CN107149672B - A kind of pharmaceutical composition for treating dry eyes and/or cornea and conjunctival damage - Google Patents
A kind of pharmaceutical composition for treating dry eyes and/or cornea and conjunctival damage Download PDFInfo
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- CN107149672B CN107149672B CN201710217040.5A CN201710217040A CN107149672B CN 107149672 B CN107149672 B CN 107149672B CN 201710217040 A CN201710217040 A CN 201710217040A CN 107149672 B CN107149672 B CN 107149672B
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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
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/18—Growth factors; Growth regulators
- A61K38/185—Nerve growth factor [NGF]; Brain derived neurotrophic factor [BDNF]; Ciliary neurotrophic factor [CNTF]; Glial derived neurotrophic factor [GDNF]; Neurotrophins, e.g. NT-3
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
- A61K31/51—Thiamines, e.g. vitamin B1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
- A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
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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
- A61K9/0048—Eye, e.g. artificial tears
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Abstract
The invention discloses a kind of pharmaceutical compositions for treating dry eyes and/or cornea and conjunctival damage, the pharmaceutical composition includes NGF and glucocorticoid, the two has synergistic effect, dry eye symptoms can significantly be alleviated, it can be used for severe dry eye, it also may include vitamin B in composition of the invention, therapeutic effect is more preferable in particular according to the treatment of dry eyes and/or cornea and conjunctival damage that DEWS Report (2007) dry eyes severity is 3 or more.And pharmaceutical composition provided by the invention can also be effectively improved the raised adverse reaction of intraocular pressure caused by glucocorticoid, since intraocular pressure raising further causes the risk of glaucoma when advantageously reducing glucocorticoid for eye disease treatment.
Description
Technical field
The present invention relates to biomedicine technical fields, and in particular to a kind of to treat dry eyes and/or cornea and conjunctival damage, spy
It is not the pharmaceutical composition of the dry eyes and/or cornea and conjunctival damage that are 3 or more according to DEWS Report (2007) dry eyes severity
Object.
Background technique
Xerophthalmia, also known as keratoconjunctivitis sicca, are a kind of multifactorial diseases of tear and eye surface, which causes
Symptom have uncomfortable, dysopia and unstable with the tear film to eye surface potential damage, and be accompanied by the infiltration of tear film
Property increase and eye surface inflammation.Xerophthalmia is considered as a kind of obstacle of lacrimal gland function unit, a lacrimal gland function unit
Holonomic system include: lachrymal gland, eye surface (cornea, conjunctiva and Meibomian gland) and eyelid and the feeling for connecting them
And kinesitherapy nerve.This lacrimal gland function unit is controlled the main component of the tear film in a manner of a kind of adjusting and to environment, interior
Eccrisology and cortex influence responds.The function of the unit be to maintain the integrality of tear film, the transparency of cornea,
And project to the quality of image on retina.To any part (the incoming sensory nerve, the autonomous mind of outflow of lacrimal gland function unit
Through and kinesitherapy nerve and lacrimal secretion gland) disease or damage tear film can be made unstable and cause itself to show
For the diseases of eye surface of xerophthalmia.
According to DEWS Report (2007) (referring to " The Definition and Classification of Dry
Eye Disease " (p75 92)), 4 levels are divided into dry eyes severity.For dry eyes severity 1 and 2, there are many recommendations
Therapeutic agent.For 3 or more dry eyes severity, particularly the ocular surface damage such as cornea and conjunctiva, can be used autoserum,
Glucocorticoid etc. is treated, but glucocorticoid long-time service may cause intraocular pressure raising, cataract etc., is only limited to short-term
Using come the severe attack that controls dry eyes.
Nerve growth factor (Nerve growth factor, NGF) is early 1950s by Levi-
First neurotrophic factor that Montalcini has found in mice sarcoma cell is one kind by neuron, innervation
What target tissue or spongiocyte generated can promote maincenter and peripheral nerve to break up, grow and the reactive protein of survival.In recent years,
Many internal and external experimental study shows that NGF becomes in some diseases such as retinal pigment for the treatment of vision system both at home and abroad
Property, optic neuritis, view contusion, optic atrophy and ischemic optic neuropathy, detachment of retina caused by glaucoma etc.
Postoperative visual function difference etc. has a better effect.As patent document US2012102591 discloses a kind of controlling for pigmentary retinopathy
Treatment method makes in retinal ganglial cells in the content of NGF including the preparation that the ocular local application in subject contains NGF
The step of rising；Patent document CN201210008398.4 discloses a kind of nerve growth factor ophthalmic gel, is used for restoring ocular
Neurotrosis.But it yet there are no NGF and other known dry eye treatment method and/or therapeutic agent (such as artificial tears, sugared cortical hormone
Element, immunosuppressor, lachrymal gland stimulant (such as androgen tear), autoserum, sex hormone, Chinese medicine, especially sugared cortical hormone
Element) combined application treatment of severe dry eyes in dry eyes are especially report.
Summary of the invention
The present invention provides one kind for treating and/or prevention dry eyes, especially in severe dry eyes pharmaceutical composition,
The pharmaceutical composition includes NGF and glucocorticoid.
Preferably, the NGF is source of mouse NGF or source of people NGF, more preferably source of people NGF；
In specific preferred embodiment of the invention, the NGF is people's Recombinant Naja naja atra nerve growth factor.
Preferably, the glucocorticoid is selected from: alclometasone, beclomethasone, betamethasone, budesonide, strop
Nai De, clobetasol, clocortolone, deoxidation cortisone, cortisol, cortivazol, deflazacort, Deprodone, desonide,
Sai meter Song, Difluprednate, fludroxycortide, flunisolide, fluocinolone acetonide, fluocinolone acetonide, fluocortolone, fluorometholone, fluticasone, Kazakhstan
Xi Naide, Halometasone, Halopredone, hydrocortisone, Loteprednol, meprednisone, methylprednisolone, Mometasone, naflocort,
19 remove first desoxycortone, 19 norprogesterones, neomycin, deflazacort, paramethasone, prednicarbate, prednisolone, sprinkle Buddhist nun
Pine, Prednylidene, Rimexolone, allusion quotation must different, triamcinolone, Rimexolone and Ulobetasols；Preferably be selected from: dexamethasone, times he
Meter Song, prednisone, prednisolone, meprednisone and hydrocortisone；
In a preferred embodiment of the invention, the glucocorticoid is dexamethasone；
Preferably, the mass ratio of NGF and glucocorticoid is 1:0.1-100 in the pharmaceutical composition, more preferably
For 1:1-10, further preferably 1:1-5, such as 1:1,1:2,1:3,1:4,1:5.
It in a preferred embodiment of the invention, further include vitamin B in the pharmaceutical composition；
Preferably, the vitamin B is selected from: one in vitamin B1, vitamin B2, vitamin B6 and vitamin B12
Kind is a variety of；It is furthermore preferred that the vitamin B is vitamin B1；
Preferably, in the pharmaceutical composition, the mass ratio of NGF and vitamin B is 10-100:1, more preferably 10-
50:1, such as 10:1,20:1,30:1,40:1,50:1.
Preferably, aforementioned pharmaceutical compositions can be prepared into through local administration, gastrointestinal administration or parenteral administration
Various preparations；The local administration preparation is the preparation by ophthalmic administration, such as: eye drops, injection, powder-injection, eye ointment
Agent, emulsion, liposome, microcapsules, gel, implant, inserting agent, ocular inserts, inclusion eye drops and other can be used for eye
The dosage form of portion's administration；The parenterals are suitable intravenous injection, intramuscular injection, subcutaneous injection, marrow note
It penetrates, the dosage forms such as cutaneous penetration, mucosa delivery, inhalation；
In a preferred embodiment of the invention, the pharmaceutical composition is the preparation of ophthalmic administration, preferably is selected from: drop
Eye agent, Eye ointments, gel, ocular inserts；
When the pharmaceutical composition of the invention for treating xerophthalmia is used as a kind of ophthalmic solution, it is provided as any
For the dosage form of ophthalmic solution, for example, a kind of aqueous eye drops (such as aqueous ophthalmic solution, aqueous suspension ophthalmic solution, sticky eye
With solution, ophthalmic solution etc. of solubilising) or a kind of non-aqueous eye drops (such as non-aqueous ophthalmic solution and non-aqueous suspension are ophthalmically acceptable
Solution).
Preferably, the pharmaceutical composition is aqueous eye drops, wherein the content of NGF is 10-1000 μ g/ml, preferably
For 2-500 μ g/ml, more preferably 100-300 μ g/ml；
Preferably, the pharmaceutical composition is aqueous eye drops, wherein the content of glucocorticoid is 1-1000 μ g/
Ml, preferably 100-1000 μ g/ml, more preferably 200-800 μ g/ml；
Preferably, the pharmaceutical composition is aqueous eye drops, further includes vitamin B in the pharmaceutical composition,
The content of vitamin B is 1-100 μ g/ml, preferably 1-50 μ g/ml, more preferably 1-20 μ g/ml；
It preferably, further include pharmaceutically acceptable additive in aforementioned pharmaceutical compositions；
Preferably, the additive is selected from: bacteriostatic agent, pH adjusting agent, osmotic pressure regulator, solubilizer (stabilizer),
One of thickener and chelating agent etc. are a variety of；
Preferably, the bacteriostatic agent includes but is not limited to: thimerosal, quaternary ammonium salt, Domiphen, chlorohexidene, trichlorine uncle
One of butanol, parabens and sorbic acid or a variety of combinations；Preferably, the quaternary ammonium salt bacteriostatic agent such as benzene pricks chlorine
Ammonium, benzalkonium bromide, parabens such as ethyl hydroxy benzoate etc.；
Preferably, antiseptic content is 0.001-1.0% in the pharmaceutical composition；
Preferably, the pH adjusting agent includes but is not limited to: phosphate, acetate, citric acid and its salt, carbonate are molten
One of liquid, sodium hydroxide, potassium hydroxide, hydrochloric acid, boric acid and phosphoric acid etc. are a variety of；
Preferably, pH is 5.5-7.5 in the pharmaceutical composition；
Preferably, the osmotic pressure regulator includes but is not limited to: carbohydrate (such as sorbierite, glucose, mannitol), more
First alcohols (such as glycerol, polyethylene glycol, polypropylene glycol), salt such as sodium chloride；
Preferably, the solubilizer includes but is not limited to: cyclodextrin and its derivative, water-soluble polymer (such as poly- second
Alkene pyrrolidone), surfactant (such as polysorbate80, trade name: Tween 80)；
Preferably, the thickener is selected from: methylcellulose, carboxymethyl cellulose, hydroxypropyl methyl cellulose hydroxyl second
Base cellulose and hydroxypropyl cellulose and its esters it is one or more；
Preferably, the chelating agent includes but is not limited to: edetate sodium, sodium citrate, Vitrafos.
In one embodiment of the invention, described pharmaceutical composition is gel for eye use, ophthalmic ointment, wherein further including base
Matter compound；
Preferably, the ointment bases includes vegetable oil, animal tallow, and the semisolid hydrocarbons obtained from petroleum, such as:
Lanolin, vaseline, atoleine, mineral oil etc.；
Preferably, the gel-type vehicle compound is the polymer substance that biocompatibility is good, can form gel,
Such as: poloxamer, gellan gum, chitosan, sodium alginate, Sodium Hyaluronate, hydroxypropyl methylcellulose, xanthan gum, carbomer；
Preferably, the preparation of aforementioned pharmaceutical compositions includes ordinary preparation, controlled release preparation, targeting preparation etc..
The present invention also provides a kind of aforementioned pharmaceutical compositions in preparation treatment and/or prevention dry eyes and/or cornea and knot
Application in the drug of membrane damage；
Preferably, the xerophthalmia is severe dry eye, in particular according to DEWS Report (2007) dry eyes severity
For 3 or more dry eyes and/or cornea and conjunctival damage；
Side effect caused by glucocorticoid is used alone to be mitigated or eliminated in the application；
Preferably, the side effect is intraocular pressure raising.
Another aspect of the present invention also provides a kind of contact lenses, it includes, carry or be connected with aforementioned pharmaceutical compositions,
Patient can achieve the purpose that drug treatment by wearing the contact lenses.
Pharmaceutical composition provided by the invention includes NGF and glucocorticoid, and the two has synergistic effect, can significantly alleviate
Dry eye symptoms can be used for middle severe dry eye, be 3 or more in particular according to DEWS Report (2007) dry eyes severity
The treatment of dry eyes and/or cornea and conjunctival damage also may include vitamin B in composition of the invention, and therapeutic effect is more preferable.
And pharmaceutical composition provided by the invention can also be effectively improved the raised adverse reaction of intraocular pressure caused by glucocorticoid, be conducive to
It reduces when glucocorticoid is treated for eye disease since intraocular pressure raising further causes the risk of glaucoma.
Specific embodiment
Below in conjunction with the embodiment of the present invention, technical solution of the present invention is clearly and completely described, it is clear that institute
The embodiment of description is only a part of the embodiment of the present invention, instead of all the embodiments.Based on the embodiments of the present invention, originally
Field those of ordinary skill every other embodiment obtained without creative efforts, belongs to the present invention
The range of protection.
1 eye drops of embodiment
Eye drops is prepared according to preparation method known in the art, main component and content are as follows:
2 eye drops of embodiment
Eye drops is prepared according to preparation method known in the art, main component and content are as follows:
3 eye drops of embodiment
Eye drops is prepared according to preparation method known in the art, main component and content are as follows:
4 eye drops of embodiment
5 eye drops of embodiment
Eye drops is prepared according to preparation method known in the art, main component and content are as follows:
6 eye drops of embodiment
7 eye drops of embodiment
Eye drops is prepared according to preparation method known in the art, main component and content are as follows:
8 gel for eye use of embodiment
Gel for eye use is prepared according to preparation method known in the art, main component and content are as follows:
The ophthalmically acceptable paste of embodiment 9
Ophthalmically acceptable paste is prepared according to preparation method known in the art, main component and content are as follows:
10 ocular inserts of embodiment
Ocular inserts is prepared according to preparation method known in the art, main component and content are as follows:
11 cornea and conjunctiva injury in treating effect of embodiment
According to DEWS Report (2007), the classification of dry eyes severity is as shown in table 1 (referring to " Management and
Therapy of Dry Eye Disease”(p163-178)。
1 dry eyes Severity gradation table of table
*Must there are sign and symptom.TBUT: fluorescein tears resolving time.MGD: meibomian gland disease
Here " according to the dry eyes severity of DEWS Report (2007) be 3 or more dry eyes and/or cornea and conjunctiva
The dry eyes that it is 3 or more according to the dry eyes severity of above-mentioned classification that damage ", which refers to corresponding to, and/or show this dry eyes
The cornea and conjunctival damage of any sign and symptom.
1. experimental material and condition
Given the test agent: the eye drops of embodiment 1-7 preparation；
Control sample: physiological saline；
Experimental animal: cleaning grade new zealand rabbit, no eye disease, half male and half female.
2. Animal Model and experimental group
Experimental animal is taken, by intramuscular injection of ketamine (10mg/kg) and xylazine (4mg/kg), then eye is given
The oxybuprocaine (every two drop) for giving 0.4% is anaesthetized.It keeps accumbency to place rabbit and instils before use into one eye
0.04ml (0.01ml × 4 time) n-heptanol solution (n-heptanol: ethyl alcohol=8: 2), so that n-heptanol solution covers cornea of preparation
And bulbar conjunctiva.Then, the rabbit is forced to blink 3 times and close one's eyes 2 minutes after third time is blinked.Two eyes are carried out above-mentioned
Program.Cornea and conjunctival damage model are made as a result,.
By the successful lagophthalmos of modeling, stochastic averagina be divided into the 8 groups: 1st group be control group, 2-8 group is test sample group.Often
Its administration 2 times successive administration 10 days, carries out before medication and respectively fluorescent staining experiment after medication, to the shape of cornea and conjunctiva
State is observed.
Fluorescent staining experiment: 1% luciferin of 2 μ l is instilled in eye, after 2 minutes, by having cobalt blue in illumination region
Optical filtering (FUJI FILTER BPB45), the number with Yellow filter mirror (FUJI FILTER SC52) is aobvious before the lens
Micro mirror (VHX 900, KEYENCE CORPORATION (Japan)), is taken pictures and is observed to the dyeing of cornea and conjunctiva, then
It scores the degree of corneal injury.For scoring, by each cornea be divided into 5 regions (center, top, temples, nose, under
Portion region), the fluorescent staining intensity in each region is scored with 3 points of full marks, by total score (full marks 15 divide) for evaluating.Without dye
Staining power is rated as 0 when color；Part dyeing is 1；The dyeing in about 2/3rds regions is 2；All dyeing is 3.Score number
It is worth smaller, corresponding sample repairing effect is higher.
The fluorescent staining appraisal result of cornea is as shown in table 2.Compared with reference substance, the angle of test sample group experimental animal
The scoring of film fluorescent staining significantly reduces, and shows that repairing effect is preferable；Compared with the sample that NGF, dexamethasone are administered alone, two
It is more preferable that person is administered in combination effect.
The corneal fluorescein that 2 n-heptanol of table induces the rabbit of cornea and conjunctiva damage dyes appraisal result
Embodiment 12 reduces intraocular pressure effect
1. experimental material and condition
Given the test agent: eye drops (being denoted as eye drops 1 and eye drops 2 respectively) prepared by embodiment 3,7；
Control sample: physiological saline；
Positive control medicine: eye drops prepared by embodiment 6；
Experimental animal: healthy C57BL/6J mouse.
2. experimental animal and grouping
Experimental animal mean random is grouped, after administration 4 weeks, tonometer detects mouse intraocular pressure.Experimental result such as 3 institute of table
Show.
3 detection of eyeball tension result of table
As seen from the results in Table 3, NGF is applied in combination with glucocorticoid, especially NGF, glucocorticoid and vitamin B1
Be applied in combination, the raised adverse reaction of intraocular pressure caused by glucocorticoid can be effectively improved, advantageously reduce glucocorticoid
Since intraocular pressure raising further causes the risk of glaucoma when for eye disease treatment.
The foregoing is merely illustrative of the preferred embodiments of the present invention, is not intended to limit the invention, all in essence of the invention
Within mind and principle, made any modification, equivalent replacement etc. be should all be included in the protection scope of the present invention.
Claims (12)
- It include NGF and glucocorticoid in the pharmaceutical composition 1. a kind of pharmaceutical composition, in the pharmaceutical composition The mass ratio of NGF and glucocorticoid is 1:0.1-100；It and/or in the pharmaceutical composition further include vitamin B.
- 2. pharmaceutical composition as described in claim 1, which is characterized in that the NGF is source of mouse NGF or source of people NGF；With/ Or,The glucocorticoid is selected from: alclometasone, beclomethasone, betamethasone, budesonide, ciclesonide, chlorine times he Rope, clocortolone, deoxidation cortisone, cortisol, cortivazol, deflazacort, Deprodone, desonide, dexamethasone, difluoro Sprinkle Buddhist nun's ester, fludroxycortide, flunisolide, fluocinolone acetonide, fluocinolone acetonide, fluocortolone, fluorometholone, fluticasone, Halcinonide, halogen rice Pine, Halopredone, hydrocortisone, Loteprednol, meprednisone, methylprednisolone, Mometasone, naflocort, 19 go first to deoxygenate Cortisone, 19 norprogesterones, neomycin, deflazacort, paramethasone, prednicarbate, prednisolone, prednisone, Prednylidene, Rimexolone, allusion quotation must different, triamcinolone, Rimexolone and Ulobetasols.
- 3. pharmaceutical composition as claimed in claim 2, which is characterized in that the NGF is people's Recombinant Naja naja atra nerve growth factor；And/or it is described Glucocorticoid be selected from: dexamethasone, betamethasone, prednisone, prednisolone, meprednisone and hydrocortisone.
- 4. pharmaceutical composition as described in claim 1, which is characterized in that the vitamin B is selected from: vitamin B1, dimension life One of plain B2, vitamin B6 and vitamin B12 are a variety of；And/orIn the pharmaceutical composition, the mass ratio of NGF and vitamin B is 10-100:1.
- 5. pharmaceutical composition as described in claim 1, which is characterized in that the pharmaceutical composition is the system of ophthalmic administration Agent preferably is selected from: eye drops, Eye ointments, gel and ocular inserts.
- 6. pharmaceutical composition as claimed in claim 5, which is characterized in that the pharmaceutical composition is aqueous eye drops, In, the content of NGF is 10-1000 μ g/ml；And/or the content of glucocorticoid is 1-1000 μ g/ml.
- 7. pharmaceutical composition as claimed in any one of claims 1 to 6, which is characterized in that further include in the pharmaceutical composition Pharmaceutically acceptable additive.
- 8. pharmaceutical composition as claimed in claim 7, which is characterized in that the additive is selected from: bacteriostatic agent, pH are adjusted One of agent, osmotic pressure regulator, solubilizer, thickener and chelating agent are a variety of.
- 9. a kind of if the described in any item pharmaceutical compositions of claim 1-8 are at preparation treatment and/or prevention dry eyes and/or angle Application in film and the drug of conjunctival damage.
- 10. application as claimed in claim 9, which is characterized in that the xerophthalmia is severe dry eye.
- 11. application as claimed in claim 10, which is characterized in that the xerophthalmia is the dry eyes that dry eyes severity is 3 or more And/or cornea and conjunctival damage；And/orSide effect caused by glucocorticoid is used alone to be mitigated or eliminated in the application.
- 12. application as claimed in claim 11, which is characterized in that the side effect is intraocular pressure raising.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008157614A2 (en) * | 2007-06-21 | 2008-12-24 | Yale University | Sustained intraocular delivery of drugs from biodegradable polymeric microparticles |
| CN105435232A (en) * | 2014-08-08 | 2016-03-30 | 深圳君圣泰生物技术有限公司 | Liquid preparation composition and preparation method and use and solid preparation thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008157614A2 (en) * | 2007-06-21 | 2008-12-24 | Yale University | Sustained intraocular delivery of drugs from biodegradable polymeric microparticles |
| CN105435232A (en) * | 2014-08-08 | 2016-03-30 | 深圳君圣泰生物技术有限公司 | Liquid preparation composition and preparation method and use and solid preparation thereof |
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