CN1583744A - Pirenzepine organic acid salt and eye drops for treating myopia - Google Patents
Pirenzepine organic acid salt and eye drops for treating myopia Download PDFInfo
- Publication number
- CN1583744A CN1583744A CN 200410046270 CN200410046270A CN1583744A CN 1583744 A CN1583744 A CN 1583744A CN 200410046270 CN200410046270 CN 200410046270 CN 200410046270 A CN200410046270 A CN 200410046270A CN 1583744 A CN1583744 A CN 1583744A
- Authority
- CN
- China
- Prior art keywords
- pirenzepine
- salt
- organic acid
- acid
- acid salt
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 229960004633 pirenzepine Drugs 0.000 title claims abstract description 125
- -1 Pirenzepine organic acid salt Chemical class 0.000 title claims abstract description 43
- 208000001491 myopia Diseases 0.000 title claims abstract description 32
- 230000004379 myopia Effects 0.000 title claims abstract description 30
- 239000003889 eye drop Substances 0.000 title claims abstract description 17
- 229940012356 eye drops Drugs 0.000 title claims description 16
- 239000002253 acid Substances 0.000 claims abstract description 11
- 150000001875 compounds Chemical class 0.000 claims abstract description 6
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- 150000003839 salts Chemical class 0.000 claims description 57
- 238000002360 preparation method Methods 0.000 claims description 39
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- 229960000293 pirenzepine hydrochloride Drugs 0.000 claims description 21
- FFNMBRCFFADNAO-UHFFFAOYSA-N pirenzepine hydrochloride Chemical compound [H+].[H+].[Cl-].[Cl-].C1CN(C)CCN1CC(=O)N1C2=NC=CC=C2NC(=O)C2=CC=CC=C21 FFNMBRCFFADNAO-UHFFFAOYSA-N 0.000 claims description 20
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Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
This invention relates to a new compound that treat the myopia, named pirenzepine organic acid and the related eye drop. The pirenzepine organic acid has more lipophilic compare to mineral acid, and could boost the permeability to the canthus membrane of the pirenzepine organic acid, so the curative effect is accelerated.
Description
Technical field:
The present invention relates to be fit to the pirenzepine organic acid salt and the pharmaceutical composition thereof of eye drops, with the pirenzepine inorganic acid salt, the example hydrochloric acid pirenzepine is compared, and this class salt has bigger lipotropy, can increase the permeability of pirenzepine corneal, improves curative effect.
Background technology:
Myopia (Myopia) is the extremely common disease of a class, often originates in childhood.Along with popularizing of urbanization and TV, computer, the crowd of myopia is being developed to direction occurred frequently.At present, the myopia patient is crowd's 25% in the global range, has among higher ratio, the especially teenager ratio higher in China and surrounding countries, more is the trend of rising in recent years, and according to statistics, rate of myopia is up to more than 80% in the of the right age crowd of college entrance examination.Myopia not only will have influence on patient's orthobiosis, and easily produce other complication.
Myopia is how long because of axial length before and after the eyeball, and under ungoverned situation, parallel rays focuses in the preretinal vitreum, and the result forms the diffusion ring of light, blurring of vision at retina.Have only object is shifted near, could imaging on retina, see object clearly.The generation of myopia is usually with closely to look thing for a long time relevant with accurate operation work.Must shrink constantly to increase lenticular curvature owing to see nearly thing or small objects, ciliary muscle for a long time, if things go on like this, cause the ciliary muscle atrophy, adjusting power reduces.
In recent years, the someone adopts anticholinergic drug by blocking the dominating role of cholinergic nerve to pupil shape flesh and papillary sphincter muscle, is used for the treatment of myopia.McBrien is in the simple eye chicken intravitreal injection coromegine that carries out form deprivation, find that the near-sighted number of degrees and axial length of the eye are significantly less than control group, and see that coromegine can not weaken the regulating effect of carbachol (cholinomimetic) and the pupil contraction under the illumination, thereby reach a conclusion, coromegine can stop axis oculi to prolong, reduce the dioptry of experimental myopia by non-regulation mechanism.Stone can stop the axis oculi of form-deprivation myopia to prolong by the chicken experiment being found non-selective m receptor blocker coromegine, experimental results show that further the mechanism of atropinic treatment myopia mainly directly acts on sclera.Yet coromegine is non-selective m receptor blocker, simultaneously M1 capable of blocking, M2, M3 acceptor.Because the M1 acceptor is positioned at nervous tissue, and the M3 acceptor mainly is positioned at intraocular flesh, treatment myopia only needs to have only the M1 acceptor to get final product in the blocking-up iris.
Pirenzepine (pirenzepine) is a selectivity M1 receptor-blocking agent, has the selectivity cholinolytic effect.Discovering in recent years, pirenzepine has positive effect to generation, the development that prevents and treats myopia, single can reduce the retina vagusstoff and the choline level reaches 9h (Cottriall CL at vitreum intracavitary administration pirenzepine, Annies R, BrewJ, et al.Pirenzepine reduces retinal acetylcholine and dopamine levels.Proc AustNeurosci Soc, 1999,10:55).Studies show that in rhesus monkey, chicken and other Mammals experimental models, pirenzepine can stop the generation of experimental myopia, its effect is suitable with coromegine, and side effect (the Cottriall CL that does not have coromegine to bring because of selectivity is relatively poor, McBrien NA, Annies R, et al.Prevention of formdeprivation myopia with pirenzepine:a study of drug delivery and distribution.OphthalPhysiol Opt, 1999,4:327-335).Studies show that: it is more direct, effective that pirenzepine is considered to treat near-sighted effect.Different with coromegine, the platycoria side effect of pirenzepine is little, safe, is easily accepted by the patient.
WO 90/15604 and US5637604 applied for the axial length of back at the moment of the treatment animal development day after tomorrow prolong due to the eye drops of myopia.This patent adopts selectivity cholinocepter retarding agent, and they act on brain, nervous tissue or neurone, block its cholinergic receptor, and the eye ciliary muscle is not had effect.Comprising pirenzepine, special logical sequence Xiping etc.This patent does not relate to the design of drug delivery system.
WO 02/096418 has applied for the patent of the gelifying agent of a pirenzepine.The range of viscosities of the pirenzepine gelifying agent in this patent 20 ℃, cut under the condition that the speed of answering is 1s-1 and to be 10000-300000cps, the concentration that wherein contains pirenzepine is 0.001-3%, and viscosity is the derivatived cellulose 0.5-5% of 15000-200000 and other components such as sodium-chlor, cetrimonium bronmide, Benzalkonii Chloridum, boric acid, yellow soda ash, Repone K, propylene glycol, polyoxyethylene, polyoxypropylene, polyvinyl alcohol, poloxamer 188, Sodium Citrate, Zonon D etc.Consider the stability problem of pirenzepine, the preparation of eye drip gelifying agent divides two portions, and the HPMC coagulant liquid adopts pressure sterilizing, and the solution of pastille adopts filtration sterilization, and the pH of eye drops is 5.0.
Yet above-mentioned patent does not all relate to the problem that absorbs of pirenzepine.The pirenzepine wetting ability is very high, and lipotropy is lower, thereby adopts simple eye drops administration, and it is lower through the specific absorption that cornea enters sclera.Dai Yikang, Chu Renyuan point out: because lipotropy is lower, pirenzepine is difficult to see through cornea and arrives intraocular (Dai Yikang, Chu Renyuan, the pharmacokinetic of pirenzepine eye drops in the rabbit aqueous humor, eye optometry magazine, 2002,4 (4): 228-229).Although the appropriate pH scope of ophthalmic preparation is 5-9,, the pH among the WO 02/096418 is 5.0, has been lower limit, is easy to generate in producing, storing to be lower than 5.0 situation, causes the generation to eye irritation.
Reported the pirenzepine preparation in, pirenzepine exists with inorganic salt form, the present invention is for overcoming above-mentioned defective, the organic acid salt of pirenzepine is provided, improved that it is fat-soluble, stable, to guarantee pirenzepine nonirritant in the application of treatment myopia, preparation stabilization, pirenzepine can see through vitreous layer preferably simultaneously, guarantees its validity.
Summary of the invention:
The invention provides pirenzepine organic acid salt and the double salt that contains the pirenzepine organic acid salt; pirenzepine organic acid salt of the present invention is meant the salt that pirenzepine and organic acid form; described organic acid includes but not limited to following organic acid, Sorbic Acid (sorbic acid); toxilic acid (maleic acid); fumaric acid (fumaric acid); Citric Acid (citric acid); Phenylsulfonic acid; toluene sulfonic acide; gentisinic acid; lactobionic acid; glucuronic acid; tartrate; lactic acid; succsinic acid; oxalic acid; butyric acid; isopropylformic acid; 2 Ethylbutanoic acid (diethylacetic acid); valeric acid; isovaleric acid; trimethylacetic acid; phenylformic acid; toluylic acid; tetradecanoic acid (tetradecanoic acid); palmitinic acid (hexadecanoic acid); stearic acid (stearic acid); oleic acid; linolic acid; the a-linolenic acid; vanillic acid; syringic acid; chlorogenic acid; forulic acid; valeric acid; Potenlini; Oleanolic Acid; ursolic acid; sad; shikimic acid; lauric acid; styracin; taurine; nicotinic acid; Yi Yansuan; Witco 1298 Soft Acid etc.
The double salt that contains the pirenzepine organic acid salt of the present invention is meant the double salt of two or more acid and pirenzepine formation, and wherein at least a is organic acid, the pirenzepine hydrochloride organic acid salt that example hydrochloric acid pirenzepine and above-mentioned organic acid form.
The sorbate that the preferred pirenzepine organic acid salt of the present invention is a pirenzepine; maleate; fumarate; citrate; benzene sulfonate; toluenesulfonate; gentisate; Lactobionate; glucuronate; tartrate; lactic acid salt; succinate; oxalate; butyrates; isobutyrate; 2 Ethylbutanoic acid salt; valerate; isovalerate; octylate; pivalate; benzoate; phenylacetate; myristate; palmitate; stearate; oleate; linoleate; the a-linolenate; vanillate; the cloves hydrochlorate; chlorogenic acid salt; ferulate; valerate; glycyrrhetate; the olea hydrochlorate; the black bearberry hydrochlorate; the thick grass hydrochlorate; lauroleate; cinnamate; taurate; nicotinate; Yi Yansuan salt; dodecylbenzene sulfonate.
Preferred double salt is the sorbate of pirenzepine hydrochloride; maleate; fumarate; citrate; benzene sulfonate; toluenesulfonate; gentisate; Lactobionate; glucuronate; tartrate; lactic acid salt; succinate; oxalate; butyrates; isobutyrate; 2 Ethylbutanoic acid salt; valerate; isovalerate; octylate; pivalate; benzoate; phenylacetate; myristate; palmitate; stearate; oleate; linoleate; the a-linolenate; vanillate; the cloves hydrochlorate; chlorogenic acid salt; ferulate; valerate; glycyrrhetate; the olea hydrochlorate; the black bearberry hydrochlorate; the thick grass hydrochlorate; lauroleate; cinnamate; taurate; nicotinate; Yi Yansuan salt; dodecylbenzene sulfonate.
The present invention is sorbate, maleate, citrate, the gentisate double salt of pirenzepine hydrochloride more preferably.
The present invention also provides the pharmaceutical composition that contains pirenzepine organic acid salt of the present invention or double salt.Pharmaceutical composition of the present invention can add the medicine acceptable carrier in case of necessity, and in composition of the present invention, the weight percent that can contain the pirenzepine organic acid salt is 0.001-10%, and all the other are the medicine acceptable carrier.
Pharmaceutical composition of the present invention adopts the eye drops system, comprises common eye drops, Eye ointments, gel for eye (comprise bioadhesive gel, the gel of ascending the throne), colloid system (liposome, millimicro ball), cyclodextrin inclusion compound etc.
Common eye drops comprises ophthalmic solution, suspensoid.Eye ointments is meant with Vaseline to be the eye semi-solid preparation that vehicle is made.
The bioadhesive gel agent be meant with the polymkeric substance that contains a plurality of hydrophilic radicals be material make have the gelifying agent of adhesive power with cornea.This base polymer comprises glass acid, HPMC (HPMC), polyvinyl alcohol (PVA), Xylo-Mucine (CMC-Na), polyacrylic acid (PAA).This gellike agent is the rheological properties of non-Newtonian fluid usually, and promptly along with cutting the raising of answering speed, the viscosity of liquid increases, and this helps preparation stop within the eye, prevents that medicine from being rinsed out by tear, thereby improves the ratio that medicine sees through cornea.
The gel of ascending the throne be meant eye drops this as can free-pouring liquid, be subjected to pH, temperature variation, preparation forms gel after splashing into eyelid, thereby increases preparation resident in eye, improves the cornea transmitance.The thixotropic gel of ascending the throne of pH mainly is made up of cellulose acetate phthalate (CAP), carbomer etc., can become gelifying agent rapidly under the condition of preparation at pH7.4.The thixotropic gel of ascending the throne of temperature mainly is made up of the polymkeric substance that can be changed into gel at 32-36 ℃, and this base polymer comprises compositions such as gelling gum.
Colloid system comprises liposome and millimicro ball, and wherein medicine is wrapped in liposome or the millimicro ball, splash into intraocular after, the medicine slow release.
Cyclodextrin inclusion compound is meant that medicine is wrapped in the preparation that forms in the cyclodextrin, and the solubleness of medicine and stability can improve greatly.
In the ophthalmic preparation of above-mentioned pirenzepine organic acid salt, added an amount of other auxiliary material, comprise isotonic regulator, cornea absorption enhancer, sanitas etc.
Isotonic regulator is mainly used in the osmotic pressure of regulating preparation, makes it suitable with the osmotic pressure of tear, to reduce pungency.Isotonic regulator comprises sodium-chlor, Repone K etc.
The cornea promotor of pirenzepine comprises Zonon D, cationic surfactant (as benzalkonium chloride, Morpan BB etc.), polysorbate (as Polysorbate 20,80 etc.), cholate (as Sodium cholic acid, Sodium desoxycholate etc.).
In the preparation pirenzepine organic acid salt or double salt can be directly and other material soluble in water; Also can make lyophilized powder or be pressed into tablet, with before being dissolved in the The suitable solvent.
The present invention also provides the preparation method of pirenzepine organic acid salt or double salt, and this method comprises through pirenzepine free alkali and organic acid blended step, or process pirenzepine hydrochloride and organic acid blended step.
Pharmaceutical composition of the present invention can be made eye medicinal preparation of the present invention according to the routine techniques of technology of pharmaceutics.
The present invention also provides pirenzepine organic acid salt or the application of double salt in preparation treatment or prevention medicine for treating myopia.Described myopia is a myopia due to the axial length of back at the moment that the human or animal will be developed the day after tomorrow prolongs.Comprise and growing up and pupillary myopia, preferably myopia that the minor suffers from.
The object of the present invention is to provide pirenzepine organic acid salt or the double salt and the eye drops system thereof of treatment myopia, make pirenzepine be easy to see through cornea, prevent irritating generation, improve the stability of pirenzepine, make preparation reach the purpose of safe and effective treatment myopia.
Pirenzepine is hydrochloride at present, and it is fat-soluble lower, and the cornea perviousness is relatively poor, stability is not high.Pirenzepine machine hydrochlorate of the present invention or double salt are compared with hydrochloride, and this class salt has bigger fat-soluble, and the profit partition ratio is bigger, and the cornea transmitance is greatly improved.
Profit partition ratio described in this patent is meant the partition ratio in the n-Octanol/water that records in the aqueous solution of pH7.4.
Cornea transmitance described in this patent is meant that medicine sees through the degree and the speed of cornea.After medicine splashes into eyelid, obtain by measuring the concentration of medicine in aqueous humor.
The characteristics of this patent are that medicine is more stable, the cornea transmitance is higher, pungency is littler, are easy to make and use.The stable pH (pHm) of pirenzepine hydrochloride is 5.0, and pHm will be near 7.0 behind the composition double salt.
Embodiment:
Be the embodiment of this patent below, but following embodiment does not limit the interest field of putting this patent.
The preparation of pirenzepine organic acid salt:
Embodiment 1
The preparation of pirenzepine free alkali:
Get the 100g pirenzepine hydrochloride and be dissolved in an amount of distilled water,, remove methyl alcohol, on Rotary Evaporators, remove methyl alcohol and get the pirenzepine free alkali through the Zeo-karb exchange, with methanol-eluted fractions.
Embodiment 2
The preparation of Sorbic Acid pirenzepine:
Get pirenzepine free alkali 10g, be dissolved among the methyl alcohol 10mL; Other gets Sorbic Acid 6.39g, and heating makes and is dissolved in the methyl alcohol; The Sorbic Acid drips of solution is added in the pirenzepine free base solution, on Rotary Evaporators, is concentrated into 2mL, place refrigerator overnight, filter, get the Sorbic Acid pirenzepine.
Embodiment 3
The preparation of toxilic acid pirenzepine:
Get pirenzepine free alkali 10g, be dissolved among the methyl alcohol 10mL; Other gets toxilic acid 3.31g, and heating makes and is dissolved in the methyl alcohol; Maleic acid solution is dripped in the pirenzepine free base solution, on Rotary Evaporators, be concentrated into 2mL, place refrigerator overnight, filter, get the toxilic acid pirenzepine.
Embodiment 4
The preparation of Citric Acid pirenzepine:
Get pirenzepine free alkali 10g, be dissolved among the methyl alcohol 10mL; Other gets Citric Acid 5.99g, and heating makes and is dissolved in the methyl alcohol; Citric acid soln is dripped in the pirenzepine free base solution, on Rotary Evaporators, be concentrated into 2mL, place refrigerator overnight, filter, get the Citric Acid pirenzepine.
Embodiment 5
The preparation of gentisinic acid pirenzepine:
Get pirenzepine free alkali 10g, be dissolved among the methyl alcohol 10mL; Other gets gentisinic acid 8.78g, and heating makes and is dissolved in the methyl alcohol; The gentisinic acid drips of solution is added in the pirenzepine free base solution, on Rotary Evaporators, is concentrated into 2mL, place refrigerator overnight, filter, get the gentisinic acid pirenzepine.
The preparation of pirenzepine double salt:
Embodiment 6
The preparation of Sorbic Acid hydrochloric acid pirenzepine double salt:
Get pirenzepine hydrochloride 11g, be dissolved among the distilled water 2mL; Other gets Sorbic Acid 3.19g, and heating makes and is dissolved in the methyl alcohol; The Sorbic Acid drips of solution is added in the pirenzepine hydrochloride solution, places refrigerator overnight, filter, get Sorbic Acid hydrochloric acid pirenzepine double salt.
Embodiment 7
The preparation of toxilic acid hydrochloric acid pirenzepine double salt:
Get pirenzepine hydrochloride 11g, be dissolved among the distilled water 2mL; Other gets toxilic acid 1.16g, and heating makes and is dissolved in the methyl alcohol; Maleic acid solution is dripped in pirenzepine hydrochloride solution, place refrigerator overnight, filter, get toxilic acid hydrochloric acid pirenzepine double salt.
Embodiment 8
The preparation of Citric Acid hydrochloric acid pirenzepine double salt:
Get pirenzepine hydrochloride 11g, be dissolved among the distilled water 2mL; Other gets Citric Acid 3g, and heating makes and is dissolved in the methyl alcohol; Citric acid soln is dripped in pirenzepine hydrochloride solution, place refrigerator overnight, filter, get Citric Acid hydrochloric acid pirenzepine double salt.
Embodiment 9
The preparation of gentisinic acid hydrochloric acid pirenzepine double salt:
Get pirenzepine hydrochloride 11g, be dissolved among the distilled water 2mL; Other gets gentisinic acid 4.4g, and heating makes and is dissolved in the methyl alcohol; The gentisinic acid drips of solution is added in the pirenzepine hydrochloride solution, places refrigerator overnight, filter, get gentisinic acid hydrochloric acid pirenzepine double salt.
Embodiment 10
The evaluation of pirenzepine organic acid salt:
Organic acid salt to above-mentioned each pirenzepine carries out ultimate analysis respectively, and the result shows (table 1): the elementary composition and theoretical value of each organic acid salt is consistent.Proof has prepared salify.
Table 1 pirenzepine organic salt ultimate analysis data
| The element kind | Free alkali | Sorbate | Maleate | Citrate | Gentisate | |
| Theoretical value | ??C(％) ??H(％) ??O(％) ??N(％) | ??64.94 ??6.02 ??19.93 ??9.11 | ??64.70 ??6.43 ??16.70 ??12.17 | ??59.10 ??5.35 ??20.56 ??14.99 | ??53.48 ??5.53 ??28.52 ??12.48 | ??60.09 ??5.01 ??24.28 ??10.62 |
| The practical measurement value | ??C(％) ??H(％) ??O(％) ??N(％) | ??64.65 ??5.99 ??20.01 ??9.35 | ??63.85 ??6.02 ??17.21 ??12.92 | ??58.78 ??5.44 ??21.02 ??14.76 | ??52.87 ??5.77 ??28.53 ??12.83 | ??61.03 ??4.99 ??24.22 ??9.76 |
The preparation of pirenzepine organic acid salt gel for eye:
Embodiment 11
The preparation of Sorbic Acid pirenzepine gel for eye:
A) it is an amount of to get HPMC K100M, and the ratio in 4% makes and is dissolved in the water for injection, and drip 1N HCl or NaOH and regulate pH7.0,121 ℃ of sterilizations 30 minutes down, placement is spent the night.
B) be 4% to take by weighing the Sorbic Acid pirenzepine by the concentration of pirenzepine free alkali, add Benzalkonii Chloridum (ten thousand/), Zonon D (4/10000ths), add sodium-chlor an amount of (about 1%), drip 1N NaOH and be adjusted to pH7.0, solution filters through 0.22 μ m millipore filtration.
C) A, B two liquid equal-volumes are mixed can.
Embodiment 12
The eye preparation of Sorbic Acid pirenzepine:
A) it is an amount of to get HPMC K100M, ratio in 2% makes and is dissolved in the water for injection, add Benzalkonii Chloridum (5/100000ths), Zonon D (2/10000ths), add sodium-chlor an amount of (about 0.5%), drip 1N HCl or NaOH and regulate pH7.0, sterilized 30 minutes down for 121 ℃, placement is spent the night.
B) Sorbic Acid pirenzepine an amount of (being equivalent to free alkali 100mg) is aseptic subpackaged in container, gets final product in A liquid with preceding.
Embodiment 13
The preparation of salt bezoic acid pirenzepine gel for eye:
A) it is an amount of to get HPMC K100M, and the ratio in 4% makes and is dissolved in the water for injection, and drip 1N HCl or NaOH and regulate pH7.0,121 ℃ of sterilizations 30 minutes down, placement is spent the night.
B) be 4% to take by weighing pirenzepine hydrochloride by the concentration of pirenzepine free alkali, add an amount of Sorbic Acid, Benzalkonii Chloridum (ten thousand/), Zonon D (4/10000ths), add sodium-chlor an amount of (about 1%), drip 1N NaOH and be adjusted to pH7.0, solution filters through 0.22 μ m millipore filtration.
C) A, B two liquid equal-volumes are mixed can.
Embodiment 14
The eye preparation of toxilic acid pirenzepine liposome
Get phosphatidylcholine dipalmitate (DPPC), cholesterol was dissolved in the ethanol by 1.85: 1, removed ethanol on rotatory evaporator, obtained double-deck immobilized artificial membrane.Add the toxilic acid pirenzepine aqueous solution, aquation.The filter membrane of extruding by 90-100nm prepares liposome.
Embodiment 15
The eye preparation of toxilic acid pirenzepine cyclodextrin inclusion compound
By etc. mol ratio get beta-cyclodextrin and the toxilic acid pirenzepine soluble in water, cross 0.22 μ m millipore filtration to filter, through cryodesiccated toxilic acid pirenzepine cyclodextrin inclusion compound.
Embodiment 16
The mensuration of various pirenzepine organic acid salt profit partition ratios
Containing free alkali 0.1%, pH with the preparation of the saturated redistilled water of n-Octanol is 7 the various pirenzepine organic acid salts or the potassium primary phosphate-borax buffer solution of pirenzepine hydrochloride, adds sodium-chlor and regulates ionic strength to 0.154mol/L.Get each 5mL of above-mentioned solution and mix, place (34 ± 0.5) ℃ water bath with thermostatic control, balance 24hrs under the induction stirring, centrifugation two-phase with the water saturated n-Octanol of equivalent.The drug level in the solution and the concentration of oil phase Chinese traditional medicine before and after the mensuration balance are calculated the profit partition ratio respectively.
The result shows: after forming organic acid salt, the profit partition ratio of pirenzepine significantly improves, and is example with the toxilic acid, and its profit partition ratio is about nearly 20 times of pirenzepine hydrochloride.
Table 2 pirenzepine organic acid salt profit partition ratio
Hydrochloride Sorbic Acid double salt toxilic acid double salt Citric Acid double salt gentisinic acid double salt
Profit partition ratio 0.169 0.458 2.940 2.746 0.367
Embodiment 17
Isolated cornea sees through experiment
Get rabbit, anesthesia causes death.Extracing eyeball places.Crosscut is done, isolated cornea by sclera place along elongation film edge 2mm.Remove eyeball rear portion tissues such as lens, vitreum, peel off iris, must have the cornea of 2mm sclerotic ring.The interior beginning of 20min cornea sees through experiment after putting to death animal.Adopt the infiltration dispersion device, comprise supply pool and accept the pond, keep the shape of isolated cornea to be fixed between two ponds, make epithelial lining towards supply pool.Add the gelifying agent 2mL of various organic acid salts of pirenzepine or pirenzepine hydrochloride in the supply pool, accepting the pond is Ringer's solution, and whole device is put into (34 ± 0.5) ℃ water bath with thermostatic control and begun experiment.After on-test the 5th, 15,30,45,60,90,120min is from accepting pond sampling 1mL and replenishing isopyknic blank immediately and use 95% in advance: 5%O
2And CO
234 ℃ of Ringer's solutions that mixed gas is saturated.Sample is got the concentration that subsequent filtrate is measured pirenzepine with the filtering with microporous membrane of 0.22 μ m, is calculated as follows the cornea transmission coefficient of various salt.
The result shows: the cornea transmission coefficient of pirenzepine organic acid salt significantly improves.
Table 3 pirenzepine organic salt cornea transmission coefficient determination data (n=6)
Hydrochloride Sorbic Acid double salt toxilic acid double salt Citric Acid double salt gentisinic acid double salt
Cornea transmission coefficient 1.07 ± 0.08 1.42 ± 0.12 6.56 ± 0.11 4.23 ± 0.15 1.36 ± 0.09
×10
5(ug/s·cm
2)
Embodiment 18
Pharmacokinetics in the pirenzepine eye drops rabbit aqueous humor
40 rabbits are divided into 8 groups at random by the sampling time, every group of 5 rabbits.Change the prescription administration every two weeks, totally 2 times (pirenzepine hydrochloride gel for eye and Sorbic Acid pirenzepine gel for eye use respectively).In a glance conjunctival sac, drip 2 of the pirenzepine eye drops (100 μ L) that prepare, not medication of left eye during administration respectively.Behind eye drip 0.5,1,2,4,8,12,24, during 48h, totally 8 time points extract the aqueous humor 0.2ml of right eye respectively.Get aqueous humor 0.1mL, add 0.1mL methyl alcohol, whirlpool mixes, with protein precipitation and impurity.With the centrifugal 10min of 16000r/min speed, get supernatant liquor, inject high performance liquid chromatograph, the record peak area calculates content with external standard method.Each time point is got 5 eyes, with its mean value as the concentration of this time point pirenzepine in aqueous humor.
The result shows:
40 rabbit of table 3 are dripped the concentration (ng/ml) of medicine in aqueous humor behind the various pirenzepine organic salt eye drops
Time
0.5????1????2????4????8?????12?????24?????48
Hydrochloride 21.6 ± 49.1 ± 60.4 ± 77.5 ± 80.2 ± 34.6 ± 25.6 ± 12.3 ±
13.08??????21.23?????15.37????12.14????16.5??????10.76????11.34????9.26
Sorbic Acid double salt 36.4 ± 55.2 ± 71.8 ± 84.2 ± 90.6 ± 54.7 ± 37.8 ± 16.7 ±
12.56??????11.25?????17.34????13.84????14.9??????17.22????13.56????8.75
Toxilic acid double salt 58.7 ± 100.2 ± 194.9 ± 288.5 ± 208.2 ± 105.9 ± 69.2 ± 25.4 ±
12.52??????11.74?????20.51????18.7?????13.7??????13.18????12.77????10.12
Citric Acid double salt 58.4 ± 91.1 ± 175.3 ± 187.5 ± 208.8 ± 87.8 ± 55.4 ± 22.9 ±
15.11??????17.42?????13.7?????15.9?????10.1??????14.52????14.13????10.02
Gentisinic acid double salt 29.8 ± 45.9 ± 73.0 ± 88.2 ± 79.7 ± 49.2 ± 38.0 ± 21.2 ±
11.57??????14.28?????11.34????14.02????16.8??????12.57????12.48?????9.88
Claims (10)
1. be used for the treatment of or/the bathomorphic pirenzepine organic acid salt of prevention or contain the double salt of pirenzepine organic acid salt.
2. the pirenzepine organic acid salt or the double salt of claim 1, described pirenzepine organic acid salt is the salt that pirenzepine and organic acid form, described double salt is the salt of two or more acid and pirenzepine formation, and two or more acid is wherein at least a to be organic acid.
3. the pirenzepine organic acid salt or the double salt of claim 2; wherein the salt of pirenzepine and organic acid formation is selected from the sorbate of pirenzepine; maleate; fumarate; citrate; benzene sulfonate; toluenesulfonate; gentisate; Lactobionate; glucuronate; tartrate; lactic acid salt; succinate; oxalate; butyrates; isobutyrate; 2 Ethylbutanoic acid salt; valerate; isovalerate; octylate; pivalate; benzoate; phenylacetate; myristate; palmitate; stearate; oleate; linoleate; the a-linolenate; vanillate; the cloves hydrochlorate; chlorogenic acid salt; ferulate; valerate; glycyrrhetate; the olea hydrochlorate; the black bearberry hydrochlorate; the thick grass hydrochlorate; lauroleate; cinnamate; taurate; nicotinate; Yi Yansuan salt; dodecylbenzene sulfonate, the double salt that two or more acid and pirenzepine form is selected from the sorbate of pirenzepine hydrochloride; maleate; fumarate; citrate; benzene sulfonate; toluenesulfonate; gentisate; Lactobionate; glucuronate; tartrate; lactic acid salt; succinate; oxalate; butyrates; isobutyrate; 2 Ethylbutanoic acid salt; valerate; isovalerate; pivalate; benzoate; phenylacetate; myristate; palmitate; stearate; oleate; linoleate; the a-linolenate; vanillate; the cloves hydrochlorate; chlorogenic acid salt; ferulate; valerate; octylate; glycyrrhetate; the olea hydrochlorate; the black bearberry hydrochlorate; the thick grass hydrochlorate; lauroleate; cinnamate; taurate; nicotinate; Yi Yansuan salt; dodecylbenzene sulfonate.
4. contain the pirenzepine organic acid salt of claim 1-3 or the pharmaceutical composition of double salt.
5. the pharmaceutical composition in the claim 4 is the composition of administration through eye.
6. the pharmaceutical composition of claim 5 is eye drops, Eye ointments, gel for eye, eye colloid system preparation, eye cyclodextrin inclusion compound preparation.
7. the pharmaceutical composition of claim 6, wherein the weight percent of pirenzepine organic acid salt is 0.001-10%.
8. the pirenzepine organic acid salt of claim 1 or the preparation method of double salt is characterized in that, through pirenzepine free alkali or pirenzepine hydrochloride and organic acid blended step.
9. the pirenzepine organic acid salt of claim 1 or the double salt application in preparation treatment or prevention medicine for treating myopia.
10. the application of claim 8, wherein said myopia are myopia due to the axial length of back at the moment that the human or animal will be developed the day after tomorrow prolongs.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105663137A (en) * | 2016-01-14 | 2016-06-15 | 王真 | Application of pirenzepine in preparation of medicine for treating pyemia disease |
| JP2022101654A (en) * | 2017-11-03 | 2022-07-06 | アルコン インク． | Azabicyclo and diazepine derivatives for treating ocular disorders |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105663137A (en) * | 2016-01-14 | 2016-06-15 | 王真 | Application of pirenzepine in preparation of medicine for treating pyemia disease |
| JP2022101654A (en) * | 2017-11-03 | 2022-07-06 | アルコン インク． | Azabicyclo and diazepine derivatives for treating ocular disorders |
| US11884666B2 (en) | 2017-11-03 | 2024-01-30 | Alcon Inc. | Azabicyclo and diazepine derivatives |
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