saturated fatty polyol or alkyd or its mixture in film forming gel composition as cross-linking agent, advantage with following uniqueness: the used cross-linker molecules amount of (1) the present invention is less, preferably as: xylitol, mannitol, sorbitol, tartaric molecular weight are between 150～183, for containing hydroxyl or containing hydroxyl and carboxyl adds up to 4～8 C
4～C
8Carbon alkane, sterically hindered owing to not having substantially between crosslinkable hydroxyl of cross-linking agent or the carboxyl, the hydrogen bond that itself and the crosslinked back of hydroxy alkyl cellulose ester form is keeping suitable spacing, 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 crosslinkable groups 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.
The preparation method of partial film forming gel agent of the present invention is: with lidocaine hydrochloride and esterifying agent stirring and dissolving in the solvent of an amount of (can dissolve wherein solute), stir and slowly add hydroxy alkyl cellulose down, make it to dissolve fully/swelling, continue stirring and make formation even gel shape; Add cross-linking agent (can add reinforcing agent, penetration enhancer and additive etc. when needing) then, continue to be stirred to fully evenly, replenish the solvent of surplus, stir, the degassing, promptly.
Another object of the present invention provides the application of lidocaine hydrochloride partial film forming gel composition of the present invention in preparation local anesthesia or analgesic drug product.
Because lidocaine hydrochloride partial film forming gel composition of the present invention has adopted and has contained the C that hydroxyl or hydroxyl and carboxyl add up to 4～8
4～C
8Carbon alkane is as cross-linking agent, and also the insoluble alkylcellulose of available water is as reinforcing agent, and the film that makes its formation has better tenacity, wearability, persistency and hydrophobicity than other known partial film forming compositions, and its effective holdup time in the affected part is longer.Lidocaine hydrochloride partial film forming gel composition is after the surface, affected part forms film, and lidocaine hydrochloride makes the part, affected part keep higher concentration in a long time by discharging to the affected part face in the film always, thereby obtains better therapeutic; In addition, the film that forms on the surface, affected part has played the barrier protection effect, prevents that the infection of outer bound pair affected part wound or ulcer from also avoiding or alleviating outer bound pair affected part stimulating the pain that causes effectively, thereby promotes and accelerate wound, ulcer healing.
Lidocaine hydrochloride partial film forming gel composition of the present invention can adopt cotton to wipe away or directly gel is coated on the affected part of skin or oral mucosa with clean finger, by natural drying or allow patient's eupnea 1 minute of dehiscing, treat to form smooth, tough and tensile, wear-resisting, the persistent hydrophobic membrane of one deck in the affected part after the solvent volatilization, generally film can effectively keep more than 8 hours at skin surface, effectively keeps more than 5～6 hours on the oral mucosa surface.And lidocaine hydrochloride partial film forming gel composition of the present invention is used local non-stimulated to it, safety is good.
The specific embodiment
Following examples are used to describe the present invention, but not as limitation of the present invention.
Various component raw material in the following example are conventional commercially available prod.Wherein the percentage ratio of specified otherwise all is not weight percentage.
Embodiment 1～14 and comparative examples 1 '
Respectively with embodiment in the table 1 1～14 and comparative examples 1 ' in the lidocaine hydrochloride (not adding lidocaine hydrochloride in the comparative examples) of consumption and the esterifying agent stirring and dissolving in the solvent of solubilized amount, stir and slowly add hydroxypropyl cellulose down, after making fully dissolving/swelling, continue to stir to make and form the even gel shape; Add cross-linking agent (can add reinforcing agent, penetration enhancer when needing) then, continue stirring and make fully evenly; Replenish the solvent of surplus, make to reach recipe quantity, stir, the degassing, the partial film forming gel composition that makes lidocaine hydrochloride and contrast respectively respectively 100 restrains.
Table 1
Experimental result shows: the lidocaine hydrochloride partial film forming gel composition outward appearance is bright yellowish-brown, can form smooth, tough and tensile, wear-resisting, the persistent hydrophobicity of one deck at skin/mucomembranous surface and stick film.
Effect embodiment 1
Influence factor and study on the stability are carried out in lidocaine hydrochloride partial film forming gel agent to embodiment 1.With sample each influence factor test of 10 days under illumination (4500Lux), high temperature (40 ℃) condition, accelerated test (30 ℃, RH 75%) 6 months and room temperature (25 ℃, RH 60%) 6 months the study on the stability that keeps sample.The result shows: the character of lidocaine hydrochloride partial film forming gel agent of the present invention, uniformity, medicament contg, related substance etc. relatively have no significant change with initial data, the results are shown in Table 2.
Table 2
| Character | Uniformity | Content (%) | Related substance (%) | |
| Original | The yellowish-brown semi-solid gel, tool ethanol abnormal smells from the patient | Evenly, there is not outstanding absurd creature | 99.87 | 0.31 |
| Illumination | Pale brown color semi-solid gel, tool ethanol abnormal smells from the patient | Evenly, there is not outstanding absurd creature | 99.36 | 0.34 |
| High temperature | Pale brown color semi-solid gel, tool ethanol abnormal smells from the patient | Evenly, there is not outstanding absurd creature | 98.74 | 0.39 |
| Accelerated test | Pale brown color semi-solid gel, tool ethanol abnormal smells from the patient | Evenly, there is not outstanding absurd creature | 96.84 | 0.53 |
| Room temperature keeps sample | Pale brown color semi-solid gel, tool ethanol abnormal smells from the patient | Evenly, there is not outstanding absurd creature | 98.55 | 0.43 |
Effect embodiment 2
Get the lidocaine hydrochloride partial film forming gel composition that embodiment 2～14 makes, press the sample of the embodiment 1 method preparation of U.S. Pat P5081158, be called for short USP Gel-A, add lidocaine hydrochloride (prescription w/w: lidocaine hydrochloride 1.0% in the prescription, hydroxypropyl cellulose 2.5%, salicylic acid 2.5%, tannin 7%, boric acid 1%, ethanol 86%), press the sample of the embodiment Gel D method preparation of U.S. Pat P5906814, be called for short USP Gel-B, replace benzocaine (prescription w/w: lidocaine hydrochloride 1.0% with lidocaine hydrochloride, hydroxypropyl cellulose 1.5%, salicylic acid 2.0%, lauric acid monoglyceride 5.0%, disodium EDTA 0.05%, vitamin E 0.1%, ethanol 90.35% etc.) carry out vitro skin surface adhesion performance, the comparison of corrosion situation and holdup time, all contain lidocaine hydrochloride in the above gel, back two samples in contrast.
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 sample is 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 3.
The external comparison of sticking performance, corrosion time and holdup time of table 3.
| Stick performance | The corrosion situation | Holdup time | |
| USP Gel-A | Smooth, smooth, adhesion is good | 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 | 6～8hr |
| USP Gel-B | Smooth, smooth, adhesion is good | 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 | 4～5hr |
| Embodiment 2 | Smooth smooth, adhesion good | Slightly attenuation behind the 5hr, but still be kept perfectly; The 10hr caudacoria still is kept perfectly, and tightly is attached on the mucosa | ＞10hr |
| Embodiment 3 | Smooth smooth, adhesion good | Slightly attenuation behind the 5hr, but still be kept perfectly; The 10hr caudacoria still is kept perfectly, and tightly is attached on the mucosa | ＞10hr |
| Embodiment 4 | Smooth smooth, adhesion good | Slightly attenuation behind the 5hr, but still be kept perfectly; The 10hr caudacoria 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 caudacoria 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 caudacoria 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 caudacoria still is kept perfectly, and tightly is attached on the mucosa | ＞10hr |
| Embodiment 8 | Smooth smooth, adhesion good | Slightly attenuation behind the 5hr, but still be kept perfectly; The 10hr caudacoria still is kept perfectly, and tightly is attached on the mucosa | ＞10hr |
| Embodiment 9 | The surface is slightly rough, adhesion is 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 | ＞10hr |
| Embodiment 10 | Smooth smooth, adhesion good | Slightly attenuation behind the 5hr, but still be kept perfectly; The 10hr caudacoria still is kept perfectly, and tightly is attached on the mucosa | ＞10hr |
| Embodiment 11 | Rough surface, adhesion are good | Slightly attenuation behind the 5hr, but still be kept perfectly; The 10hr caudacoria still is kept perfectly, and tightly is attached on the mucosa | ＞10hr |
| Embodiment 12 | The surface is slightly rough, adhesion is 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 | ＞10hr |
| Embodiment 13 | Smooth smooth, adhesion good | Slightly attenuation behind the 5hr, but still be kept perfectly; The 10hr caudacoria still is kept perfectly, and tightly is attached on the mucosa | ＞10hr |
| Embodiment 14 | Rough surface, adhesion are good | Slightly attenuation behind the 5hr, but still be kept perfectly; The 10hr caudacoria still is kept perfectly, and tightly is attached on the mucosa | ＞10hr |
Above result shows that USP Gel-A, USP Gel-B and lidocaine hydrochloride partial film forming gel composition of the present invention all can form one deck and stick film on mucosa, but the film of USP Gel-A, USP Gel-B can be by corrosion, breakage in water.The film that lidocaine hydrochloride partial film forming gel composition of the present invention forms 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 3
Get the lidocaine hydrochloride partial film forming gel composition of embodiment 2 preparation, the sample of above-mentioned USP Gel-A, USP Gel-B carries out the comparison that the rabbit oral mucosa sticks performance, corrosion situation and holdup time.
With 12 experimental rabbits, be divided into 3 groups at random, every group 4, with mouth-gag the rabbit oral cavity is fixed, dried the moisture of oral cavity dimple mucomembranous surface, be coated in 3 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, 3 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 4 in membrane area.
Table 4. rabbit mucosa sticks the comparison of performance, corrosion phenomenon and holdup time
| Sample | USP Gel-A | USP Gel-B | Embodiment 2 |
| Stick performance | Smooth smooth, adhesion good | Smooth smooth, adhesion good | Smooth, smooth, adhesion is 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 | Beginning slowly begins corrosion, attenuation behind the 4hr, but film is still complete; The edge of 5hr caudacoria is damaged gradually; Surplus more than 1/2 during 6hr |
| Holdup time | About 4.5hr | About 3hr | ＞6hr |
Result of the test shows that 3 samples all can form one deck and stick film on the rabbit oral mucosa, but the film of USPGel-B is easily dissolved, and existing about 1/2 film disappears during 3hr, and USP Gel-A also has the film about 1/2 to disappear when 4.5hr.No matter the film that the lidocaine hydrochloride partial film forming gel composition of the embodiment of the invention 2 forms obviously is better than two control samples in the corrosion situation with on the holdup time.
Effect embodiment 4
Carry out the comparison that rat skin sticks performance, corrosion situation and holdup time with the lidocaine hydrochloride partial film forming gel agent of embodiment 1,13, the sample of above-mentioned USP Gel-A, USPGel-B.
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 on the skin of having handled in the mode that is coated with thin layer, area is 9cm
2, in each zone, being coated with sample with about 150mg, 4 samples all can form one deck solid at skin surface and stick film.Come backwash lightly 5 times every 1 hour Pilus Caprae seu Ovis brush on the surface of film, observe sticking performance, damaged situation and the holdup time on skin of film, the results are shown in Table 5 with humidity.
Table 5. skin sticks the comparison of performance, damaged situation and holdup time
| Sample | Stick performance | The corrosion situation | Holdup time |
| USP Gel-A | Smooth, smooth, adhesion is good | Begin behind the 5hr to break, come off; The irregular fragmentation of 6hr caudacoria, imperfect; Substantially disappear behind the 7hr. | About 7hr |
| USP Gel-B | Smooth, smooth, adhesion is good | Film rupture behind the 3hr, come off; The irregular fragmentation of 4hr caudacoria, imperfect; Substantially disappear during 5hr. | About 5hr |
| Embodiment 1 | Smooth, smooth, adhesion is good | Begin slowly attenuation behind the 6hr, but film is still complete; About 10hr caudacoria is damaged gradually, come off, and 12hr disappears substantially. | About 12hr |
| Embodiment 13 | Smooth, smooth, adhesion is good | Begin slowly attenuation behind the 6hr, but film is still complete; About 8hr caudacoria is damaged gradually, come off, and 10hr disappears substantially | About 10hr |
Result of the test shows that 4 samples all can form one deck and stick film on skin.But the film of USP Gel-B is easily dissolved, and film disappears substantially during 5hr, and USP Gel-A film when 7hr disappears substantially.The formed film of the lidocaine hydrochloride partial film forming gel composition of embodiment 1 is longer in the holdup time of skin surface than the formed film of lidocaine hydrochloride partial film forming gel composition (not containing reinforcing agent) of embodiment 13, illustrates in the prescription of embodiment 1 to add ethyl cellulose can prolong film as reinforcing agent holdup time; No matter the film that the lidocaine hydrochloride partial film forming gel composition of the embodiment of the invention 1,13 forms obviously is better than two control samples of USP Gel-A and USP Gel-B in damaged situation with on the holdup time.
Effect embodiment 5
Observe the analgesic effect of the lidocaine hydrochloride partial film forming gel composition of embodiment 1 to the scratch wound pain.Choose all healthy scratch wound surface patient of 6 others, patient's scratch wound surface is cleaned, sterilized.Earlier presses wound surface before the medication, allows the patient describe pain degree and note with light finger, then wound surface and around be coated with the lidocaine hydrochloride film forming gel composition, on wound surface, form layer protecting film behind the natural drying.Gently press wound surface once more with finger behind the 1hr, allow the patient describe pain degree.
By 4 grades of scorings pain degree is estimated: 0=does not have tenderness; The 1=mild tenderness; 2=moderate tenderness bounces back during weight; 3=severe tenderness, retraction when gently pressing.The evaluation of curative effect: the every improvement of wound pain degree is that effectively every improvement is a produce effects for 2 grades for 1 grade.Result of the test sees Table 6.
The variation of main therapeutic evaluation index before and after table 6 treatment
The result shows: 3 people are effective among 6 patients, 3 people's produce effects, total effective rate 100%.Wherein on patient's wound surface to stick that film on average holds time be about 8 hours.
Effect embodiment 6
Observe the local excitation reaction of partial film forming gel composition after to guinea pig skin single and multiple dosing.
The lidocaine hydrochloride partial film forming gel composition of test specimen: embodiment 1
Control sample: comparative examples 1 ' in the partial film forming gel composition of the lidocaine hydrochloride that do not contain
Method: get 12 of Cavia porcelluss, be divided into 2 groups, 6 every group, be respectively single-dose group and multiple dosing group.In advance the hair of guinea pig back is pruned totally, after disinfecting in alcohol, be coated with respectively with test specimen and control sample in two zones that Cavia porcellus has marked in advance, the single-dose group is 0.3g/ Cavia porcellus/sky; The multiple dosing group is 0.3g/ Cavia porcellus/sky, continuous 7 days, respectively at 24hr after time administration observe the coating position whether redness, hyperemia arranged, ooze out, local excitation reactions such as degeneration or necrosis.
Result of the test shows: the lidocaine hydrochloride partial film forming gel preparation is not seen the coating position of Cavia porcellus single and multiple dosing group redness, hyperemia, ooze out, local excitation reactions such as degeneration or necrosis, there was no significant difference between test group and the matched group, safety is good.
Claims (11)
1, a kind of lidocaine hydrochloride partial film forming gel composition, it comprises following components in weight percentage: hydroxy alkyl cellulose 0.5%～7%, esterifying agent 1%～10%, cross-linking agent 0.5%～5%, solvent 75%～90% and lidocaine hydrochloride 0.1%～5%; Wherein, this esterifying agent is an organic carboxyl acid, and this cross-linking agent is saturated fatty polyol or alkyd, and the chemical general formula of this saturated fatty polyol or alkyd is C
nH
2n+2-m-l(OH)
m(COOH)
l, this n, m, l are integer, n 〉=m 〉=2, and l 〉=0, m+l is 4～8, n+l is 4～8.
2, compositions according to claim 1 is characterized in that this hydroxy alkyl cellulose is 2%～5%, and esterifying agent is 3%～8%, and cross-linking agent is 1%～3%, and solvent is 80%～90%, and lidocaine hydrochloride is 1%～3%.
3, compositions according to claim 1 and 2 is characterized in that it also comprises 0.5%～5% reinforcing agent; Described reinforcing agent is ethyl cellulose and/or cellulose acetate.
4, compositions according to claim 3 is characterized in that it also comprises 2%～3% reinforcing agent.
5, compositions according to claim 1 and 2 is characterized in that it also comprises 1% laurocapram.
6, compositions according to claim 1 and 2 is characterized in that n+l is no more than 6.
7, compositions according to claim 6 is characterized in that this n=m=l=2.
8, compositions according to claim 7 is characterized in that this saturated fatty polyol acid is tartaric acid.
9, compositions according to claim 6 is characterized in that this n=m, and its numerical range is for being 5～6.
10, compositions according to claim 9 is characterized in that this saturated fatty polyol is xylitol, mannitol or sorbitol.
11, the purposes of the described lidocaine hydrochloride film forming gel composition of claim 1 in preparation body local analgesia medicine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB200610030854XA CN100571679C (en) | 2006-09-06 | 2006-09-06 | Lidocaine hydrochloride partial film forming gel composition and the application in pharmacy thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB200610030854XA CN100571679C (en) | 2006-09-06 | 2006-09-06 | Lidocaine hydrochloride partial film forming gel composition and the application in pharmacy thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101138542A CN101138542A (en) | 2008-03-12 |
| CN100571679C true CN100571679C (en) | 2009-12-23 |
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|---|---|---|---|
| CNB200610030854XA Expired - Fee Related CN100571679C (en) | 2006-09-06 | 2006-09-06 | Lidocaine hydrochloride partial film forming gel composition and the application in pharmacy thereof |
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| Country | Link |
|---|---|
| CN (1) | CN100571679C (en) |
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2006
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|---|---|
| CN101138542A (en) | 2008-03-12 |
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