CN1491724A - Polysaccharide system for gelling and thickening for treating glaucoma - Google Patents

Abstract

The medicine liquid system consists of externally applied eye disease treating medicine, buffing system, solvent system and polysaccharide hydrosol for gelling and thickening in the amount of 0.01-10 %; and contains water in 90-100 vol%. The medicine liquid system contains biological polymer material sensitive to pH value, temperature and ion concentration in eye. The present invention has high medicine bioavailability, less irritation, use convenience and high medicinal effect.

Description

A kind of one-tenth glue thickening polysaccharide system that is applicable to glaucoma treatment

Technical field

The present invention relates to a kind of can with medicine with the gel mode be used for outward eyes, to the gel delivery system of pH, temperature and ionic strength sensitivity.Especially specifically the invention relates to the method for a kind of knot medicine system and a kind of controlled release drug administration.The present invention also relates to a kind of drug-supplying system, this system is liquid and be gel during at another kind of pH when a kind of pH.

Said system can reversibly become gel and become liquid from gel from liquid.This makes this system different application to be arranged according to the different biological environment of human body.Another important application of the present invention is that we can use these gel systems to strengthen the response of medicine in drug prescription.Therefore might be able to make the frequency of utilization of medicine reduce to the every day of secondary even once a day.

Background technology

Glaucoma is because the rising of intraocular pressure causes papilla of optic nerve carrying out property pouch and atrophy, the visual field to degenerate, finally cause losing one's sight.Open-angle (chronic simple) glaucoma is a modal glaucoma in the glaucoma.Make the control intraocular pressure that heals with medicine to make the state of an illness controlled.Even for the angle closure glaucoma patient, also be necessary to use medicine to control preoperative intraocular pressure.Generally speaking, the intraocular pressure of glaucoma patient is high more, and the infringement of its optic nerve and glaucoma visual field is just serious more.The reduction of intraocular pressure may be achieved by following two kinds of approach, and promptly (1) reduces the quantum of output of aqueous humor; Or (2) increase the rate of discharge of aqueous humor from eyes.

Up to now, external is the most frequently used approach of eye knot medicine.But owing to drain and the height revolution rate of tear, be difficult to set up and keep the medicine concentration of ocular tissue and a liquid in the ideal treatment period.The Fickian diffusion requires to keep Concentraton gradient in a period of time.This just means wants the prolong drug preparation in the retention time of giving snack made with traditional Chinese medicines.Clearly, concerning any non-intrusion type administering mode, the retention time that all is necessary to prolong preparation.This point is even more important concerning eye knot medicine.As everyone knows, increase the retention time that the viscosity of eye drop can prolong eye drop.But in fact, can improving bioavailability to greatest extent, to make the patient that the range of viscosities of well tolerable property is arranged again be limited.Mucosa adsorbent or the bioabsorbable polymer material that contains medicine can be used for the cornea proparea.The mucous layer of macromolecular chain, drug molecule and superficial keratectomy just can interact by non-covalent chain like this.

The seventies is early stage, and the several parts of United States Patent (USP)s that are used for controlled release drug administration about polysaccharide have been discussed aspect contents such as prescription, product, purposes, application, packing, injection.Each this series products depends on its application, and its merits and demerits is all arranged.For example, a kind of collyrium is easy to preparation, but collyrium flows down patient's face and is difficult to accomplish accurate administration during owing to administration.1972, but Sullivan obtains as the gel and the gel prescription for the treatment of solution carrier to contain agar, Xanthan natural gum, Locust Caragana arborescens glue and liquid flux.1979, Lin and Pramoda reported a kind of eye prescription of forming with Locust Caragana arborescens glue and a kind of medicament for the eyes.

Polysaccharide is the functional macromolecular material of tool.The active material of tool chemistry and biology is wrapped in the natural high polymer carrier, in polysaccharide, has been proved to be useful at aspects such as science and industry.The multiple function that natural polysaccharide had makes it to become irreplaceable article in many commercial Application.The chemical constitution of polysaccharide can be sealing also can be open, Du Te colloidal nature stems from its one-tenth glue mechanism accordingly separately.This can be heat-staple and chemically stable, and can the tool cross-linked network structure.Because nontoxic, biocompatibility and biodegradability, for example the gluey natural polysaccharide of alginate, carrageenin, agar, chitin and gellan natural gum is being shown up prominently aspect the parcel of encapsulation and medicine.

The physicochemical property of gel influences fixing, the diffusion and the controlled release of nutrition and metabolism thing greatly.Monomer whose composition, replacement degree, become glue kinetics, gel strength, degree of shrinkage and framing structure homogeneity all to a great extent influence be wrapped in the viability of the kinetics of diffusion of medicine, vaccine and other molecule in the gel skeleton and rate of release and cell, tissue, ovum etc.

Our research is concentrated in the following areas: (1) is used for medicine according to used colloidal nature exploitation natural and the chemical modification polysaccharide and vaccine is fixed, microcapsule, active protection (microorganism, animal and plant cells, tissue, seed, ovum and embryo) and controlled-release technology; (2) be used for the polysaccharide characteristic of microcapsule, especially study the structure one character relation of biological capsule; (3) the utilization several different methods especially focuses on the new technology of the therapeutic agent of exploitation suitability for industrialized production with the function of the microorganism of understanding encapsulation preferably, plant and animal cell system biomolecule and the bioprocess technology with exploitation tool high added value; (4) the active method of the material that is wrapped up under the abominable storage condition of development evaluation.

Summary of the invention

The object of the present invention is to provide a kind of one-tenth glue thickening polysaccharide system that is applicable to glaucoma treatment, to increase bioavailability of medicament, reduce zest, conveniently to use, improve drug effect.

According to technical scheme provided by the present invention, this system is by the external medicament for the eyes of effective therapeutic dose, buffer system, solvent system and 0.001% to about 10% the medicinal fluid system that becomes the glue thickening to form with the polysaccharide hydrosol, and the medicinal fluid system by weight or stereometer moisture 90～100%.

The concentration range of the polysaccharide hydrosol is at 0.02% to 10.0% (w/w) and/or (w/v), and it is derived from Chinese herbal medicine or animal extracts or marine product or plant or antibacterial and fungus.Described external medicament for the eyes is a Betimol.

Buffer system is the biological buffer of borate buffer solution or phosphate buffer or Apiroserum Tham buffer or citric acid buffer or cocktail buffer and/or MOPS.

Described solvent system be glycerol or, 1,2 propylene glycol and/or surfactant system.Described surfactant is poloxamer (poloxamer) or protects beautiful (poloxamine) or hydroxypropyl methylcellulose and/or the surfactant of other HLB between 5～35 looked bright.

The polysaccharide hydrosol is the linear or cancellated polysaccharide of heteropolysaccharide that contains a kind of polysaccharide of monosaccharide or contain two or more monosaccharide.The contained monosaccharide of the polysaccharide hydrosol is glucose or galactose or mannose or xylose or glucuronic acid.The polysaccharide hydrosol is cationic or anionic or nonionic polysaccharide.

The described polysaccharide hydrosol is derived from Chinese herbal medicine (as Fructus Lycii, Aloe vulgaris), or animal extracts (as hyaluronic acid, gelatin, cheese dawn white and the milk surum dawn is white), or marine product (as carrageenin, agar and alginate), or plant (as pectin, the Semen sojae atricolor dawn is white, Guar is gummy, Locust Caragana arborescens glue, Tara natural gum and Konjac), or antibacterial and fungus (as Xanthan natural gum and Gellan natural gum).

Described Betimol is adrenalin hydrochloride or carteolol or betaxolol or left butanone is felt at ease or metipranolol or timolol maleate or Pilocarpine Hydrochloride or carbachol or acetazolamide or Brinzolamide or daranide or dorzolamide or methazolamide, latanoprost, brimonidine tartrate etc.

The pharmaceutical suspension that the present invention will be used for the treatment of, Emulsion and/or solution wrap up to biology adaptable hydrogel.According to the water solublity and the application thereof of medicine, it is transparent or opaque that hydrogel can be.This unique medicament for the eyes dosage form allows patient and end user use more convenient (every day 1 time or 2 times), better therapeutic effect and best economic benefit.

The used polysaccharide of the present invention all extracts from plant or animal tissue, thereby is nontoxic or the natural component of low toxicity.Typical polysaccharide has: Xanthan natural gum, (R.T.Vanderbilt Company, Inc. U.S.), Guar natural gum (Gumix International, Inc. Gellan natural gum (Pangear Sciences, Inc. Canada) U.S.),, hyaluronic acid (Pentapharm Ltd. Switzerland), carrageenin (the FMC Corp. U.S.) etc.

The eye knot medicine system of this uniqueness is made up of more than one biopolymers, and its mutual concertedness can increase bioavailability of medicament, reduce zest.

This unique prescription is owing to having similar pseudoplastic behavior with tear, so splash into the normal condition that influences tear in the eye hardly.Compare with common collyrium, this prescription because and ocular tissue, especially treat the good biology of glaucomatous cornea and join a property, thereby better bioavailability is arranged.

The specific embodiment

Following examples just illustrate the embodiment that the present invention is possible, rather than the restriction scope of invention.

Embodiment one, the prescription of a kind of typical clear gel system.

Component	????W/W
		Prescription I
Buffer system or solvent	1-25% (total measurement (volume))
		Prescription II
Water or buffer system	(10-90% total measurement (volume)) undetermined
		Polysaccharide	0.001％-10.0％
With the enough time of biphase mixing until forming stabilizing gel system (needing antiseptic to depend on final packaging)

Embodiment two

Component	????W/W	????W/W
			Come sour timolol	0.34％	0.34％
Propylene glycol	2.0-5.0％	2.0-5.0％
			Glycerol	0.50％	0.50％
Mannitol	1.00％	1.00％
			Xanthan natural gum	0.30％	0.00％
Guar natural gum	0.30％	0.00％
			Benzalkonium chloride	100ppm	100ppm
Pure water	Add to 100 grams	Add to 100 grams
			Drip the concentration that contains 0.25% timolol (ug/ml) next sour timolol after 30 minutes in the example two to lagophthalmos
Aqueous humor	4.15±1.02	2.01±0.53
			Cornea	62.31±20.52	35.41±11.14

The gel prescription that contains Xanthan natural gum and Guar natural gum is the liquid of a strong pseudoplasticity, thereby the shearing force dilution nictation characteristic of tool uniqueness.

Embodiment three

Component	????W/W
		Come sour timolol	0.34％
Phosphate or borate buffering	0.50％
		Alevaire	0.02％

Sodium chloride	0.10％
		Xanthan natural gum	0.30％
Guar natural gum	0.20％
		Benzalkonium chloride	100ppm
Pure water	Add to 100 grams

Contain the strong pseudoplasticity of gel prescription tool of Xanthan natural gum and Guar natural gum, thereby can modify other polysaccharide, for example the character of carrageenin and Gellan natural gum.

Embodiment four

Component	????W/W
		Come sour timolol	0.34％
Phosphate or borate buffering	0.50％
		Hydroxypropyl methylcellulose	0.30％
Glycerol	0.50％
		Sodium chloride	0.10％
Xanthan natural gum	0.50％
		Benzalkonium chloride	100ppm
Pure water	Add to 100 grams

Embodiment five

Component	????W/W
		Come sour timolol	0.34％
Phosphate or borate buffering	0.50％
		Hydroxypropyl methylcellulose	0.30％
Glycerol	0.50％
		Sodium chloride	0.10％
Xanthan natural gum	0.60％
		Benzalkonium chloride	100ppm
Pure water	Add to 100 grams

Embodiment six

Component	????W/W
		Chlorine sprinkles etaonate for promise	?0.25-0.50％
Phosphate-buffered	?0.5％
		Hydroxypropyl methylcellulose	?0.30％

The Kappa carrageenin	0.50％
		Sodium chloride	0.02％
Potassium chloride	0.02％
		Benzalkonium chloride	0.04％
Pure water	Add to 100 grams

Sulfuric ester gained gel band negative charge in the presence of potassium ion of band galactose skeleton.

Embodiment seven

Component	????W/W
		Brimonidine tartrate	?0.20％
The citric acid buffering	?0.50％
		Sodium chloride	?0.10％
Xanthan natural gum	?0.30％
		Guar natural gum	?0.20％
Benzalkonium chloride	?0.05％
		HCl，1N	The PH regulator is used in case of necessity
NaOH，1N	The PH regulator is used in case of necessity
		Pure water	Add to 100 grams
pH	?6.3-6.5

Embodiment eight

Component	????W/W
		Carbachol	0.75-3.00％
Phosphate or borate buffering	0.50％
		Hydroxypropyl methylcellulose	0.50％
Glycerol	0.50％
		Sodium chloride	0.10％
Xanthan natural gum	0.10％
		Benzalkonium chloride	0.005％
Pure water	Add to 100 grams

Embodiment nine

Component	????W/W
		Carbachol	0.75-3.00％
Phosphate or borate buffering	0.50％

Hydroxypropyl methylcellulose	0.50％
		Glycerol	0.50％
Sodium chloride	0.10％
		Xanthan natural gum	0.02％
Benzalkonium chloride	0.005％
		Pure water	Add to 100 grams

Embodiment ten

Component	????W/W
		Pilocarpine Hydrochloride	0.50-10.0％
Hydroxypropyl methylcellulose	0.30％
		The Kappa carrageenin	0.50％
Sodium chloride	0.02％
		Potassium chloride	0.02％
Benzalkonium chloride	100ppm
		Pure water	Add to 100 grams

Embodiment 11

Component	????W/W
		Pilocarpine Hydrochloride	0.50-10.0％
Hydroxypropyl methylcellulose	0.30％
		The Kappa carrageenin	0.001％
Sodium chloride	0.02％
		Potassium chloride	0.02％
Benzalkonium chloride	100ppm
		Pure water	Add to 100 grams

Embodiment 12

Component	????W/W
		Dorzolamide	2.00％
Hydroxypropyl methylcellulose	0.30％
		Locust Caragana arborescens glue	0.30％
Sodium chloride	0.02％
		Potassium chloride	0.02％
Benzalkonium chloride	0.0075％

Mannitol	3.60％
		Pure water	Add to 100 grams

Claims (10)

1, a kind of one-tenth glue thickening polysaccharide system that is applicable to glaucoma treatment, it is characterized in that: this system is by the external medicament for the eyes of effective therapeutic dose, buffer system, solvent system and 0.001% to about 10% the medicinal fluid system that becomes the glue thickening to form with the polysaccharide hydrosol, the medicinal fluid system is moisture 90～100%, and unit is a percetage by weight.

2, system according to claim 1 is characterized in that: the concentration range of the polysaccharide hydrosol is 0.02～10.0%, and unit is a percetage by weight.

3, system according to claim 1 is characterized in that: the polysaccharide hydrosol is derived from Chinese herbal medicine or animal extracts or marine product or plant or antibacterial and fungus.

4, system according to claim 1 is characterized in that: the external medicament for the eyes is a Betimol.

5, system according to claim 1 is characterized in that: buffer system is the biological buffer of borate buffer solution or phosphate buffer or Apiroserum Tham buffer or citric acid buffer or cocktail buffer and/or MOPS.

6, system according to claim 1 is characterized in that: solvent system be glycerol or, 1,2 propylene glycol and/or surfactant system.

7, system according to claim 1 is characterized in that: surfactant is poloxamer (poloxamer) or protects beautiful (poloxamine) or hydroxypropyl methylcellulose and/or the surfactant of other HLB between 5～35 looked bright.

8, system according to claim 1 is characterized in that: the polysaccharide hydrosol is the linear or cancellated polysaccharide of heteropolysaccharide that contains a kind of polysaccharide of monosaccharide or contain two or more monosaccharide.

9, according to claim 1 or 8 described systems, it is characterized in that: the contained monosaccharide of the polysaccharide hydrosol is glucose or galactose or mannose or xylose or glucuronic acid.

10, system according to claim 1 is characterized in that: the polysaccharide hydrosol is cationic or anionic or nonionic polysaccharide.