CN106924175A - A kind of pharmaceutical composition for treating multiple sclerosis - Google Patents
A kind of pharmaceutical composition for treating multiple sclerosis Download PDFInfo
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- CN106924175A CN106924175A CN201511016125.4A CN201511016125A CN106924175A CN 106924175 A CN106924175 A CN 106924175A CN 201511016125 A CN201511016125 A CN 201511016125A CN 106924175 A CN106924175 A CN 106924175A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/02—Peptides of undefined number of amino acids; Derivatives thereof
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0043—Nose
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Abstract
The present invention relates to a kind of pharmaceutical composition for treating multiple sclerosis, specifically related to a kind of acetic acid copaxone nasal gel composition, it is made up of acetic acid copaxone, gel-type vehicle and pharmaceutically acceptable other auxiliary materials, described acceptable other auxiliary materials include bioadhesive material 0.9%~1.75%, and the bio-adhesive material is selected from starch, chitin, glucan, the combination of xanthans one or more of which.
Description
Technical field
The present invention relates to a kind of nasal administration composition for treating multiple sclerosis syndrome.
Background technology
Multiple sclerosis syndrome (Multiple sclerosis, MS) is clinically that the maincenter in human body can occur
A kind of immunity disease of the own type in nervous system, the generation of such disease is main with Human Physiology autoreactivity
What immune t-cell caused, cause brain and spinal cord inflammation and nerve demyelination change to be characterized, its incidence of disease is not only in America and Europe etc.
Country belongs to frequently-occurring disease, and is also relatively common in our fruit Young crowds (especially in 30 years old crowd)
The reason for a kind of disease, such disease incidence, the immunoregulatory disorder typically to human body itself was related.
MS clinical classifications are generally acknowledged at present：
1. relapsing remitting MS (RRMS)
The most common course of disease type of MS, 80%MS morbidity's initial stages are this type, show as obvious recurrence and alleviate
Process, breaking-out is basic every time recovers, and does not stay or only leaves minimal residual disease.As the progress majority of the course of disease is in 5~15 years
Finally it is changed into SPMS.
2. secondary Advancement Type MS (SPMS)
A course of disease type after RRMS, shows as after remission stage is recurred, and disease can not be delayed completely with recurrence
Solve and leave part sequelae, the process that disease is gradually slowly aggravated.In RRMS patient about 50% in 10 years/80% in 20 years
Inside it is changed into this type.
3. primary Advancement Type MS (PPMS)
The rare course of disease type of MS, 10%~15%MS patients initially show as this type, and clinic recurs without alleviation
Process, disease is aggravated in slow progressive, and the course of disease is more than 1 year.
4. be in progress relapsing MS (PRMS)
The rare course of disease type of MS, about 5%~10%MS patients show as this type, and disease adds in slow progressive all the time
Weight, there is a small number of alleviation relapsing courses in the course of disease.
Acetic acid copaxone, commercial goods are entitledIt is a kind of polypeptide compounds of synthesis, by four kinds of ammonia
Base acid composition：Pidolidone, ALANINE, 1B, L- TYRs, for treating multiple sclerosis.
Curative effect and tolerance all obtain full affirmative, many researchs confirm that it can significantly lower answering for patient with clinical experience
Hair rate, improves the patient's condition of disability, reduces outside brain injury.In addition, correlative study also showsThan interferon
Recurrence rate can be more significantly decreased, neural further damage is prevented and is deteriorated, and with more preferable tolerance.At other
In the effectiveness study of long-term use (6 years to most long 12 years),Also confirm constantly delay its god of patient
In the study of Confucian classics deterioration of the course of disease or allow patient maintain stabilization the patient's condition, reduce intracerebral damage and prevent neuron from largely wrecking
Eventually to the deterioration situation of loss of function.
Acetic acid copaxone is clinically used with injecting solution, in all of clinical test and user are using feedback, is noted
It is according to observations most common adverse reaction and most of receiving to penetrate position atrophyPatient there is this to react, in additionOther most common side effects are the IR of injection site, including：Erythema, pain, swelling, itching, water
Swollen, inflammation and allergic reaction.
<United States Patent (USP) 6,214,791>Disclosed to take acetic acid copaxone by taking in or sucking, having the disadvantage cannot
Gastro-intestinal Fluid is avoided to degrade the first pass effect of the degradation of medicine and liver, enzyme metabolism and enzyme.
<U.S. Patent Application Publication No. 2001/0055568A1>In oral shortcoming it is same<United States Patent (USP) 6,214,791
>, though suction can avoid the first pass effect high, long-time inhalation from needing to inspect periodically lung physiology situation.And vinegar
Sour copaxone belongs to prolonged administration of drugs, if successive administration easily causes a certain degree of damage to lung, drug dose is not yet
Good control, usage trouble.
<CN201380067117>A kind of mode of the saturating mucosal drug delivery in oral cavity, but involuntary salivary secretion in oral cavity are disclosed
And swallow the efficiency of influence mucous membrane of mouth approach；The taste stimulation of medicine influences the compliance of the approach.
In order to overcome existing drug administration by injection that the various adverse reactions of patient, compliance difference or treatment pause etc. may be caused negative
Load, develops alternative Glatiramer acetate dosage regimen, acetic acid copaxone is effectively treated a kind of form using described scheme
Multiple Sclerosis Symptoms.
Nasal drug delivery system refers to the class preparation that locally or systemically treatment or prevention effect are played via nasal-cavity administration, especially
It is applied to other approach in addition to injection and medicine that is difficult and need to playing general action is administered, and is such as orally difficult to the polarity for absorbing
The strong medicine of medicine, medicine unstable in the gastrointestinal tract, liver first-pass effect and albumen and polypeptide drug etc..
The content of the invention
The mean molecule quantity of acetic acid copaxone should not pass through bronchia mucosal between 5000 dalton~9000 dalton
Absorbed, experimenter has found that some sorbefacients contribute to the absorption of acetic acid copaxone in experimentation, but glutinous to nose
Film has certain toxic action, promotes the scavenging action of cilium, reduces the bioavilability of medicine, and inventor is unexpected by testing
It was found that the particular organisms adhesion material of certain content can avoid the scavenging action of mucociliary in nasal cavity, increase medicine in mucous membrane
On residence time, so as to improve the bioavilability of medicine, while the toxicity to ciliary movement can be reduced.
In order to overcome above-mentioned technological deficiency, one aspect of the invention to be combined there is provided a kind of acetic acid copaxone nasal gel
Thing, it is made up of acetic acid copaxone, gel-type vehicle and pharmaceutically acceptable other auxiliary materials, described acceptable other auxiliary materials
Including bioadhesive material 1.15%~1.75% (1.15%, 1.20%, 1.25%, 1.30%, 1.35%, 1.40%,
1.45%th, 1.50%, 1.55%, 1.60%, 1.65%, 1.70%, 1.75%), the bio-adhesive material is selected from starch, first
Shell element, glucan, the combination of xanthans one or more of which.
Further, described acceptable other auxiliary materials include sorbefacient, bioadhesive material, osmotic pressure regulation
Agent, NMF, preservative, pH adjusting agent, the percentage by weight for accounting for gel combination of its component for sorbefacient 2%~
5%th, osmotic pressure regulator 4.5%~9.0%, NMF 1%~5%, preservative 0.1%~0.25, pH adjusting agent 0.25%
~0.35.
Further, sorbefacient is selected from lauryl sodium sulfate, deoxysodium cholate, sodium taurocholate, sodium glycocholate, ox sulphur
Sodium taurocholate, disodium ethylene diamine tetraacetate, 2-HP-BETA-CD, lecithin one or more of which；Osmotic pressure regulator is selected
From sodium chloride, mannitol, glucose, sucrose one or more of which；NMF is selected from propane diols, glycerine, sorbierite, mannitol
One or more of which；Preservative is selected from BZK, phenmethylol, benzyl carbinol, EDTA one or more of which；PH adjusting agent is selected
From acetic acid, NaOH one or more of which.
Further, the percentage by weight that gel-type vehicle accounts for gel combination is 5.25%~6.25%, selected from polyethylene
One or more in alcohol, Hydroxypropyl methylcellulose, Carbomer, methylcellulose.
Further, the percentage by weight that acetic acid copaxone 1% accounts for gel combination is 1%.
In a specific embodiment of the invention, acetic acid copaxone nasal gel composition includes acetic acid copaxone
1%, 2-HP-BETA-CD 1%-5%, glucan 1.15%-1.75%, Carbomer 5.25%-6.25% and infiltration
Pressure conditioning agent, NMF, preservative and pH adjusting agent；Preferably include acetic acid copaxone 1%, 2-HP-BETA-CD
5%, glucan 1.15%, Carbomer 6.25% and osmotic pressure regulator, NMF, preservative and pH adjusting agent.
In a specific embodiment of the invention, acetic acid copaxone nasal gel composition includes acetic acid copaxone
1%, lecithin 1%-5%, chitin 0.9%-1.75%, polyvinyl alcohol 5.25%-6.25% and osmotic pressure regulator, guarantor
Humectant, preservative and pH adjusting agent；Preferably include acetic acid copaxone 1%, lecithin 1%, chitin 1.75%, polyvinyl alcohol
5.25% and osmotic pressure regulator, NMF, preservative and pH adjusting agent.
In a specific embodiment of the invention, acetic acid copaxone nasal gel composition includes acetic acid copaxone
1%, sodium glycocholate 1%-5%, starch 0.9%-1.75%, Hydroxypropyl methylcellulose 5.25%-6.25% and osmotic pressure are adjusted
Agent, NMF, preservative and pH adjusting agent；Preferably include acetic acid copaxone 1%, glycocholic acid 3.75%, starch 1.5%, hydroxyl
Third methylcellulose 5.5% and osmotic pressure regulator, NMF, preservative and pH adjusting agent.
In a specific embodiment of the invention, acetic acid copaxone nasal gel composition includes acetic acid copaxone
1%, sodium glycocholate 1%-5%, xanthans 0.9%-1.75%, methylcellulose 5.25%-6.25% and osmotic pressure are adjusted
Agent, NMF, preservative and pH adjusting agent；Preferably include acetic acid copaxone 1%, glycocholic acid 3.75%, xanthans 0.9%,
Methylcellulose 6% and osmotic pressure regulator, NMF, preservative and pH adjusting agent.
Further, the preparation method of the gel combination is：
Carbomer is added to the water, it is fully swelling, adjust pH value with the pH adjusting agent of alkalescence and obtain gel, then by acetic acid lattice
Draw and be dissolved in water for thunder, add other components mixing, stir evenly, obtain acetic acid copaxone solution, it is molten that this solution is added into Carbomer
In swollen thing, acetic acid copaxone gel for nose is obtained；Or
Methylcellulose or Hydroxypropyl methylcellulose are added to the water, fully it is swelling, be subsequently adding acetic acid copaxone and
Other auxiliary materials mix, and stir evenly, and obtain acetic acid copaxone gel for nose；Or
Polyvinyl alcohol is added to the water, it is fully swelling, adjust pH value with acidic ph modifier and obtain gel, then by acetic acid lattice
Drawing is dissolved in water for thunder, adds other auxiliary materials to mix, and stirs evenly, and obtains acetic acid copaxone solution, and this solution is added into polyvinyl alcohol
In swelling thing, acetic acid copaxone gel for nose is obtained.
Another aspect of the present invention is related to the preparation method of foregoing acetic acid copaxone nasal gel composition,
It comprises the following steps：
Carbomer is added to the water, it is fully swelling, adjust pH value with pH (7.0-8.0) conditioning agent of alkalescence and obtain gel, so
Acetic acid copaxone is dissolved in water afterwards, other components mixing is added, stirred evenly, obtain acetic acid copaxone solution, this solution is added
To in the swelling thing of Carbomer, acetic acid copaxone gel for nose is obtained；Or
Methylcellulose or Hydroxypropyl methylcellulose are added to the water, fully it is swelling, be subsequently adding acetic acid copaxone and
Other auxiliary materials mix, and stir evenly, and obtain acetic acid copaxone gel for nose；Or
Polyvinyl alcohol is added to the water, it is fully swelling, adjust pH value with acid pH (5.0-6.0) conditioning agent and obtain gel, so
Acetic acid copaxone is dissolved in water afterwards, adds other auxiliary materials to mix, stirred evenly, obtain acetic acid copaxone solution, this solution is added
To in the swelling thing of polyvinyl alcohol, acetic acid copaxone gel for nose is obtained.
It is multiple hard in preparation treatment that another aspect of the invention provides acetic acid copaxone nasal gel composition
Change the purposes in the medicine of syndrome.
It is a kind of pharmaceutical composition for treating multiple sclerosis syndrome that the present invention is provided, and said composition is drawn by acetic acid lattice and replaced
Thunder, gel-type vehicle and pharmaceutically acceptable other auxiliary material sorbefacient, bioadhesive material, osmotic pressure regulator, moisturizings
Agent, preservative, pH adjusting agent composition, its percentage by weight be acetic acid copaxone 1%, gel-type vehicle 5.25%~6.25%,
Sorbefacient 2%~5%, bioadhesive material 1.15%~1.75%, osmotic pressure regulator 4.5%~9.0%, NMF
1%~5%, preservative 0.1%~0.25, pH adjusting agent 0.25%~0.35, remaining is aqueous solvent.
Beneficial effect
1st, bioavilability is high.Compared with oral administration, nasal-cavity administration can avoid medicine from being degraded and liver in gastro-intestinal Fluid
First pass effect, bioavilability is high.Close to intravenous injection, macromolecular polypeptides class medicine is higher than mouth to small molecule drug bioavailability
Clothes.
2nd, quick-acting, schneiderian membrance area is big, and blood vessel enriches very much under mucous membrane, and artery, vein and capillary interweave and reticulate,
Liquid can be absorbed rapidly, and human circulation is entered from blood vessel.Distribution of the medicine in brain tissue can be increased by nasal-cavity administration, be can be used for
Treatment central nervous system disease.
3rd, the medicine being easily destroyed in intestines and stomach, polarity is big and intestines and stomach are difficult to the medicine for absorbing, and schneiderian membrance can be fine
Absorption, the big polypeptide of molecular weight, protein medicaments also can preferably absorb in the presence of sorbefacient.
4th, easy to use, patient compliance is good.Compared with drug administration by injection, nasal-cavity administration is easy to use, it is easy to connect by patient
Receive, be easy to self-medication.
5th, the method for the present invention improves the mucocutaneous transmitance of the acetic acid copaxone of macromolecule, by increasing capacitance it is possible to increase vinegar
The bioavilability of sour copaxone, and reduce scavenging action.
Brief description of the drawings
Accompanying drawing 1 is the releasing result curve map of the partial results of embodiment 13.
Accompanying drawing 2 is the releasing result curve map of the partial results of embodiment 13.
Specific embodiment
Embodiment 1：
Acetic acid copaxone gel for nose is constituted：
The preparation process of every 200 grams of gel preparation is:
(1) the gel-type vehicle Carbomer of recipe quantity is taken, plus 3~water of 5 times of weight, stirring makes it fully swelling, and hydrogen is added dropwise
Sodium oxide molybdena adjusts pH value to 7.0~8.0, stirs to obtain gel；
(2) the another recipe quantity acetic acid copaxone that takes plus 2~water dissolves of 5 times of weight；
(3) glucan, glucose, glycerine, EDTA are added 2~stirring of 3 times of weight water, dissolves it；
(4) solution of step (2) and step (3) is added in the gel-type vehicle solution of step (1), adds rush and absorb
Agent 2-HP-BETA-CD, stirs, and then adds water to 200g, stirs, i.e. finished product gel.
Embodiment 2
The preparation process of every 200 grams of gel preparation is:
(1) the gel-type vehicle polyvinyl alcohol of recipe quantity is taken, plus 4~water of 7 times of weight, vinegar acid for adjusting pH value to 5.0 is added dropwise
~6.0, stirring makes it fully swelling；
(2) the another recipe quantity acetic acid copaxone that takes plus 2~water dissolves of 5 times of weight；
(3) mannitol, BZK, propane diols, chitin are added 1~stirring of 2 times of weight water, dissolves it；
(4) solution of step (2) and step (3) is added in the gel-type vehicle solution of step (1), adds rush and absorb
Agent lecithin, stirs, and then adds water to 200g, stirs, i.e. finished product gel.Embodiment 3：
Acetic acid copaxone gel for nose is constituted：
The preparation process of every 200 grams of gel preparation is:
(1) Hydroxypropyl methylcellulose of recipe quantity is weighed, the water of 4~7 times of weight is added, it is stirring while adding, make it fully molten
It is swollen；
(2) the another recipe quantity acetic acid copaxone that takes plus 2~water dissolves of 5 times of weight；
(3) sodium chloride, EDTA, glycerine, starch are added 3~stirring of 4 times of weight water, dissolves it；
(4) solution of step (2) and step (3) is added in the gel-type vehicle solution of step (1), adds rush and absorb
Agent sodium glycocholate, stirs, and then adds water to 200g, stirs, i.e. finished product gel.
Embodiment 4：
The preparation process of every 200 grams of gel preparation is:
(1) methylcellulose of recipe quantity is weighed, the water of 4~7 times of weight is added, it is stirring while adding, make it fully swelling；
(2) the another recipe quantity acetic acid copaxone that takes plus 2~water dissolves of 5 times of weight；
(3) sodium chloride, EDTA, glycerine, xanthans are added 3~stirring of 4 times of weight water, dissolves it；
(4) solution of step (2) and step (3) is added in the gel-type vehicle solution of step (1), adds rush and absorb
Agent sodium glycocholate, stirs, and then adds water to 200g, stirs, i.e. finished product gel.
Embodiment 5
The preparation process of every 200 grams of gel preparation is:
(1) methylcellulose of recipe quantity is weighed, the water of 4~7 times of weight is added, it is stirring while adding, make it fully swelling；
(2) the another recipe quantity acetic acid copaxone that takes plus 2~water dissolves of 5 times of weight；
(3) sodium chloride, EDTA, glycerine, PVP are added 3~stirring of 4 times of weight water, dissolves it；
(4) solution of step (2) and step (3) is added in the gel-type vehicle solution of step (1), adds rush and absorb
Agent 2-HP-BETA-CD, stirs, and then adds water to 200g, stirs, i.e. finished product gel
Embodiment 6
Preparation process is with embodiment 1.
Embodiment 7
Preparation process is with embodiment 1.
Embodiment 8
Preparation process is with embodiment 1.
Embodiment 9
Preparation process is with embodiment 1.
Embodiment 10
Preparation process is with embodiment 1.
The Blank gel matrix control group of embodiment 11
The preparation process of every 200 grams of gel preparation is:
(1) the gel-type vehicle Carbomer of recipe quantity is taken, plus 3~water of 5 times of weight, stirring makes it fully swelling, and hydrogen is added dropwise
Sodium oxide molybdena adjusts pH value to 7.0~8.0, stirs to obtain gel；
(2) glucan, glucose, glycerine, EDTA are added 2~stirring of 3 times of weight water, dissolves it；
(3) solution of step (2) is added in the gel-type vehicle solution of step (1), adds absorption enhancers 2- hydroxypropyls
Group-beta-cyclodextrin, stirs, and then adds water to 200g, stirs, i.e. finished product gel.
The inanimate object adhesion material control group of embodiment 12
The preparation process of every 200 grams of gel preparation is:
(1) the gel-type vehicle Carbomer of recipe quantity is taken, plus 3~water of 5 times of weight, stirring makes it fully swelling, and hydrogen is added dropwise
Sodium oxide molybdena adjusts pH value to 7.0~8.0, stirs to obtain gel；
(2) the another recipe quantity acetic acid copaxone that takes plus 2~water dissolves of 5 times of weight；
(3) glucose, glycerine, EDTA are added 2~stirring of 3 times of weight water, dissolves it；
(4) solution of step (2) and step (3) is added in the gel-type vehicle solution of step (1), adds rush and absorb
Agent 2-HP-BETA-CD, stirs, and then adds water to 200g, stirs, i.e. finished product gel.
The nasal absorption model of the medicine of embodiment 13：
The vitro release of acetic acid copaxone gel is determined using the Franz diffusion cells of improvement, by pellicle (retention phase
Molecular mass 6500~9000) be fixed on the pond of diffusion cell two is asked, the pond internal diameter of diffusion cell two is 1.3cm, drug release area is about
1.33cm2, 2mL acetic acid copaxone gels are added to accurate in administration pond, diffusion cell is put into 37 DEG C of artificial nose liquid of 16ml
In, to added in reception tank be pre-heated to 37 DEG C of artificial nose liquid 10mL put as reception liquid, in reception tank a stirrer with
The rotational speed of 100r/min, in 15,30,45,60,90,120,180min is separately sampled, medium is all taken out and is mended rapidly
Plus the artificial nose liquid of equivalent preheating, sample liquid is through appropriate dilution, 0.45 μm of filtering with microporous membrane, and subsequent filtrate presses chromatographic condition,
The peak area of acetic acid copaxone is determined, Accumulation dissolution is calculated.
Chromatographic process：According to high performance liquid chromatography, using Kromasil NH2Chromatographic column, 4.6 × 250mm, 5 μm, flowing
It is mutually 0.08mol/L phosphate buffers (phosphoric acid adjusts pH to 4.0 ± 0.1)-acetonitrile (35：65) it is mobile phase, carries out isocratic washing
De-, Detection wavelength 275nm, column temperature is 30 DEG C, flow velocity 1.0ml/min.Acetic acid copaxone tailing factor should be less than 3.0.
Result see the table below (unit:%)：
From table knowable to the result of data and accompanying drawing 1, some bioadhesive materials can greatly improve the drawing of acetic acid lattice and replace
The release of thunder, the initial release time accelerates, and rate of release stabilization, burst size is carried compared to the sample without bio-adhesive material
It is high 2 times, the bioavilability of medicine is significantly improved, and simultaneously not all bio-adhesive material can reach good effect.This can
Can be due to causing its effect also to have very big difference in the presence of interaction between different bio-adhesive materials and acetic acid copaxone
It is different.When selecting PVP as bioadhesive material, the release of its composition is unable to reach at the appointed time controls curative effect
The requirement of fruit.From table knowable to the result of data and accompanying drawing 2, it can be seen that burst size is close with the species of bio-adhesive material
Correlation, the bio-adhesive material result of non-invention is poor, only similar with the result without bio-adhesive material.
The medicine of embodiment 14 influences model test to nasal cavity maxilla Mucociliary transport：
Bufo gargarizans Cantor 30 is chosen, 6 groups, every group 5, i.e. acetic acid copaxone gel delivery group are randomly divided into；Blank
Control group, i.e. 0.9% sodium chloride injection；Toad is lain on the back fixation, oral cavity is opened, maxilla mucous membrane, Yu Shang is separated and clean
Test sample solution 0.3ml is added dropwise at jaw mucous membrane, makes submergence maxilla mucous membrane, cleaned with physiological saline after continuous contact 4h, will be glutinous
Face is laid on slide upwards, and physiological saline, covered, in 44 × 10 times of optical microphotograph Microscopic observation ciliums is added dropwise
Motion conditions, be then held in the chromatography cylinder added with a small amount of distilled water, it is closed, make the nearly saturation state of vapor, environment temperature
It is 20~25 DEG C, taking-up sample observation at regular intervals later to spend, and records what is stopped from detergency test sample to ciliary movement
Time, with physiological saline clean mucous membrane on liquid, continue observe ciliary movement whether recover, record recover after persistent movement when
Between.In testing above, the mucous membrane for taking from toad palate is first divided into two fritters, and test solution is received in one of dropwise addition, and another piece is added dropwise life
Reason salt solution obtains cilium persistent movement relative with the cilium persistent movement time of test specimen as control divided by the time of control group
Percentage, percentage is higher, represents that test specimen is smaller to the toxic effect of cilium.The persistent movement time may indicate that after recovery
Whether sample is reversible to ciliary toxicity.
As can be known from the table data, the toxic effect of 1,2 pairs of ciliums of embodiment is minimum, and 3,4 pairs of ciliums of embodiment have certain
Toxic effect, embodiment 5 influences larger to ciliary toxicity, and can be extensive with output, the sample of embodiment 5 by run duration after recovery
The persistent movement time after multiple is drastically dropped within 1min, and this proves to employ PVP as biology in the sample of embodiment 5
Adhesion material damages big to ciliary movement, and its toxic action is irreversible, and the toxic action of remaining four embodiment is reversible.
The Local irritation study of embodiment 15：
SD rats 50 are taken, random 5 groups, every group 10 of layering.Acetic acid copaxone gel delivery group, blank are set
Group (giving physiological saline), excipient group (Blank gel matrix).It is administered once daily, continuous 7 days, after last time is administered
24h puts to death rat, takes out topical intranasal mucous membrane, and observation whether there is the phenomenons such as hyperemia, redness, as a result see the table below：
| Overall health of patients | Local excitation symptom | Local mucosa tissues situation | |
| Blank control group | Have no obvious situation | Have no asthma, cough, vomiting, asphyxia | Without congested, red and swollen, diabrosis |
| Embodiment 11 | Have no obvious situation | Have no asthma, cough, vomiting, asphyxia | Without congested, red and swollen, diabrosis |
| Embodiment 1 | Have no obvious situation | Have no asthma, cough, vomiting, asphyxia | Without congested, red and swollen, diabrosis |
| Embodiment 2 | Have no obvious situation | Have no asthma, cough, vomiting, asphyxia | Without congested, red and swollen, diabrosis |
| Embodiment 3 | Have no obvious situation | Have no asthma, cough, vomiting, asphyxia | Without congested, red and swollen, diabrosis |
| Embodiment 4 | Have no obvious situation | Have no asthma, cough, vomiting, asphyxia | Without congested, red and swollen, diabrosis |
As can be known from the table data, under routine administration dosage, the nasal gel of embodiment 1~4 will not be to the part of drug user
Tissue produces obvious stimulation.
Claims (8)
1. a kind of acetic acid copaxone nasal gel composition, it is by acetic acid copaxone, gel-type vehicle and pharmaceutically acceptable
Other auxiliary materials be made, described acceptable other auxiliary materials include bioadhesive material 0.9%~1.75%, the bio-adhesive
Material is selected from starch, chitin, glucan, the combination of xanthans one or more of which.
2. acetic acid copaxone nasal gel composition according to claim 1, wherein, described acceptable other auxiliary materials
Including sorbefacient, bioadhesive material, osmotic pressure regulator, NMF, preservative, pH adjusting agent, each component accounts for gel
The percentage by weight of composition be sorbefacient 1%~5%, osmotic pressure regulator 4.5%~9.0%, NMF 1%~
5%th, preservative 0.1%~0.25%, pH adjusting agent 0.25%~0.35%.
3. the acetic acid copaxone nasal gel composition according to claim any one of 1-2, wherein, sorbefacient choosing
From lauryl sodium sulfate, deoxysodium cholate, sodium taurocholate, sodium glycocholate, natrium taurocholicum, disodium ethylene diamine tetraacetate, 2- hydroxyls
Propyl-beta-cyclodextrin, lecithin one or more of which；Osmotic pressure regulator is selected from sodium chloride, mannitol, glucose, sucrose
One or more of which；NMF is selected from propane diols, glycerine, sorbierite, mannitol one or more of which；Preservative is selected from benzene
Prick chloramines, phenmethylol, benzyl carbinol, EDTA one or more of which；PH adjusting agent is selected from acetic acid, NaOH one of which or many
Kind.
4. the acetic acid copaxone nasal gel composition according to claim any one of 1-3, wherein, gel-type vehicle accounts for solidifying
The percentage by weight of glue composition is 5.25%~6.25%, fine selected from polyvinyl alcohol, Hydroxypropyl methylcellulose, Carbomer, methyl
One or more in dimension element.
5. the acetic acid copaxone nasal gel composition according to claim any one of 1-4, wherein, acetic acid copaxone
The percentage by weight for accounting for gel combination is 1%.
6. the acetic acid copaxone nasal gel composition according to claim any one of 1-5, the gel combination
Preparation method is：
Carbomer is added to the water, it is fully swelling, adjust pH value with the pH adjusting agent of alkalescence and obtain gel, then acetic acid lattice are drawn and is replaced
Thunder is dissolved in water, adds other components mixing, stirs evenly, and obtains acetic acid copaxone solution, and this solution is added into the swelling thing of Carbomer
In, obtain acetic acid copaxone gel for nose；Or
Methylcellulose or Hydroxypropyl methylcellulose are added to the water, fully it is swelling, be subsequently adding acetic acid copaxone and other
Auxiliary material mixes, and stirs evenly, and obtains acetic acid copaxone gel for nose；Or
Polyvinyl alcohol is added to the water, it is fully swelling, adjust pH value with acidic ph modifier and obtain gel, then acetic acid lattice are drawn and is replaced
Thunder is dissolved in water, adds other auxiliary materials to mix, and stirs evenly, and obtains acetic acid copaxone solution, and it is swelling that this solution is added into polyvinyl alcohol
In thing, acetic acid copaxone gel for nose is obtained.
7. the preparation method of the acetic acid copaxone nasal gel composition according to claim any one of 1-6,
It comprises the following steps：
Carbomer is added to the water, it is fully swelling, adjust pH value with pH (7.0-8.0) conditioning agent of alkalescence and obtain gel, then will
Acetic acid copaxone is dissolved in water, adds other components mixing, stirs evenly, and obtains acetic acid copaxone solution, and this solution is added into card
In the swelling thing of ripple nurse, acetic acid copaxone gel for nose is obtained；Or
Methylcellulose or Hydroxypropyl methylcellulose are added to the water, fully it is swelling, be subsequently adding acetic acid copaxone and other
Auxiliary material mixes, and stirs evenly, and obtains acetic acid copaxone gel for nose；Or
Polyvinyl alcohol is added to the water, it is fully swelling, adjust pH value with acid pH (5.0-6.0) conditioning agent and obtain gel, then will
Acetic acid copaxone is dissolved in water, adds other auxiliary materials to mix, and stirs evenly, and obtains acetic acid copaxone solution, this solution is added to poly-
In the swelling thing of vinyl alcohol, acetic acid copaxone gel for nose is obtained.
8. the acetic acid copaxone nasal gel composition according to claim any one of 1-6 is multiple hard in preparation treatment
Change the purposes in the medicine of syndrome.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201511016125.4A CN106924175B (en) | 2015-12-29 | 2015-12-29 | Pharmaceutical composition for treating multiple sclerosis |
| PCT/CN2016/112274 WO2017114379A1 (en) | 2015-12-29 | 2016-12-27 | Nasal gel composition for treating multiple sclerosis |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201511016125.4A CN106924175B (en) | 2015-12-29 | 2015-12-29 | Pharmaceutical composition for treating multiple sclerosis |
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| CN106924175B CN106924175B (en) | 2020-07-03 |
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| CN201511016125.4A Active CN106924175B (en) | 2015-12-29 | 2015-12-29 | Pharmaceutical composition for treating multiple sclerosis |
Country Status (2)
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| CN (1) | CN106924175B (en) |
| WO (1) | WO2017114379A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112076310A (en) * | 2019-06-14 | 2020-12-15 | 苏州融析生物科技有限公司 | Pharmaceutical composition for treating multiple sclerosis and preparation thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103784941A (en) * | 2013-12-26 | 2014-05-14 | 深圳市健元医药科技有限公司 | Nasal gel composite and preparation method thereof |
| CN104869983A (en) * | 2012-12-21 | 2015-08-26 | 泰华制药工业有限公司 | Transmucosal delivery of glatiramer acetate |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2710529A1 (en) * | 1993-09-29 | 1995-04-07 | Zirinis Phedon | Aqueous gel for nasal use, pellets, and process for preparing them |
| IL153236A0 (en) * | 2000-06-05 | 2003-07-06 | Teva Pharma | The use of glatiramer acetate (copolymer 1) in the treatment of central nervous system disorders |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104869983A (en) * | 2012-12-21 | 2015-08-26 | 泰华制药工业有限公司 | Transmucosal delivery of glatiramer acetate |
| CN103784941A (en) * | 2013-12-26 | 2014-05-14 | 深圳市健元医药科技有限公司 | Nasal gel composite and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| SHAHER DUCHI ET AL.: "Nasal administration of drugs as a new non-invasive strategy for efficient treatment of multiple sclerosis", 《JOURNAL OF NEUROIMMUNOLOGY 》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112076310A (en) * | 2019-06-14 | 2020-12-15 | 苏州融析生物科技有限公司 | Pharmaceutical composition for treating multiple sclerosis and preparation thereof |
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| CN106924175B (en) | 2020-07-03 |
| WO2017114379A1 (en) | 2017-07-06 |
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