CN106924175B - Pharmaceutical composition for treating multiple sclerosis - Google Patents
Pharmaceutical composition for treating multiple sclerosis Download PDFInfo
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- 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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Abstract
The invention relates to a pharmaceutical composition for treating multiple sclerosis, in particular to a glatiramer acetate nasal gel composition which is prepared from glatiramer acetate, a gel matrix and other pharmaceutically acceptable auxiliary materials, wherein the other acceptable auxiliary materials comprise 0.9-1.75% of a biological adhesion material, and the biological adhesion material is selected from one or more of starch, chitin, glucan and xanthan gum.
Description
Technical Field
The invention relates to a nasal mucosa administration composition for treating multiple sclerosis syndrome.
Background
Multiple sclerosis syndrome (MS) is a kind of autoimmune disease that can occur in the central nervous system of human body in clinic, and the occurrence of the disease is mainly characterized by brain and spinal cord inflammation and nerve demyelination changes caused by immune T cells with human physiological self-reactivity, and the incidence of the disease not only belongs to high-incidence diseases in countries such as europe and the united states, but also is a common disease in people of young and old age (especially in people of thirty years), and the cause of the disease is generally related to the immune regulation disorder of human body.
Currently accepted clinical typing of MS:
1. relapsing remitting form of MS (RRMS)
The most common course of MS is the type of disease in 80% of MS patients, with the initial onset of disease being the type of disease, manifested as significant relapse and remission with substantial recovery from each episode or with only minor sequelae. The disease course is mostly converted into SPMS within 5-15 years.
2. Secondary Progressive MS (SPMS)
One type of disease course after RRMS is a process in which after the remission stage of the recurrence, the disease is gradually and slowly aggravated as the recurrence fails to completely remit and leaves partial sequelae. About 50% of RRMS patients turn to this form within 10 years/80% within 20 years.
3. Primary Progressive MS (PPMS)
The disease is characterized by the rare course of the disease, 10-15% of patients with MS are initially present in the disease, the disease does not have a clinical remission and recurrence process, the disease is gradually aggravated, and the disease course is more than one year.
4. Progressive Relapsing MS (PRMS)
The disease is characterized by the rare course of disease of MS, about 5-10% of MS patients show the disease, the disease is gradually aggravated all the time, and few remitting and recrudescent processes exist in the course of disease.
Glatiramer acetate, sold under the trade name glatiramer acetate
Is a synthesized polypeptide compound, which consists of four amino acids: l-glutamic acid, L-alanine, L-lysine, and L-tyrosine, and can be used for treating multiple sclerosis.
The curative effect and tolerance of the traditional Chinese medicine are proved to be very positive, and a plurality of researches and clinical experiences prove that the traditional Chinese medicine can greatly reduce the relapse rate of patients, improve the disabled condition and reduce the brain injury. In addition, related studies have also shown
Compared with interferon, the medicine can lower recurrence rate obviously, prevent further damage and deterioration of nerve and has better tolerance. In other long-term efficacy studies (6 years to up to 12 years),
it has also been demonstrated to continuously delay the neurological deterioration or maintain a stable condition in patients, reduce intracerebral damage and prevent neuronal massive deterioration leading to loss of function.
Glatiramer acetate is used clinically as an injection solution, and in all clinical trials and user feedback of use, injection site atrophy is observed as the most common adverse reaction and is mostly accepted
Has the reaction, in addition
Other most common side effects are injection site irritation responses, including: erythema, pain, swelling, itching, edema, inflammation and allergic reactions.
< U.S. Pat. No. 6,214,791> discloses taking glatiramer acetate by ingestion or inhalation, which has the disadvantage that degradation of the drug by gastrointestinal fluids and first pass effects, enzymatic metabolism and enzymatic degradation of the liver cannot be avoided.
The oral administration of the drug disclosed in U.S. patent application publication No. 2001/0055568A1 has the same disadvantages as in U.S. patent No. 6,214,791, and although the inhalation mode can avoid the high first pass effect, the long-term inhalation administration requires periodic examination of the physiological condition of the lungs. Moreover, the glatiramer acetate belongs to a long-term taken medicine, if the continuous administration is carried out, certain damage is easily caused to the lung, the dosage of the medicine is not easy to control, and the use is troublesome.
< CN201380067117> discloses a mode of oral transmucosal administration, but the oral involuntary salivary secretion and swallowing affect the efficacy of oral mucosal pathways; taste stimulation of drugs affects compliance with this pathway.
In order to overcome the burden that the existing injection administration may cause various adverse reactions, poor compliance or treatment suspension of patients, and the like, an alternative glatiramer acetate administration scheme is developed, and the scheme is used to enable glatiramer acetate to effectively treat one form of multiple sclerosis symptoms.
The nasal administration system refers to a preparation which is administrated through the nasal cavity and plays a role in local or systemic treatment or prevention, and is particularly suitable for medicines which are difficult to administrate by other routes except injection and need to play a systemic role, such as polar medicines which are difficult to absorb by oral administration, medicines which are unstable in gastrointestinal tracts, medicines with strong first pass effect of livers, protein and polypeptide medicines and the like.
Disclosure of Invention
The average molecular weight of glatiramer acetate is 5000 dalton-9000 dalton, should not see through the nasal cavity mucosa and absorb, the experimenter discovers that some absorption enhancers help the absorption of glatiramer acetate in the experimental process, but have certain toxic action to the nasal mucosa, promote the clearance effect of cilia, reduce the bioavailability of medicine, the inventor finds out the clearance effect that the specific biological adhesion material of specific content can avoid the cilia in the nasal cavity through the experiment accident, increase the dwell time of medicine on the mucosa, thereby improve the bioavailability of medicine, can reduce the toxicity to cilia movement simultaneously.
In order to overcome the technical defects, the invention provides a glatiramer acetate nasal gel composition which is prepared from glatiramer acetate, a gel matrix and other pharmaceutically acceptable auxiliary materials, wherein the other acceptable auxiliary materials comprise 1.15-1.75% (1.15%, 1.20%, 1.25%, 1.30%, 1.35%, 1.40%, 1.45%, 1.50%, 1.55%, 1.60%, 1.65%, 1.70%, 1.75%) of a biological adhesion material, and the biological adhesion material is selected from one or more of starch, chitin, glucan and xanthan gum.
Further, the acceptable other auxiliary materials comprise absorption enhancer, biological adhesion material, osmotic pressure regulator, humectant, preservative and pH regulator, wherein the components of the gel composition comprise, by weight, 2% -5% of the absorption enhancer, 4.5% -9.0% of the osmotic pressure regulator, 1% -5% of the humectant, 0.1% -0.25% of the preservative and 0.25% -0.35% of the pH regulator.
Furthermore, the absorption enhancer is selected from one or more of sodium dodecyl sulfate, sodium deoxycholate, sodium cholate, sodium glycocholate, sodium taurocholate, disodium edetate, 2-hydroxypropyl- β -cyclodextrin and lecithin, the osmotic pressure regulator is selected from one or more of sodium chloride, mannitol, glucose and sucrose, the humectant is selected from one or more of propylene glycol, glycerol, sorbitol and mannitol, the preservative is selected from one or more of benzalkonium chloride, benzyl alcohol, phenethyl alcohol and EDTA, and the pH regulator is selected from one or more of acetic acid and sodium hydroxide.
Further, the gel matrix accounts for 5.25-6.25 wt% of the gel composition and is selected from one or more of polyvinyl alcohol, hypromellose, carbomer and methylcellulose.
Further, glatiramer acetate 1% accounts for 1% by weight of the gel composition.
In a specific embodiment of the invention, the glatiramer acetate nasal gel composition comprises 1% of glatiramer acetate, 1% -5% of 2-hydroxypropyl- β -cyclodextrin, 1.15% -1.75% of glucan, 5.25% -6.25% of carbomer, an osmotic pressure regulator, a humectant, a preservative and a pH regulator, and preferably comprises 1% of glatiramer acetate, 5% of 2-hydroxypropyl- β -cyclodextrin, 1.15% of glucan, 6.25% of carbomer, an osmotic pressure regulator, a humectant, a preservative and a pH regulator.
In a specific embodiment of the invention, the glatiramer acetate nasal gel composition comprises 1% of glatiramer acetate, 1% -5% of lecithin, 0.9% -1.75% of chitin, 5.25% -6.25% of polyvinyl alcohol, an osmotic pressure regulator, a humectant, a preservative and a pH regulator; preferably comprises 1 percent of glatiramer acetate, 1 percent of lecithin, 1.75 percent of chitin, 5.25 percent of polyvinyl alcohol, osmotic pressure regulator, humectant, preservative and pH regulator.
In a specific embodiment of the invention, the glatiramer acetate nasal gel composition comprises 1% of glatiramer acetate, 1% -5% of sodium glycocholate, 0.9% -1.75% of starch, 5.25% -6.25% of hypromellose, an osmotic pressure regulator, a humectant, a preservative and a pH regulator; preferably comprises 1 percent of glatiramer acetate, 3.75 percent of glycocholic acid, 1.5 percent of starch, 5.5 percent of hydroxypropyl methylcellulose, an osmotic pressure regulator, a humectant, a preservative and a pH regulator.
In one specific embodiment of the invention, the glatiramer acetate nasal gel composition comprises 1% of glatiramer acetate, 1% -5% of sodium glycocholate, 0.9% -1.75% of xanthan gum, 5.25% -6.25% of methyl cellulose, an osmotic pressure regulator, a humectant, a preservative and a pH regulator; preferably comprises 1 percent of glatiramer acetate, 3.75 percent of glycocholic acid, 0.9 percent of xanthan gum, 6 percent of methyl cellulose, osmotic pressure regulator, humectant, preservative and pH regulator.
Further, the preparation method of the gel composition comprises the following steps:
adding carbomer into water, fully swelling, adjusting pH with an alkaline pH regulator to obtain gel, dissolving glatiramer acetate in water, adding other components, mixing, stirring to obtain glatiramer acetate solution, and adding the solution into carbomer swelling substance to obtain glatiramer acetate nasal gel; or
Adding methylcellulose or hydroxypropyl methylcellulose into water, fully swelling, then adding glatiramer acetate and other auxiliary materials, mixing, and stirring to obtain glatiramer acetate nasal gel; or
Adding polyvinyl alcohol into water, fully swelling, adjusting pH value with an acidic pH regulator to obtain gel, dissolving glatiramer acetate in water, adding other auxiliary materials, mixing, and stirring to obtain glatiramer acetate solution, and adding the solution into a polyvinyl alcohol swelling material to obtain the glatiramer acetate nasal gel.
Another aspect of the present invention relates to a process for the preparation of a glatiramer acetate nasal gel composition as described above,
which comprises the following steps:
adding carbomer into water, fully swelling, adjusting pH with alkaline pH (7.0-8.0) regulator to obtain gel, dissolving glatiramer acetate in water, adding other components, mixing, stirring to obtain glatiramer acetate solution, and adding the solution into carbomer swelling material to obtain glatiramer acetate nasal gel; or
Adding methylcellulose or hydroxypropyl methylcellulose into water, fully swelling, then adding glatiramer acetate and other auxiliary materials, mixing, and stirring to obtain glatiramer acetate nasal gel; or
Adding polyvinyl alcohol into water, fully swelling, adjusting pH value with an acidic pH (5.0-6.0) regulator to obtain gel, dissolving glatiramer acetate in water, adding other auxiliary materials, mixing, stirring to obtain a glatiramer acetate solution, and adding the solution into a polyvinyl alcohol swelling material to obtain the glatiramer acetate nasal gel.
In a further aspect of the invention there is provided the use of a glatiramer acetate nasal gel composition in the manufacture of a medicament for the treatment of multiple sclerosis syndrome.
The invention provides a pharmaceutical composition for treating multiple sclerosis syndrome, which comprises 1% of glatiramer acetate, 5.25% -6.25% of gel matrix, 2% -5% of absorption enhancer, 1.15% -1.75% of biological adhesion material, 4.5% -9.0% of osmotic pressure regulator, 1% -5% of humectant, 0.1% -0.25% of preservative, 0.25% -0.35% of pH regulator and the balance of solvent water.
Advantageous effects
1. Has high bioavailability. Compared with oral administration, nasal administration can avoid degradation of the drug in gastrointestinal fluid and liver first-pass effect, and has high bioavailability. The bioavailability of the micromolecule medicine is close to intravenous injection, and the bioavailability of the macromolecule polypeptide medicine is higher than that of oral administration.
2. Quick acting, large nasal mucosa area, rich blood vessels under mucosa, and interlaced artery, vein and capillary vessels into mesh, and the medicinal liquid can be absorbed rapidly and enter human body circulation from blood vessels. The nasal administration can increase the distribution of the medicine in brain tissue, and can be used for treating central nervous system diseases.
3. The medicine which is easy to destroy in the gastrointestinal tract, the medicine which has large polarity and is difficult to be absorbed by the gastrointestinal tract can be well absorbed by the nasal mucosa, and the polypeptide medicine and the protein medicine with large molecular weight can be well absorbed in the presence of the absorption enhancer.
4. Convenient use and good patient compliance. Compared with injection administration, the nasal cavity administration is convenient to use, easy to be accepted by patients and convenient for self administration.
5. The method of the invention improves the skin mucosa transmittance of the glatiramer acetate with large molecular weight, can increase the bioavailability of the glatiramer acetate, and can reduce the clearance effect.
Drawings
FIG. 1 is a graph of the release results of part of the results of example 13.
FIG. 2 is a graph of the release results of part of the results of example 13.
Detailed Description
Example 1:
the nasal gel agent consists of glatiramer acetate:
the preparation steps of each 200g of the gel preparation are as follows:
(1) taking gel matrix carbomer in a prescription amount, adding 3-5 times of water by weight, stirring to fully swell the gel matrix carbomer, dropwise adding sodium hydroxide to adjust the pH value to 7.0-8.0, and stirring to obtain gel;
(2) dissolving glatiramer acetate in a prescribed amount by adding 2-5 times of water by weight;
(3) adding 2-3 times of water by weight into glucan, glucose, glycerol and EDTA, and stirring to dissolve the glucan, the glucose, the glycerol and the EDTA;
(4) and (3) adding the solutions in the step (2) and the step (3) into the gel matrix solution in the step (1), adding 2-hydroxypropyl- β -cyclodextrin serving as an absorption enhancer, uniformly stirring, adding water to 200g, and uniformly stirring to obtain the finished gel.
Example 2
The preparation steps of each 200g of the gel preparation are as follows:
(1) taking gel matrix polyvinyl alcohol with the formula amount, adding water with the weight of 4-7 times, dropwise adding acetic acid to adjust the pH value to 5.0-6.0, and stirring to fully swell;
(2) dissolving glatiramer acetate in a prescribed amount by adding 2-5 times of water by weight;
(3) adding 1-2 times of water by weight into mannitol, benzalkonium chloride, propylene glycol and chitin, and stirring to dissolve;
(4) and (3) adding the solution obtained in the step (2) and the solution obtained in the step (3) into the gel matrix solution obtained in the step (1), adding lecithin serving as an absorption promoter, uniformly stirring, adding water to 200g, and uniformly stirring to obtain the finished gel. Example 3:
the nasal gel agent consists of glatiramer acetate:
the preparation steps of each 200g of the gel preparation are as follows:
(1) weighing hydroxypropyl methylcellulose in a prescription amount, adding 4-7 times by weight of water, and stirring while adding to fully swell the hydroxypropyl methylcellulose;
(2) dissolving glatiramer acetate in a prescribed amount by adding 2-5 times of water by weight;
(3) adding 3-4 times of water by weight into sodium chloride, EDTA, glycerol and starch, and stirring to dissolve the sodium chloride, the EDTA, the glycerol and the starch;
(4) and (3) adding the solutions in the step (2) and the step (3) into the gel matrix solution in the step (1), adding absorption accelerator sodium glycocholate, stirring uniformly, adding water to 200g, and stirring uniformly to obtain the finished gel.
Example 4:
the preparation steps of each 200g of the gel preparation are as follows:
(1) weighing methyl cellulose according to the prescription amount, adding 4-7 times of water by weight, and stirring while adding to fully swell the methyl cellulose;
(2) dissolving glatiramer acetate in a prescribed amount by adding 2-5 times of water by weight;
(3) adding 3-4 weight times of water into sodium chloride, EDTA, glycerol and xanthan gum, and stirring to dissolve the sodium chloride, the EDTA, the glycerol and the xanthan gum;
(4) and (3) adding the solutions in the step (2) and the step (3) into the gel matrix solution in the step (1), adding absorption accelerator sodium glycocholate, stirring uniformly, adding water to 200g, and stirring uniformly to obtain the finished gel.
Example 5
The preparation steps of each 200g of the gel preparation are as follows:
(1) weighing methyl cellulose according to the prescription amount, adding 4-7 times of water by weight, and stirring while adding to fully swell the methyl cellulose;
(2) dissolving glatiramer acetate in a prescribed amount by adding 2-5 times of water by weight;
(3) adding 3-4 times of water by weight into sodium chloride, EDTA, glycerol and povidone, and stirring to dissolve;
(4) adding the solution obtained in the step (2) and the solution obtained in the step (3) into the gel matrix solution obtained in the step (1), adding 2-hydroxypropyl- β -cyclodextrin serving as an absorption enhancer, uniformly stirring, adding water to 200g, and uniformly stirring to obtain the finished gel
Example 6
The procedure was as in example 1.
Example 7
The procedure was as in example 1.
Example 8
The procedure was as in example 1.
Example 9
The procedure was as in example 1.
Example 10
The procedure was as in example 1.
Example 11 blank gel matrix control
The preparation steps of each 200g of the gel preparation are as follows:
(1) taking gel matrix carbomer in a prescription amount, adding 3-5 times of water by weight, stirring to fully swell the gel matrix carbomer, dropwise adding sodium hydroxide to adjust the pH value to 7.0-8.0, and stirring to obtain gel;
(2) adding 2-3 times of water by weight into glucan, glucose, glycerol and EDTA, and stirring to dissolve the glucan, the glucose, the glycerol and the EDTA;
(3) and (3) adding the solution in the step (2) into the gel matrix solution in the step (1), adding 2-hydroxypropyl- β -cyclodextrin serving as an absorption enhancer, uniformly stirring, adding water to 200g, and uniformly stirring to obtain the finished gel.
Example 12 control group without bioadhesive Material
The preparation steps of each 200g of the gel preparation are as follows:
(1) taking gel matrix carbomer in a prescription amount, adding 3-5 times of water by weight, stirring to fully swell the gel matrix carbomer, dropwise adding sodium hydroxide to adjust the pH value to 7.0-8.0, and stirring to obtain gel;
(2) dissolving glatiramer acetate in a prescribed amount by adding 2-5 times of water by weight;
(3) adding 2-3 weight times of water into glucose, glycerol and EDTA, and stirring to dissolve the mixture;
(4) and (3) adding the solutions in the step (2) and the step (3) into the gel matrix solution in the step (1), adding 2-hydroxypropyl- β -cyclodextrin serving as an absorption enhancer, uniformly stirring, adding water to 200g, and uniformly stirring to obtain the finished gel.
Example 13 nasal absorption model of drug:
the in-vitro release degree of glatiramer acetate gel is determined by adopting an improved Franz diffusion cell, a semipermeable membrane (with the intercepted relative molecular mass of 6500-9000) is fixed between two diffusion cells, the inner diameter of the two diffusion cells is 1.3cm, and the release area is about 1.33cm2Accurately adding 2mL of glatiramer acetate gel into a dosing pool, placing a diffusion pool into 16mL of 37 ℃ artificial nasal fluid, adding 10mL of the artificial nasal fluid preheated to 37 ℃ into a receiving pool as receiving fluid, placing a stirrer in the receiving pool, rotating at the rotating speed of 100r/min, respectively sampling at 15 min, 30 min, 45 min, 60 min, 90 min, 120 min and 180min, taking out all media, rapidly supplementing the same amount of preheated artificial nasal fluid, properly diluting the sample fluid, filtering with a 0.45 mu m microporous filter membrane, continuously filtering according to chromatographic conditions, measuring the peak area of glatiramer acetate, and calculating the cumulative release degree.
The chromatographic method comprises the following steps: performing high performance liquid chromatography with Kromasil NH2Chromatographic column, 4.6 × 250mm, 5 μm, mobile phase 0.08mol/L phosphate buffer (pH adjusted to 4.0 + -0.1 by phosphoric acid) -acetonitrile (35: 65) as mobile phase, performing isocratic elution, detecting wavelength 275nm, column temperature 30 deg.C, flow rate 1.0ml/min, and glatiramer acetate tailing factor should be smallAt 3.0.
The results are shown in the following table (unit:%):
as can be seen from the data in the table and the results shown in the attached figure 1, some bioadhesive materials can greatly improve the release of glatiramer acetate, the initial release time is accelerated, the release speed is stable, the release amount is improved by 2 times compared with a sample without the bioadhesive material, the bioavailability of the drug is obviously improved, and not all bioadhesive materials can achieve good effects. This is probably due to the large difference in effect between different bioadhesive materials and glatiramer acetate due to their interaction. When povidone is selected as the bioadhesive material, the composition has a release rate that does not meet the therapeutic requirements for a given period of time. As can be seen from the data in the table and the results of FIG. 2, the release amount is closely related to the type of the bioadhesive material, and the bioadhesive material not according to the present invention is less effective, and is similar to the result without the bioadhesive material.
Example 14 model test of the effect of drug on ciliary movement of the nasal palate:
selecting 30 Chinese big toads, randomly dividing the toads into 6 groups, wherein each group comprises 5 toads, namely a glatiramer acetate gel administration group, a blank control group, namely 0.9% sodium chloride injection, fixing the toads in a supine position, opening the oral cavity, separating and cleaning the palatal mucosa, dripping 0.3ml of test sample solution at the palatal mucosa to immerse the palatal mucosa, continuously contacting for 4 hours, cleaning with physiological saline, spreading the mucosa on a glass slide in a flatly-facing manner, dripping the physiological saline, covering a cover glass, observing ciliary movement conditions under an optical microscope of 44 × 10 times, then placing the glass in a chromatographic cylinder with a small amount of distilled water, sealing to enable the water vapor to be in a nearly saturated state, keeping the ambient temperature of 20-25 ℃, taking out a sample at intervals, observing, recording the time from the cleaning test sample to the stopping of ciliary movement, using the physiological saline on the mucosa to continuously observe whether the ciliary movement is recovered, recording the time of the recovery of the ciliary movement, and taking the contrast group that the mucosa from the cleaning test sample to the palatal block is divided into two small blocks, wherein the smaller the time of the contrast group indicates whether the ciliary movement of the ciliary movement is influenced by the continuous movement of the physiological saline, and the toxicity of the contrast group is obtained by the contrast group, and the contrast group to obtain the contrast group.
As can be seen from the data in the table, the toxicity effect on cilia is the smallest in examples 1 and 2, a certain toxicity effect is exerted on cilia in examples 3 and 4, the toxicity effect on cilia is larger in example 5, and the cilia can be produced through the movement time after recovery, and the continuous movement time after recovery of the sample in example 5 is sharply reduced to be within 1min, which proves that the damage to cilia movement caused by adopting povidone as a biological adhesive material in the sample in example 5 is large, the toxicity effect is irreversible, and the toxicity effect of the other four examples is reversible.
Example 15 local irritation test:
SD rats were taken as 50 rats, and randomly divided into 5 groups of 10 rats. A glatiramer acetate gel administration group, a blank control group (given physiological saline), and an excipient group (blank gel matrix) were provided. The administration is carried out 1 time per day for 7 days continuously, rats are killed 24 hours after the last administration, local nasal mucosa is taken out, and the phenomena of congestion, red swelling and the like are observed, and the results are shown in the following table:
| general condition of the whole body | Symptoms of local irritation | Local mucosal tissue condition | |
| Blank control group | No obvious condition is seen | Without asthma, cough, emesis, asphyxia | No congestion, red swelling, ulceration |
| Example 11 | No obvious condition is seen | Without asthma, cough, emesis, asphyxia | No congestion, red swelling, ulceration |
| Example 1 | No obvious condition is seen | Without asthma, cough, emesis, asphyxia | No congestion, red swelling, ulceration |
| Example 2 | No obvious condition is seen | Without asthma, cough, emesis, asphyxia | No congestion, red swelling, ulceration |
| Example 3 | No obvious condition is seen | Without asthma, cough, emesis, asphyxia | No congestion, red swelling, ulceration |
| Example 4 | No obvious condition is seen | No asthma is seen,Cough, vomiting and asphyxia | No congestion, red swelling, ulceration |
As can be seen from the data in the table, under the conventional dosage, the nasal gel of the examples 1 to 4 can not generate obvious stimulation to the local tissues of the patients.
Claims (7)
1. The nasal gel composition of glatiramer acetate is prepared from glatiramer acetate, a gel matrix and other pharmaceutically acceptable auxiliary materials, wherein the other acceptable auxiliary materials comprise 0.9-1.75% of a biological adhesion material, and the biological adhesion material is selected from one or more of starch, chitin, glucan and xanthan gum; the gel matrix accounts for 5.25-6.25 wt% of the gel composition and is selected from one or more of polyvinyl alcohol, hydroxypropyl methylcellulose, carbomer and methylcellulose.
2. The glatiramer acetate nasal gel composition of claim 1, wherein the acceptable additional excipients comprise an absorption enhancer, a bioadhesive material, an osmotic pressure regulator, a humectant, a preservative, and a pH regulator, wherein the absorption enhancer, the osmotic pressure regulator, the humectant, the preservative, and the pH regulator are present in an amount of 1 to 5 wt%, 4.5 to 9.0 wt%, 1 to 5 wt%, 0.1 to 0.25 wt%, and 0.25 to 0.35 wt% of the gel composition, respectively.
3. The glatiramer acetate nasal gel composition of claim 2, wherein the absorption enhancer is selected from one or more of sodium dodecyl sulfate, sodium deoxycholate, sodium cholate, sodium glycocholate, sodium taurocholate, disodium edetate, 2-hydroxypropyl- β -cyclodextrin and lecithin, the osmotic pressure regulator is selected from one or more of sodium chloride, mannitol, glucose and sucrose, the humectant is selected from one or more of propylene glycol, glycerol, sorbitol and mannitol, the preservative is selected from one or more of benzalkonium chloride, benzyl alcohol, phenethyl alcohol and EDTA, and the pH regulator is selected from one or more of acetic acid and sodium hydroxide.
4. The glatiramer acetate nasal gel composition of claim 1, wherein the glatiramer acetate is present in an amount of 1% by weight of the gel composition.
5. The glatiramer acetate nasal gel composition of any one of claims 1-4 prepared by a method comprising:
adding carbomer into water, fully swelling, adjusting pH with an alkaline pH regulator to obtain gel, dissolving glatiramer acetate in water, adding other components, mixing, stirring to obtain glatiramer acetate solution, and adding the solution into carbomer swelling substance to obtain glatiramer acetate nasal gel; or
Adding methylcellulose or hydroxypropyl methylcellulose into water, fully swelling, then adding glatiramer acetate and other auxiliary materials, mixing, and stirring to obtain glatiramer acetate nasal gel; or
Adding polyvinyl alcohol into water, fully swelling, adjusting pH with an acidic pH regulator to obtain gel, dissolving glatiramer acetate in water, adding other auxiliary materials, mixing, and stirring to obtain glatiramer acetate solution, and adding the solution into a polyvinyl alcohol swelling material to obtain the glatiramer acetate nasal gel.
6. The method for preparing the glatiramer acetate nasal gel composition according to claim 5,
which comprises the following steps:
adding carbomer into water, fully swelling, adjusting pH with an alkaline pH regulator to obtain gel, wherein the pH value of the pH regulator is 7.0-8.0, dissolving glatiramer acetate in water, adding other components, mixing, stirring to obtain glatiramer acetate solution, and adding the solution into carbomer swelling matter to obtain glatiramer acetate nasal gel; or
Adding polyvinyl alcohol into water, fully swelling, adjusting pH with an acidic pH regulator to obtain gel, wherein the pH value of the pH regulator is 5.0-6.0, then dissolving glatiramer acetate in water, adding other auxiliary materials, mixing, stirring uniformly to obtain a glatiramer acetate solution, and adding the solution into a polyvinyl alcohol swelling material to obtain the glatiramer acetate nasal gel.
7. Use of the glatiramer acetate nasal gel composition of any one of claims 1-4 in the preparation of a medicament for treating multiple sclerosis syndrome.
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| 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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| 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 |
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| FR2710529A1 (en) * | 1993-09-29 | 1995-04-07 | Zirinis Phedon | Aqueous gel for nasal use, pellets, and process for preparing them |
| EP1292279A4 (en) * | 2000-06-05 | 2005-01-12 | Teva Pharma | The use of glatiramer acetate (copolymer 1) in the treatment of central nervous system disorders |
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|---|---|---|---|---|
| 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 |
|---|
| Nasal administration of drugs as a new non-invasive strategy for efficient treatment of multiple sclerosis;Shaher Duchi et al.;《Journal of Neuroimmunology 》;20131231;第258卷;第32-40页 * |
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