CN101371824B - Oral cavity pasting tablets using Methylprednisolone and derivatives thereof as active components - Google Patents
Oral cavity pasting tablets using Methylprednisolone and derivatives thereof as active components Download PDFInfo
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- CN101371824B CN101371824B CN200710059249XA CN200710059249A CN101371824B CN 101371824 B CN101371824 B CN 101371824B CN 200710059249X A CN200710059249X A CN 200710059249XA CN 200710059249 A CN200710059249 A CN 200710059249A CN 101371824 B CN101371824 B CN 101371824B
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Abstract
The invention discloses an oral sticking tablet used for treating canker sore of humans or mammals. The oral sticking tablet comprises a sticking layer containing an active ingredient and a water insoluble protective layer, wherein, a non-active ingredient contained in the sticking layer consists of a filling agent, an adhesive sustained-release agent and a lubricant which are applicable to tablets; the water insoluble protective layer is composed of polyacrylic acid resin and/or ethyl cellulose which can be used as protective coating, and a plasticizer; in addition, the active ingredient is methylprednisolone, or one or a combination of pharmaceutically acceptable esters.
Description
Technical field:
The present invention relates to the pharmaceutical composition and the application thereof of a kind of people of being used for the treatment of or mammal oral ulcer, relate in particular to a kind of oral cavity sticking tablet
Background technology:
Oral ulcer also is recurrent aphtha, is commonly called as aphtha, is a kind of common oral mucosa membrane disease.Recurrent oral ulceration refers to that specially a class is agnogenio, repeatedly outbreak but self limiting, isolated that produce, circular or oval-shaped ulcer are arranged.Be recurrent aphtha (aphtha is the meaning of Greek " scorching hot and ulcer ") or recurrent aphtha etc. again.Size, the depth and number difference according to the ulcer performance can be divided into three types again clinically: the light-duty oral ulcer of recurrent, recurrent stomatitis ulcer and mikulicz's ulcer.
Recurrent oral ulceration is one of modal disease in the diseases of oral mucosa, among people's all one's life, oral ulcer does not take place almost, just has the people to take place once in a while, has the people frequently to show effect; And about people of about 20% suffers from oral ulcer in various degree, and child, between twenty and fifty people and old people can be taken place, and it is fallen ill and does not have obvious relation season.Oral ulcer can betide any position of oral mucosa, and pinhead-sized dots in red appears in pathological changes initial stage mucous hyperemia, rubescent, edema, and the scorching hot discomfort of local sense has violent spontaneous pain; Stimulation such as hot and cold, sour, sweet all makes pain increase the weight of, and can show effect repeatedly.Though oral ulcer be oral disease, can spontaneous recovery because morbidity is frequent, the state of an illness increases the weight of gradually, brings and have a strong impact on for people's work, life.Recurrent oral ulceration cause of disease complexity is still not really clear and definite so far.Modern medicine is then thought: the variation of viral infection, bacterial infection, digestive system disease and dysfunction, hormonal change, spiritual neural factor, inherited genetic factors, immunologic function, and lack trace element zinc, ferrum, folic acid, vitamin B2, B6, B12 etc. in other factors such as the human body and can cause oral ulcer.
The present external used medicine of treatment oral ulcer, it is a variety of to comprise that Chinese medicine and western medicine has, the Chinese medicine class have with Borneolum Syntheticum, Indigo Naturalis, etc. be XILEI SAN, BINGPENG SAN, the pearl Huang of the main component infantile malnutrition powder such as loose that disappears, but this dosage form inconvenience when using is scattered and disappeared very soon behind the coating with saliva.Western medicine has gargarism, ointment, reaches the membrane of some medicines etc., main active component is the glucocorticoid that has based on dexamethasone, dexamethasone acetate, based on the antibiotic of metronidazole etc., based on the vitamin medicaments of vitamin B group, with lidocaine hydrochloride, tetracaine hydrochloride local anesthetic of representative etc.Wherein, most widely used with the Therapeutic Method of topical application glucocorticoid again.Disclose a kind of dexamethasone acetate plaster and preparation method thereof (i.e. " meaning can be pasted ", Shenzhen Mrs's Pharmaceutical is produced) as Chinese patent CN00132507.3, formed by a kind of adhered layer and a kind of fluid-tight protective layer of pastille.Dexamethasone acetate can play antiphlogistic effect, can promote ulcer surface to shrink, and quickens ulcer healing, yet because glucocorticoid has side effect, even topical application also is easy to generate systemic side effects when life-time service, i.e. the inhibition of hypothalamus-hypophysis-adrenal gland (HPA) axle.And used the plasticizer of harmful dioctyl phthalate as protective layer according to the described stickup tablet of this patent; each sticking tablet contains dioctyl phthalate up to 0.8mg; though this phthalic ester plasticizer acute toxicity is very little; yet; studies show that phthalic ester plasticizer exists very big chronic toxicity to human health; even zooscopy result both domestic and external shows the low dosage phthalic ester plasticizer, also can be to the nerve of animal, reproductive system especially male reproductive system toxigenicity.And from January 16th, 2007, European Union also implemented in EU countries about the instruction (2005/84/EC number instruction) of restriction toy and child care products phthalate (ester) content.According to this instruction, for toy and child care products, the content of phthalate (ester) all must not surpass 0.1%, and the potential hazard of the plasticizer of phthalate to the health existence is described thus from the side.Yet, open that upright superfine (plasticizer is preferred in the osmosis type acrylic resin coated slow release film, Acta Pharmaceutica Sinica, 2001,36 (12): 937-941) reported because the water-insoluble physical property of plasticizer of phthalate ideal plasticizer when being considered in the prior art prepare the waterproof coating.
At present the nontoxic plasticizer of generally acknowledging mainly contains just own ester etc. of citric acid ester plasticizer, epoxy soybean oil, trimellitic acid esters plasticizer, tetraoctyl 1,2,4,5-benzenetetra-carboxylate, diethylene glycol dibenzoate, DOTP, decanedioic acid two, wherein is most widely used with citric acid ester plasticizer again.And above-mentioned several plasticizer is mainly used in the purposes such as packing of food and medicine in the prior art again, and does not use it for the report of plasticizer in the medicine coating.
Methylprednisolone (Methylprednisolone) is a kind of not halogen-containing glucocorticoid medicine of synthetic,, have pharmacological actions such as antiinflammatory, immunosuppressant, antiallergic, shock.The antiinflammatory action of this medicine is stronger, is equivalent to 5 times of hydrocortisone, is 1.4 times of prednisone.In numerous glucocorticoids, the affinity of methylprednisolone and glucocorticoid receptor (GR) is the strongest, is 12 times of hydrocortisone, 23 times of prednisone.And mineralocorticoid sample effect (as water, sodium retention) is faint, is about 1/200 of deoxycorticosterone, and significantly less than prednisone, to the inhibitory action of hypothalamus-hypophysis-hypothalamic pituitary adrenal axis a little less than, and this medicine itself promptly exists with the active component form, onset is rapid.
The derivant of methylprednisolone is mainly its pharmaceutically useful carboxylate, in the derivant of methylprednisolone, some derivant has special local anti-inflammatory activity, as methylprednisolone aceponate, (Methylprednisolone aceponate, MPA, CAS:86401-95-8), by synthetic production of German ScheringAG factory, Jin Peiying etc. (psoriatic external therapy,, 1997 the 23rd the 1st phases of volume of foreign medical science skin cypridology fascicle, 22～27) reported that methylprednisolone aceponate can be widely used in the treatment psoriasis, anti-inflammatory activity is stronger slightly than clobetasol.It is the superpower glucocorticoid of the strong halogen-free group of a kind of antiphlogistic effects.
Summary of the invention:
The invention provides a kind of is the stickup tablet of the nontoxic plasticizer of the use of active component with methylprednisolone or its pharmaceutically useful carboxylate especially methylprednisolone aceponate.
Every active component that contains of stickup tablet of the present invention is one or more in methylprednisolone or its pharmaceutically useful carboxylate, as methylprednisolone, methylprednisolone acetate, methylprednisolone aceponate, and preferred methylprednisolone aceponate.The amount that every sticking tablet preferably contains active component is counted 0.01mg to 1mg with methylprednisolone, preferred 0.05mg to 0.5mg.Preferred especially 0.1mg to 0.2mg.For avoiding the side effect of glucocorticoid, the accumulated dose of the active component that use every day is no more than 4mg.
When stickup tablet of the present invention was used for the treatment of oral ulcer, used 1～3 preferred every day, uses 1～3 at every turn.
This tablet is made of adhesion layer that contains active component and water-fast protective layer, and the non-active ingredient that adhesion layer contained is by tablet filler commonly used, as amylum pregelatinisatum, lactose, sucrose,, in the mannitol, dextrin one or more, preferred dextrin; And the adhesion slow releasing agent includes but are not limited in carbomer (crosslinked polypropylene acid resin), polyvinylpyrrolidone (PVP), hydroxypropyl emthylcellulose (HPC), polyvinyl alcohol (PVA), sodium carboxymethyl cellulose (CMC-Na), hydroxypropyl cellulose (HPC), the hydroxypropyl emthylcellulose (HPMC) one or more, preferred carbomer.Can also contain lubricant for example but be not limited only to magnesium stearate, micropowder silica gel, Pulvis Talci, preferred magnesium stearate.
Adhesion layer described in every dose of sticking tablet can contain filler 10mg to 80mg, preferred 20mg to 50mg, and the consumption that adheres to slow releasing agent is 20% to 40% of a filler weight (dry weight), preferred 25% to 35%.Lubricant quantity is 0.05%～1% of an adhesion layer weight (dry weight).The weight of water-fast protective layer (dry weight) is 10%～20% of adhesion layer weight.
Water-fast protective layer in the described sticking tablet by can be as the protection polyacrylic resin of coating and/or ethyl cellulose, plasticizer, and optionally, pharmaceutically useful coloring agent and/or the white color ingot that can better differentiate the different layer of sticking tablet when order is used constitute.Described polyacrylic resin, (commodity are by name to comprise methacrylic acid and methyl methacrylate (1:1) copolymer (2005 editions described polyacrylic resin II of Chinese Pharmacopoeia) or methacrylic acid and ethyl acrylate (1:1) copolymer
L100-55 and
L30D-55 originates from German Degussa company), preferred
L100-55 or
L30D-55.When selecting ethyl cellulose for use, also need use plasticizer.Described white color ingot is preferred but be not limited only to titanium dioxide, described coloring agent be can be medicinal pigment, preferably but be not limited only in yellow ferric oxide, Brown Ferric Oxide, the red ferric oxide one or more.
Described plasticizer can be selected from but be not limited only in epoxy soybean oil, the citric acid ester plasticizer one or more, described citric acid ester plasticizer can be enumerated but be not limited to citric acid tri-n-hexyl ester (THC), the just own ester of acetyl tributyl citrate three (ATHC), trioctyl lemon acid (TOC), acetyl tributyl citrate three monooctyl esters (ATOC), tributyl citrate (TBC), tributyl 2-acetylcitrate (ATBC), butyryl citric acid three own esters (BTHC), plasticizer optimization citric acid tributyl and/or tributyl 2-acetylcitrate.Described plasticizer consumption is 5% to 30%, preferred 10%～25% of a protective layer weight (dry weight).
Find through experiment; in the plasticizer of citric acid ester type; common triethyl citrate, acetyl triethyl citrate etc. are because water solublity is stronger; protective layer water absorption rate and the plasticizer dissolution rate that forms is higher (according to the coating membrane water absorption rate 15.21% of embodiment method preparation; plasticizer dissolution rate 8.45%); and when with the carbon number of the alcohol of Citrin ester more than or equal to 4 the time (as tributyl citrate); the water absorption rate of the coating membrane that makes as shown in the Examples, and plasticizer dissolution rate significantly reduce.Draw thus, better with the carbon number of the alcohol of Citrin ester more than or equal to the coating membrane protective effect that formed in 4 o'clock, can realize purpose of the present invention.
Technical scheme of the present invention can also be made only has the monolayer sticking tablet of adhesion layer as mentioned above.
Stickup tablet of the present invention (above-mentioned monolayer, double-deck sticking tablet) prepares by the following method: active component is dissolved; mix with filler after granulate, granulate; tabletting gets the monolayer sticking tablet after add adhering to slow releasing agent and magnesium stearate mixing, and the solution spraying that will contain acrylic resin, plasticizer and pigment by Membrane jetter is made protective layer in the tablet surface and got double-deck sticking tablet again.
The double-deck tablet of pasting of the present invention has overcome existing stickup tablet in the prior art uses the phthalate of potential hazard to the person the defective of plasticizer, has used the plasticizer nontoxic to human body instead.Show that by the contrast experiment compared with prior art effect is suitable for the protective action of employing nontoxic plasticizer protective layer, even better, has overcome the potential hazard of original phthalic ester plasticizer to human body.
Show by experimental example 2, not halogen-containing methylprednisolone and medicinal carboxylate thereof have been adopted, particularly methylprednisolone aceponate is the sticking tablet of active component, when drug effect improves, the side effect that causes atrophoderma also obviously reduces, can draw when acting on oral mucosa thus, the side effect that causes atrophy to oral mucosa also can greatly reduce, and the oral mucosa atrophy itself is exactly a kind of important clinical symptom performance of oral ulcer, thereby adopt methylprednisolone aceponate be the sticking tablet of active component when the treatment oral ulcer except therapeutical effect to ulcer surface, its low atrophic that causes has special therapeutical effect for the treatment oral ulcer.In addition, oral ulcer for recurrent, owing to need treat repeatedly at same position, thereby so to adopt low atrophic active component such as the methylprednisolone aceponate of causing be that the sticking tablet of active component can avoid the atrophy of oral mucosa to reach better therapeutic effect in the treatment oral ulcer preferably.
Show by the contrast experiment in addition, compare with the dexamethasone acetate oral cavity sticking tablet of prior art Chinese patent CN00132507.3 disclosed method preparation, the ratio that the various sticking tablets of the employing embodiment of the invention 1～8 cause thrush (fungal infection) in use is all lower, prior art thrush incidence rate is 4.67%, and the thrush incidence rate of the various sticking tablets of the embodiment of the invention is 0.97%～3.21%, incidence rate and active component dosage linear correlation.
To product of the present invention by illumination (2500LUX), high temperature (40 ℃, 60 ℃, 80 ℃, high humidity (RH75%, 92.5%), each influence factor of 10 days test of air at room temperature, the study on the stability that accelerated test (40 ℃, RH75%) three months and room temperature kept sample 24 months, its medicated layer character, related substance, dissolubility, content etc. have no significant change.
Present composition effect system passes through mucosa absorption, employing is the sticking tablet of the present invention (as embodiment 1,3,5,7 made sticking tablets) of active component with the methylprednisolone aceponate, with the chicken gizzard capsule is biomembranous model, can observe principal agent compare by mucosa absorption and with the ordinary tablet of same dose active component, 5 hours as a result transmitance situations see the following form (in methylprednisolone MP%).
Table 15 hour transmitance information slip
| Embodiment 1/ ordinary tablet | Embodiment 2/ ordinary tablet | Embodiment 3/ ordinary tablet | Embodiment 4/ ordinary tablet | Embodiment 5/ ordinary tablet | Embodiment 6/ ordinary tablet | Embodiment 7/ ordinary tablet | Embodiment 8/ ordinary tablet | |
| MP％ | 65/47 | 58/40 | 60/50 | 59/40 | 62/45 | 63/45 | 61/42 | 62/44 |
(the tinidazole oral film is to the therapeutical effect of experimental rat periodontitis and to the research of oral mucosa zest, Chinese clinical pharmacology and therapeutics, 2004Jan with reference to Wang Linhui etc. for product of the present invention; 9 (1)) disclosed mucomembranous irritant test method, observe the stimulation of this product to the oral mucosa of rat, the result shows: this product and excipient contrast level (blank sticking tablet), successive administration 7 days, 1 hour hour execution rat after the last administration, observe the rat oral mucosa, the result does not have obvious hyperemia and edema phenomenon, and histopathologic examination and matched group do not see that the mucosa morphosis is unusual.
Specific embodiment
Embodiment 1
Paste lamella
Methylprednisolone aceponate 0.1g
Carbomer 10g
Dextrin 30g
Magnesium stearate 0.03g
Protective layer
Titanium dioxide 1g
Yellow ferric oxide 1g
Tributyl 2-acetylcitrate (ATBC) 0.8g
Preparation technology:
With methylprednisolone aceponate 5ml anhydrous alcohol solution, the solution of above-mentioned active component was joined in the dextrin of 100 mesh sieves fully mixing after 30 mesh sieves are granulated, after 60 ℃ of oven dry, through 40 mesh sieve granulate, after adding the abundant mixing of carbopol, magnesium stearate of 100 mesh sieves, promptly get 1000 with diameter 6mm flat punch tabletting, every contains methylprednisolone aceponate 0.10mg.With recipe quantity
L100-55 dissolves with 95% alcohol 95 ml, adds ATBC, titanium dioxide, the yellow ferric oxide of recipe quantity, every heavily about 50mg.
Embodiment 2
The prescription of embodiment 1 changes active component into methylprednisolone aceponate 0.2g, and plasticizer changes other preparation technologies of tributyl citrate (TBC) into embodiment 1
Embodiment 3
Paste lamella
Methylprednisolone 0.5g
Carbomer 5g
Polyvinylpyrrolidone (PVP) 3g
Dextrin 30g
Magnesium stearate 0.05g
Protective layer
L100-55 4g
Titanium dioxide 0.5g
Citric acid three own ester (THC) 0.8g
Preparation technology:
With an amount of anhydrous alcohol solution of methylprednisolone, the solution of above-mentioned active component was joined in the dextrin of 100 mesh sieves fully mixing after 30 mesh sieves are granulated, after 60 ℃ of oven dry, through 40 mesh sieve granulate, after adding the abundant mixing of carbomer, PVP, magnesium stearate of 100 mesh sieves, promptly get 1000 with diameter 6mm flat punch tabletting, contain methylprednisolone 0.5mg with recipe quantity
L100-55 dissolves with 95% alcohol 95 ml, and the THC, the titanium dioxide that add recipe quantity grind evenly, evenly are sprayed at the tablet surface with Membrane jetter, form the protective layer of tablet after drying, every heavily about 50mg.
Embodiment 4
As the prescription of embodiment 3, change active component into methylprednisolone acetate 0.5g, change plasticizer into acetyl tributyl citrate three own esters (ATHC).Other preparation technologies are with embodiment 3.
Embodiment 5
Paste lamella
Methylprednisolone 1.0g
Carbomer 5g
Hydroxypropyl cellulose (HPC) 3g
Dextrin 30g
Magnesium stearate 0.05g
Protective layer
Epoxy soybean oil 0.6g
Preparation technology:
With methylprednisolone with an amount of anhydrous alcohol solution after, joined in the dextrin of 100 mesh sieves fully mixing respectively after 30 mesh sieves are granulated, after 60 ℃ of oven dry, through 40 mesh sieve granulate, after adding the abundant mixing of carbomer, HPC, magnesium stearate of 100 mesh sieves, promptly get 1000 with diameter 6mm flat punch tabletting, contain methylprednisolone 1.0mg.With recipe quantity
L30D-55 dissolves with 95% alcohol 95 ml, and the epoxy soybean oil grinding that adds recipe quantity is even, evenly is sprayed at the tablet surface with Membrane jetter, after drying, forms the protective layer of tablet.Every heavily about 50mg
Embodiment 6
Paste lamella
Methylprednisolone acetate 0.7g
Polyvinylpyrrolidone (PVA) 5g
Hydroxypropyl emthylcellulose (HPMC) 5g
Amylum pregelatinisatum 30g
Magnesium stearate 0.05g
Protective layer
L30D-55 4g
Trioctyl lemon acid (TOC) 1.5g
Behind an amount of anhydrous alcohol solution of methylprednisolone acetate, joined in the dextrin of 100 mesh sieves fully mixing respectively after 30 mesh sieves are granulated, after 60 ℃ of oven dry, through 40 mesh sieve granulate, after adding the abundant mixing of PVA, HPMC, magnesium stearate of 100 mesh sieves, get 1000 with diameter 6mm flat punch tabletting, every heavily about 50mg contains methylprednisolone acetate 0.7mg.With recipe quantity
L30D-55 dissolves with 95% alcohol 95 ml, and the TOC that adds recipe quantity grinds evenly, evenly is sprayed at the tablet surface with Membrane jetter, after drying, forms the protective layer of tablet.
Embodiment 7
Paste lamella
Methylprednisolone aceponate 0.06g
Sodium carboxymethyl cellulose (CMC-Na) 5g
Hydroxypropyl cellulose (HPC) 7g
Dextrin 30g
Pulvis Talci 0.1g
Protective layer
Lemon acid three monooctyl esters (ATOC) 1.5g
Titanium dioxide 0.5g
With methylprednisolone aceponate with an amount of dissolve with ethanol after, joined in the dextrin of 100 mesh sieves fully mixing respectively after 30 mesh sieves are granulated, after 60 ℃ of oven dry, through 40 mesh sieve granulate, after adding the abundant mixing of CMC-Na, HPC, Pulvis Talci of 100 mesh sieves, get 1000 with diameter 6mm flat punch tabletting, every heavily about 50mg contains methylprednisolone aceponate 0.06mg.With recipe quantity
L30D-55 dissolves with 95% alcohol 95 ml, and the ATOC that adds recipe quantity grinds evenly, evenly is sprayed at the tablet surface with Membrane jetter, after drying, forms the protective layer of tablet.
Embodiment 8
Paste lamella
Methylprednisolone aceponate 0.3g
Sodium carboxymethyl cellulose (CMC-Na) 5g
Hydroxypropyl emthylcellulose (HPMC) 7g
Dextrin 30g
Magnesium stearate 0.2g
Protective layer
Ethyl cellulose 4g
Butyryl citric acid three is ester (BTHC) 1.5g
With the methylprednisolone aceponate of recipe quantity respectively with after an amount of dehydrated alcohol, the purified water dissolving, joined in the dextrin of 100 mesh sieves fully mixing respectively after 30 mesh sieves are granulated, after 60 ℃ of oven dry, through 40 mesh sieve granulate, after adding the abundant mixing of CMC-Na, HPMC, Pulvis Talci of 100 mesh sieves, get 1000 with diameter 6mm flat punch tabletting, every heavily about 50mg contains methylprednisolone aceponate 0.3mg.The ethyl cellulose of recipe quantity is dissolved with 95% alcohol 95 ml, and the BTHC that adds recipe quantity grinds evenly, evenly is sprayed at the tablet surface with Membrane jetter, after drying, forms the tablet protective layer.
Embodiment 9～16
Press prescription and the method preparation monolayer of embodiment 1～8 respectively and paste tablet.
The contrast of test comparative example 1 drug effect
Experimental drug: according to the sticking tablet of embodiment 1,2,7,8 preparations.
Laboratory animal: 44 of healthy Japan large ear rabbits, body weight 2.0～2.5kg, male and female are not limit.
Experimental technique:
1. modeling
With reference to Chen Ke, Ren Yuguang, Luo Yuning etc. (animal experiment study of Chinese document laser therapy oral ulcer, YAG. uses laser, and 1998,18 (3): 135～136) disclosed method grinds the hole that diameter is 3mm with the plastic centrifuge tube bottom.Be stained with 90% carbolic acid (moistening, do not overflow be degree) with cotton pellet and put aperture place in the pipe; Rabbit is used 3% Nembutal vein anesthetic, retract upperlip, expose buccal, oral cavity mucosa, centrifuge tube burnt 30 seconds perpendicular to oral mucosa, made local oral mucosa be pale asphyxia.Wound surface forms roun ulcer next day, the surface is congested, no pseudomembrane, and the border is more clear.Two ulcer surfaces about every rabbit is burnt.Respectively form ulcer hyperemia, the edema situation of face and carry out integration relatively.
2. experiment
Be divided into 8 groups at random after the modeling success, prepare dexamethasone acetate plaster according to Chinese patent 00132507.8 disclosed method and be the prior art matched group for 3 kinds, every dexamethasone acetate content is respectively 0.1mg, 0.3mg, 0.5mg is divided into existing 1,2,3.And the sticking tablet that makes of embodiment 1,2,7,8 to be divided into be 7 experimental grouies and positive controls, following table between the grouping situation
Table 2: grouping information slip
| Embodiment 1 | Embodiment 2 | Embodiment 7 | Embodiment 8 | Existing 1 | Existing 2 | Existing 3 | Positive control |
| A1 | A2 | A7 | A8 | B1 | B2 | B3 | C |
| Methylprednisolone aceponate | Methylprednisolone aceponate | Methylprednisolone aceponate | Methylprednisolone aceponate | Dexamethasone acetate | Dexamethasone acetate | Dexamethasone acetate | —— |
Experimental technique:
2 each a slices of every group of administration every day are pasted other medicine of respective sets, and blank group is coated with normal saline.The ulcer area of each group of different time sees Table 3 in the treatment
Ulcer area (the mm of each group of different time in table 3 treatment
2))
| Group | Active component | Before the treatment | Treat after 1 day | Treat after 2 days | Treat after 3 days |
| The mg/ sheet | |||||
| A1 | 0.1 | 46.01±1.14 | 40.21±1.21 | 34.78±1.14 | 26.68±0.98 |
| A2 | 0.2 | 45.27±1.11 | 37.87±1.01 | 33.01±0.92 | 24.45±1.01 |
| A7 | 0.06 | 45.81±1.08 | 41.10±1.09 | 34.58±0.87 | 27.89±0.96 |
| A8 | 0.3 | 45.57±0.93 | 35.18±0.78 | 29.47±0.97 | 23.14±0.84 |
| B1 | 0.1 | 45.63±1.14 | 43.22±0.99 | 38.14±1.05 | 33.67±0.69 |
| B2 | 0.3 | 46.29±0.86 | 40.91±1.14 | 35.14±0.84 | 28.03±0.92 |
| B3 | 0.5 | 46.51±0.99 | 39.88±1.16 | 33.75±1.33 | 27.04±0.95 |
| C | 46.30±1.50 | 47.02±1.05 | 45.98±0.97 | 44.14±0.76 |
From the experimental result of table 3, each experimental group is compared during with positive controls corresponding treatment natural law, and the ulcer area all has significance (P＜0.05).Compare with preferred version B2 group of the prior art, ulcer area during A8, A2 group corresponding treatment natural law has significance (P＜0.05), ulcer area during A1 group corresponding treatment natural law does not have significance (P〉0.05), illustrate that A8, A2 group therapeutic effect is better than the B2 group, the therapeutic effect of A1 group and B2 group are quite.
And the A7 group is compared with the B1 group as prior art, ulcer area during the corresponding treatment natural law does not have significance (P〉0.05), this explanation is under this drug effect embodiment condition, the particularly preferred active component methylprednisolone aceponate of the present invention only need be used lower dosage when reaching the same effect of dexamethasone acetate, and curative effect is better than dexamethasone acetate plaster far away under the Isodose.
Test comparative example 2, local action causes atrophy effect contrast
Laboratory animal: 50 of white Cavia porcelluss childhood, body weight 300g ± 20g
Experiment medicine: A group medicine, (the 0.3mg/ sheet is by prior art manufacturing among the test comparative example 1 for dexamethasone acetate plaster.
B organizes medicine, and the sticking tablet that makes according to embodiment 1,2,7,8 is divided into B1, B2, B7, B8 group respectively, and medicament contg is respectively (0.1mg/ sheet, 0.2mg/ sheet, 0.06mg/ sheet, 0.3mg/ sheet).
Grouping and experiment: Cavia porcellus is divided into 5 groups at random, and A organizes (dexamethasone acetate plaster), and B1, B2, B7, B8 organize (sticking tablet that embodiment 1,2,7,8 makes)
Just every guinea pig back left and right sides antimere selects the zone of 3cm * 3cm, shaves hair, and the experimental group sticking tablet is labelled to a side, and the blank sticking tablet of corresponding embodiment is used in the another side.Medication every day 2 times was pasted 5 hours at every turn.Continuous use, after medication the 5th day with every group of Cavia porcellus drug withdrawal, medication district, back and check plot skin are put to death and got respectively to Cavia porcellus, the ratio of measuring medication district skin thickness and check plot skin thickness is to determine the atrophoderma degree.The results are shown in Table 6
Compare with A group, the atrophy degree that causes of B group (B1, B2, B7, B8) has significance (P＜0.05), illustrate thus methylprednisolone and derivant especially methylprednisolone aceponate is when local action, side effect is littler.The toleration of body is better.
The contrast of test comparative example 3 coatings barrier propterties
The effect key of enforcement of the present invention is the barrier propterty of coatings, have only barrier propterty good, fluid-tight coatings can better realize that just technique effect of the present invention promptly reduces dissolving and tablet the two-way adhesion between gums and oral mucosa of medicine to the offside of mucosa.
Equipment:; Teflon coils (Shanghai Chemical Plant's customization)), calibrator (0.001mm, Taizhou Jiangjiang Seiko measurer company), digestion instrument
Produce disclosed coating solution among coating solution in the embodiment of the invention 1～8 and ZL 00 1 32507.8 embodiment respectively.Quantitatively move in the Teflon dish that is stamped upside down funnel,, choose thickness 350 ± 50 μ m and examine under a microscope the film of no indentation standby in (20 ± 1) ℃, 60% time drying of relative humidity (RH) 48 hours.
The coating membrane that disclosed coating solution is made among coating membrane that coating solution among the embodiment 1～8 is made and ZL 00 1 32507.8 embodiment is divided into 1～8 group of embodiment and matched group, every group of 3 films, every 300mg is respectively in the digestion instrument of the phosphate buffered solution that fills pH6.8, at 37 ℃, stripping is 8 hours under the 100r/min, blot the film surface moisture with filter paper after precision weigh (ml), place drying to think highly of to constant weight film, precision is weighed (m2), surveys water absorption rate and plasticizer dissolution rate.
Water absorption rate %=(m1-m2)/m2 * 100%
The heavy plasticizer weight of plasticizer dissolution rate=buffer/(300mg * plasticizer loading) experimental result sees Table 4
Table 4: coating membrane water absorption rate and plasticizer dissolution rate meansigma methods table
| Water absorption rate % | Plasticizer dissolution rate % | |
| Embodiment 1 (ATBC) | 3.42 | 2.98 |
| Embodiment 2 (TBC) | 3.14 | 2.72 |
| Embodiment 3 (THC) | 2.83 | 2.15 |
| Embodiment 4 (ATHC) | 2.50 | 1.75 |
| Embodiment 5 (epoxy soybean oil) | 3.01 | 2.64 |
| Embodiment 6 (TOC) | 1.37 | 0.95 |
| Embodiment 7 (ATOC) | 1.40 | 0.97 |
| Embodiment 8 (BTHC) | 1.48 | 0.85 |
| Matched group (DOP) | 2.52 | 2.01 |
As can be seen from Table 4; respectively organize plasticizer among the embodiment and can both reach the certain protection effect; (water absorption rate＜5%; plasticizer dissolution rate＜5%); the water absorption rate of the coating membrane of gained is compared quite with matched group or is omited with the plasticizer dissolution rate when preferred TOC, ATOC, BTHC especially; illustrate that the various plasticizers that the present invention selects for use are the goal of the invention that citric acid ester plasticizer, epoxy soybean oil all can be realized the protective layer coating, make the sticking tablet that makes reach the effect of unidirectional administration.
Claims (14)
1. oral cavity sticking tablet that is used for the treatment of people or mammal oral ulcer; constitute by adhesion layer that contains active component and water-fast protective layer; the non-active ingredient that adhesion layer contains is by the filler that is applicable to tablet; adhering to slow releasing agent and lubricant forms; described water-fast protective layer is by can be used as polyacrylic resin or the ethyl cellulose that protects coating; and plasticizer constitutes; it is characterized in that; described active component is one or more in methylprednisolone or its pharmaceutically useful carboxylate; every sticking tablet contains active component 0.01mg to 1mg, and described plasticizer is an epoxy soybean oil; in the citric acid ester plasticizer one or more.
2. sticking tablet as claimed in claim 1 is characterized in that described active component is one or more in methylprednisolone, methylprednisolone acetate, the methylprednisolone aceponate,
3. sticking tablet as claimed in claim 2 is characterized in that described active component is a methylprednisolone aceponate.
4. sticking tablet as claimed in claim 1, the every preferred 0.1mg to 0.2mg of active component that sticking tablet contains.
5. as arbitrary described sticking tablet in the claim 1 to 4, the filler 10mg to 80mg that adhesion layer described in every sticking tablet contains, be amylum pregelatinisatum, lactose, sucrose, mannitol, in the dextrin one or more, the consumption of described adhesion slow releasing agent is 20% to 40% of a filler dry weight, be carbomer, polyvinylpyrrolidone, polyvinyl alcohol, sodium carboxymethyl cellulose, hydroxypropyl cellulose, in the hydroxypropyl emthylcellulose one or more, described lubricant quantity is 0.05% to 1% of an adhesion layer dry weight, is magnesium stearate, microcrystalline Cellulose, in the Pulvis Talci one or more; The dry weight of described water-fast protective layer is 10% to 20% of an adhesion layer weight; described polyacrylic resin is polyacrylic resin II and/or methacrylic acid and 1: 1 copolymer of ethyl acrylate; described plasticizer is; in epoxy soybean oil, citric acid three own esters, acetyl tributyl citrate three own esters, trioctyl lemon acid, acetyl tributyl citrate three monooctyl esters, tributyl citrate, tributyl 2-acetylcitrate, the butyryl citric acid three own esters one or more, described plasticizer consumption is 5% to 30% of a protective layer dry weight.
6. sticking tablet as claimed in claim 5 is characterized in that in the just own ester of described plasticizer optimization citric acid three, the just own ester of acetyl tributyl citrate three, trioctyl lemon acid, acetyl tributyl citrate three monooctyl esters one or more.
7. sticking tablet as claimed in claim 5 is characterized in that the preferred dextrin of filler of described adhesion layer.
8. sticking tablet as claimed in claim 5 is characterized in that also containing in the described water-fast protective layer pharmaceutically useful coloring agent and/or white color ingot.
9. sticking tablet as claimed in claim 5 is characterized in that the preferred magnesium stearate of lubricant in the described adhesion layer.
10. sticking tablet as claimed in claim 5 is characterized in that the preferred carbomer of adhesion slow releasing agent in the described adhesion layer.
11. sticking tablet as claimed in claim 5 is characterized in that the consumption of the adhesion slow releasing agent in the described adhesion layer is preferably 25% to 35% of filler dry weight.
12. sticking tablet as claimed in claim 5.It is characterized in that plasticizer dosage is preferably 10% to 25% of protective layer dry weight in the described protective layer.
13. sticking tablet as claimed in claim 5; preparation by the following method: active component is dissolved; mix with filler after granulate, granulate; tabletting promptly gets the monolayer sticking tablet after add adhering to slow releasing agent and lubricant mixing, and the solution spraying that will contain polyacrylic resin, plasticizer by Membrane jetter is made protective layer in the tablet surface and promptly got double-deck sticking tablet again.
14. sticking tablet as claimed in claim 8; preparation by the following method: active component is dissolved; mix with filler after granulate, granulate; tabletting promptly gets the monolayer sticking tablet after add adhering to slow releasing agent and lubricant and pigment mixing, and the solution spraying that will contain polyacrylic resin, plasticizer and pigment by Membrane jetter is made protective layer in the tablet surface and promptly got double-deck sticking tablet again.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200710059249XA CN101371824B (en) | 2007-08-23 | 2007-08-23 | Oral cavity pasting tablets using Methylprednisolone and derivatives thereof as active components |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200710059249XA CN101371824B (en) | 2007-08-23 | 2007-08-23 | Oral cavity pasting tablets using Methylprednisolone and derivatives thereof as active components |
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| Publication Number | Publication Date |
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| CN101371824A CN101371824A (en) | 2009-02-25 |
| CN101371824B true CN101371824B (en) | 2011-08-31 |
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| CN104706578B (en) * | 2013-12-14 | 2019-04-23 | 天津金耀集团有限公司 | A kind of preparation method of methylprednisolone acetate suspension injection composition |
| CN106474137B (en) * | 2016-08-30 | 2017-09-26 | 广东科玮生物技术股份有限公司 | A kind of film for treating oral ulcer containing chlorophyll and preparation method thereof |
| CN107137371B (en) * | 2017-06-27 | 2020-06-12 | 石家庄学院 | Double-layer adhesive patch for treating dental ulcer |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1389200A (en) * | 2000-11-24 | 2003-01-08 | 深圳太太药业股份有限公司 | Dexamethasone acetate plaster and its prepn. |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1389200A (en) * | 2000-11-24 | 2003-01-08 | 深圳太太药业股份有限公司 | Dexamethasone acetate plaster and its prepn. |
Non-Patent Citations (2)
| Title |
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| 陈新谦等.甲泼尼龙.《新编药物学》.人民卫生出版社第15版,2003,第568页. * |
| 鲁凤兰.无毒增塑剂的生产与应用.《精细石油化工进展》.2006,第7卷(第9期),40-45. * |
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