CS207808B1 - Matrix - Google Patents

Abstract

1499751 Compositions containing glucosamines AMERICAN CYANAMID CO 30 Jan 1975 [11 Feb 1974] 4193/75 Heading A5B [Also in Division C3] A pharmaceutical preparation comprises a matrix of an enzymatically degradable form of poly(N - acetyl - D - glucosamine) selected from purified chitin; poly[N - acetyl - 6 - O - (carboxymethyl) - D - glucosamine]; poly[N - acetyl - 6 - O - (2' - hydroxyethyl) - D - glucosamine]; and poly[N - acetyl - 6 - O - (ethyl) - D - glucosamine], and cross - linked polymers formed from these poly(N - acetyl - D - glucosamines); and intimately dispersed in the matrix a drug which is at least partly soluble in body fluid. A number of suitable drugs are specified but in preferred embodiments the preparation is in the form of an ocular insert containing pilocarpine or an intrauterine contraceptive device containing an anti-fertility agent.

Description

The invention relates to a matrix that is adapted to be inserted into the conjunctival sac of the eye to release the drug.

Very much Sasu has devoted efforts to measure the rate of drug release. When considering that drugs can be administered for many purposes and under different different conditions, different drugs have different water and oil solubilities and that. the period of time for the desired administration can vary from immediate administration to a long period of years, it being clear that there is a wide range of drugs and a wide range of controllable conditions.

See U.S. Patent Nos. 3,911,098; 2,040,879; 2, C40,880; 2,168,374; 3,632,754; 3,736,646 and 3,845,201 and the following literature:

Woordeo Rayoo. Textile МопОПу, 1941 XXII (9), at 49

Developments in Organic NoColluosic Fibrous Materials, CCe. Collection 79 No. 322 o (1973), Ch. Bs 73 c 73 No. 43828a (197C); *

Tanhqusry .A.C. and Bacey RE .: Cotrolled Re-Ase of Biologically Active Agents, AAd.in Exp.Med.BBoO.47, Plenum .1974;

Majkus et al .: J.Biomed. MMa. Res. J, 443 (1969);

Krejčí a spoO .: čs. πfrtlžologie 27. 265, 1971;

Praus et al., Oher et al., 1994, 165, 62;

Praus et al., Oplrtlml. Res. 6, 291 (1974);

Kroho and Βγ ^ ΓΓοΙ ^ ι »: Invest · CphehelmoO. 14, 152 (1975);

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207 008

Armmly and Faío: Symp.Acul. Ther. 6, 80 (1973);

Place et al., Am.J.Cphthalmol. 80, 706 (1975);

WooHand and Yolles: J. Med. Chem. 16, 893 (1973).

It has now been found that enzymatically degradable forms of poles (N-acetyl-D-glucoaaminul), further abbreviated as PAG, are stable and resistant to thyrolytic degradation in storage, so that the substances can be incorporated in mattresses such as biodegradable PAG, and the drug is then released in the tissue of living animals by enzymatic degradation of the biodegradable form of PAG The lysozyme enzyme is particularly effective in enzymatic degradation of the biodegradable form of PAG Different forms of PAG may have different degradations and this rate may vary depending on the application site. medicine·

The invention ιηβΜοβ which is adapted for insertion apojivkovéto bag of the eye to release - drug and is formed by -a eye which is characterized in that it comprises: - from enzymaticty odbouurtelné form ^YH ol ^y - ^[N-t TCE yl66-0- ( ^t- carboxymethyl) -D-glycol glycol having an average molecular weight of 40,000 to 50,000 and dispersed and ion-bound free bases of the eye drug and water soluble.

A low molecular weight PAG of less than 40,000 results in a shorter disintegration time.

As a drug, it may be incorporated into the maize by enzymatically from the methyl form of PAG, e.g.

It is generally desirable that the drug delivery device be mechanically acceptable at the site of administration. For example, an ophthalmic insert may be used by placing the cap in an aperture-like bag arriving at the eyeball. The liner must be soft to minimize irritation of the eyeball, and the degradation products are preferably such that they can be washed away by a tear stream without the need to remove the load upon release of the drug capsule. For Others. As implantation under the skin of the skin or insertion into the work-as a contraceptive, the likelihood of mechanical irritation by mnot is minor.

Since the requirements for use in human eye are widespread, the device will be particularly described in eye use, although it is understood that

JcHtOH u use с at another place. X ^ř

N-Acutyl-D-glucotamine has the formula (/)

R

The device according to the invention

H

H or

H20H / HCCH3

O

CH1.OH

NHCCH3 II o oh

The ski spheres spherically below the insulated plane are represented by a dotted bond.

Poles (N-acetyl 1-D-glucosami) h 1 has a formula 0 (hydrogen in the core are omitted for clarity) МИДе ⁰ / ^0/3 Ц 'íj & HIM

Poly (N-tert-ethyl-D-glucamine) - is a major constituent of naturally occurring naturally occurring material - not only sticks (N-acetyl-Dg), but also inorganic salts such as calcium carbonate and proteinaceous material not yet known. The term chitin refers to various naturally occurring forms of sensitizing agents, including protein and inorganic carbonate components. The term purified titanium refers to honor after

207 808 purification to remove calcium carbonate and other inorganic salts and various proteins that may be present, and it is essentially the poles (N-acety1-D-glucosamine). There are various discrepancies in the literature because the name chitin is used as a term for poles- (N-acetyl-D-glucosamine) without specifying whether it is a naturally occurring material containing inorganic salts and proteins or whether the term refers to purified poly- (N-acetyl-D-glucosamine) without indicating the degree of purity or nature of the impurities present.

The term enzymatically degradable form of poly (N-acetyl-D-glucosamine) refers to purified poles (N-acetyl-D-glucosamine) from derivative derivatives, etc.

Carboxymethyl derivative, chitin and carboxymethyl, hydroxyethyl and O-ethyl-linked poly [N-acetyl-6-O- (carboxymethyl) -D-glucose right

o (I) correctly named poles of (N-acetyl-6-O-) 2'-hydroxyethyl) -D-gluconic acid roxyethyl derivative,

The O-ethyl derivative, correctly named poly-N-acetyl-6-O- (ethyl) -D-glucosamine, has (II)

Other similar derivatives that are enzymatically degradable, in particular lysozyme, are (III) included under the generic term enzymatically degradable forms of poly (N-acetyl-D-glucosamine).

Due to the nature of the polymers, carboxymethylation, hydroxyethylation or ethylation cannot be 100% and can in part take place on 3-hydroxyl. Unless otherwise noted, the biodegradable form of PAG is included under the substitution of poly [N-acetyl-6-O-carboxymethyl) -D-glucosamine3.

One test for the degree of substitution is solubility in a particular solvent. For example, the O-ethyl derivative is soluble in water when the ratio of ethyl group to glucosamine is about 1, and soluble in organic solvents when the degree of substitution is greater than 1.

The term drug is used to refer to a substance other than a diet intended to affect the structure or body function of a human or other animal. This term is sometimes broader than the term drug, which is sometimes confined to an agent that is administered to affect or control pathogenic conditions. The broader term drug also includes steroids and other fertility regulating agents that may be incorporated into an intrauterine contraceptive, or other materials that may be used to affect fertility of women or men either as an intrauterine device or subcutaneously.

207 00В

The term dispensation is used to refer to a method of administering a drug to humans or other animals and includes the release of drugs to a desired site, such as the eyes, gastrointensinal tract, intrauterine, intraroeval, subcutaneous or nasal mucosa, into the mouth under the tongue (sublingually) or rectally etc. an extended period of time indicates a decrease in the rate of drug release compared to the rate that would be expected if the drug was administered alone includes a few minutes, such as for a pilocarpine-containing eye pad for up to 6 months to a year which may be required for administration a steroid in an intrauterine contraceptive. For some conditions, a longer period of administration, such as the patient's lifetime, may be required, but usually a medical range of several hours to 6 months is most preferred.

Since the enzymatically degradable form of the poles (N-acetyl-D-glucosamine) is a solid that can be removed, the subcutaneous tablet β protruding effect is quite practical, however, if any medical reason is required to discontinue drug administration, simply remove by cutting.

The term enzymatically degradable refers to the form of the poly (N-acetyl-D-glucosamine) or derivatives thereof that break down into soluble constituents of body fluid and which are washed out, for example, in tears or transferred with tears or other body fluid to another site and further degraded or metabolized in the body or excreted.

The problem of retention or ejection of the remaining matrix is minimal or non-existent.

Although other enzymes can also affect the enzymatic degradation of poles (N-acetyl-D-glucosamine), the most potent enzyme is lysozyme, which is best distributed in the body. Lysozyme occurs in virtually all body fluids, especially tears, and effectively breaks down the polymer chain into water-soluble or removable components.

Chitosan, which is the common name of the deacylated form of pol (N-acetyl-D-glucosamine) and which is poly (D-glucosamine), is not enzymatically degradable by lysozyme.

In contrast, the enzymatically degradable forms of the poles (N-acetyl-D-glucosamine) are not readily hydrolyzable by water. For example, Form I in phosphate buffer at pH 7.2 at 37 ° C for 24 hours is not hydrolyzed, while hydrolysis occurs at the same temperature and time in the presence of lysozyme.

It is highly preferred that the enzymatically degradable form of poly (N-acetel-D-glucosamine) be degraded only by the enzyme, since resistance to hydrolytic degradation greatly reduces production and storage problems in the presence of ambient moisture and provides a stable, smooth surface rather than erosion the fragmentation process generally caused by polymers that are hydrolyzed by small molecules.

The pharmacological use and nontoxicity of chitosene and of the hair is evidenced by the following references: Naturel chelating polymers, R. A. A. Muzzarelll, Pergamon Prese, N.Y.1973, pp. 164-169 and pp. 176.

Toxicity of chitosan, K. Arai, T.Kinumeke and T.Fujita, Tokaiku Sulsan Kenkyusho Kenkuy Hokoku (Bull.Tokai Reg.Res.Lab.) £ 2 <1968);

German Cffen. 1,906,155 - English Language Abstract;

Great Britain 1,252,372 - Abstract.

Any drug used to treat the eye and surrounding tissues can be used in accordance with the present invention with the poly (N-acetyl-D-glucosamine) degradable enzyme of the invention. It is also practical to use the eye and tissues as an input (metho for systemic substances that enter the bloodstream and its pharmacological response at a site distant from the point of drug administration - and the enzymatically reshapable forms of poly (acetyl-1-glucosamine)). Years that pass through the eye and blood circulation tissues, but which are not used in the therapy of the eye itself, may be incorporated in the body. PAG-shrimp · Marine medicaments for use in the treatment of the eye in the form of a liner including but not limited to: sulfonamides, sulfacetamide, sllfamerlauul and sllfisoxtzull; proiviviruses, including idoxuridine;

anti-invasive foreign nitroftrazone and sodium propionate; γι ^ ΙγΙζ ^ οΜ, such as antaροΖ ^ πΗΙ ^, chlorpheniramine, pyrilamine and profenpyugidtmin; Progesters such as Drtionone, Hydrocitaminate, Dexamethasone, Tritene, Mitryson, Transiso, Iolone 21-phosphate, and Deconneestrrtia (Phenylene), such as Phenylephrine, Naphazoline, and / or Drazole tinoline tinoline; carbaHsopPC) УУCulphoofate, phosphoric iodide and demecariumbmmid; mtropin, polyimide, alcatrupine, and lydroxyamine, and scmpaahoulinne, such as epinephrine. Drugs may cůzných forms such as unchanged moUθkul ^y component moUekulárních kommlexů nzdráž'armauUogicky or a suitable salt, such as hydrochloride, L ^y drubromid, sulfate, phosphate, in ,. borate, acetate, maleate, tartrate, silica, ttd. It is also possible to use simple * ^s drugs (such as ethers, esters, amides, etc.) which required clarakUtri8tiUl II and release but - which will easily tělenným pH, enzymes TTD. The amount incorporated into the ophthalmic pad varies widely, depending on the particular drug, the desired effect and the time span over which the pad is to be used. since the ointment is intended to provide a complete dosage regimen for ophthalmic therapy after an interval of 24 hours, there is no critical upper limit of the amount of drug in the insert. závvsí lower limit on the drug účlnnooti his e ^ those able to be released - ^y. Accordingly, it is not practical to define an amount of drug in a pad for a therapeutic effect. However, one microgran to one milligram is included in each pad, and the polymeric marerée used to form the ocular is selected. inserts for use with a particular drug. and the ability to release the drug at an appropriate rate during a wasted time period. SppehficUé, tlc not omezuujcí examples of combinations of drugs and polymers for ocular insert pouHtí zthrnuuí: Polc [N - say ye ^yl-6-0- (karboxcPθZ ^ HCl-D-GLL] ^and ^ ^l ^ ol taefri ^{y [N-acetyl C} l-6-0- ⁽⁰ Oxyper ^Lye KiB) -Dg uko8amin ^L ^ ^J, and the mixture oct ^ inl ^with RID inifri ^la ^! ^ ol ^{l y} [N-acet ^yl-6-0 - ^((Cy 2'l -hydroxy et ^{ly c} l) -Dg ^{l u l} ustminЗt rcettzo O] ^c - £ N- ^and C ^r TCE-6-9- (ztl ^yl) -D ^{gel u} usapln ^t3 fos t ^ Mn ^ jo; lol ^y [N-Ar-yl б ^from 0- ^(for marketing / OD -guUosamin] ^b and not the father of the above-jatykdiv Uve ^{r l} enýh ^drugs sILoUc odbourntelnou lolcat form (N-D-tcercl gluUostmlnu) including .Select grade 1 or less than 1, and related derivatives, such as other lower-alkyl derivatives,

- ^RC et ^yl-6-O- (ettyl) -P · karboxyaltyluvé other derivatives and esters ízíLcI

207 80β and salts, hydroxyalkyl derivatives, etc. The rate of degradation of the enzymatically degradable form of poly (N-acetyl-D-glucoamine) can be reduced by crosslinking if a lower release rate is preferred.

The ophthalmic insert may be formed in any suitable shape for satisfactory retention in the conjunctival sac. However, it is important that the device does not have sharp or uneven edges that may irritate sensitive eye tissue. The peripheral contour of the liner may be ellipsoidal, bean-shaped, rectangular, etc. In a cross-section it may be concave-convex, rectangular, etc. Since the liner is flexible and sclerical curvature is assumed in use, it is not important to regulate the original shape. The dimensions of the insert can vary widely. The lower limit is governed by the amount of a particular drug to be administered to the eye and surrounding tissues to obtain the desired pharmacological responses, as well as the smallest size of the insert that can normally be inserted or removed from the eye. The upper limit of the insert size is controlled by the limited space within the conjunctival sac into which the ophthalmic insert can be inserted satisfactorily. The eye pad is 4 to 20 mm long, 1 to 12 mm wide and 0.1 to 1 mm thick. It is preferably ellipsoidal in shape and preferably 6x4x0.5 mm in size.

In addition to use as an eye pad, the matrix of the invention may include drugs for other purposes. For example, if the drug is to be taken orally, a tablet of size and shape for swallowing is preferred. If it is to be placed subcutaneously, a tablet or stick is selected which can be placed under the skin at a suitable location. The amount of drug and the time during which it is to be released is controlled by selecting the size of the imptentate.

When combining the drug with the enzymatically degradable form of the PAG-matrix by any conventional method, it is particularly advantageous to dissolve both components in a conventional solvent which allows the enzymatically degradable form of PAG to be cast as a matrix containing the dispersed drug.

Poles (N-acety1-D-glucosamine) are insoluble in all solvents except 88% phosphoric acid, which greatly degrades the polymer. Unexpectedly, it has now been found that Hexafluoroisopropanol and hexafluoroacetone sesquihydrate are solvents suitable for the polymer. They are extremely effective solvents, so drugs that are compatible with these solvents must be carefully selected in order to form casting solutions.

Poly [N-acetyl-6-O- (carboxymethyl) -D-glucosamine] of formula I, poly [M-acetyl-6-O- (2'-hydroxyethyl) -D-glucosamine] of formula II and polyf (N-acetylated 1- The 6-Ю-ethyl) -D-glucoeandine compounds of formula III are preferred because of their solubility with various drugs in conventional solvents including water. Non-toxic solvents are preferred.

Forms I and II are water-soluble as 5% and Form III is water-soluble as 5% if the degree of substitution is not greater than 1 and are soluble in organic solvents when the degree of substitution is greater than 1. As organic solvents alcohols, chloroform, benzene, toluene, mixtures of benzene and toluene and alcohols ketones can be used ·

Pilocarpine or other drugs can be incorporated into the matrix of these enzymatically degradable forms of PAG by hydrogen bonding, covalent bonding, ion bonding, or single bonding. The matrix can be reinforced with various physical or chemical agents. resistance to handling.

207 808

In the prior art topical therapy, drops and ointments are used. It has some drawbacks: (1) It is impossible to tighten the 24-hour onemooněnn regulation. (2) It is wasteful due to the amount of drug used. (3) Some people show a strong hypersensitivity due to cholesterol and adrenergic drops. (4) Many patients are not using enough medicines, resulting in little successful treatment of the disease. (5) There are side effects - when passing drugs. l-acrymeal vessel into the circulatory system. These problems are eliminated using the method of. The invention provides a method of continuously releasing a drug into a tear film at therapeutic levels. The device is biodegradable and therefore it is not necessary to remove it from the eye and is also capable of delivering a large dose, thereby obtaining a wide leaching of the drug. According to you ⁿ ELEZ gave much will make a more ^ way of drug release, which prolongs and enhances the drug effect.

The process according to the invention is illustrated by the following examples in which the temperature is given in degrees Celsius and the weight is by weight unless otherwise stated.

Example 1>

Chitin cleaning

CCitin-like commercials (Cd-Biochemiids) were finely pulverized overnight in a ball mill to pass through a 6 mm sieve and retain - with a 1 mm sieve. 149 g of finely divided maatriálu dekalcifibuje the ex ^t Response system ^{82 of} 5 ml of 2N ^HC1 at 4 ° ^C -after 48th hours in flask with. with an ethical reagent. The material is centrifuged and washed several times with water until neutral. The ash content was 0.40.5%. The detected chitin was then stirred at a temperature. - locationH - over - night. with 1 500 mo 90% carboxylic acid. The mixture is centrifuged and the residue is washed several times with water. The chitin-free is then suspended in ~ 2 liters of a 1% NaCH solution and heated at ⁹ ~ ^-100 ~ C for 2.5 hours. ^E rubs solution filtered, the cake with water until neutral lip ^{to CE,} washed several times with - absolute ethanol - - and ether - and dried - at - 40 ° C under reduced pressure; yield 66. infrared spet-rum (KBr tablets) shows bands at 3500 cm ^-1 (S), 2900 (W, 1619 (S), 1550 (S) 1370 (S), 1300 ( 70., 1070 (wide), (S is strong, M is medium, W 'is weak).

Treasure 2 *

Poly [N-acetyl-6-O- (carboxymethyl) -D-glucosamine] g loll (N-acetyl-D-glucosali) of Example 1. 100%. ml dimethylsulfoxide. To this highly swollen salt is added -40C-ml of 2-propanol and the mixture is stirred vigorously under nitrogen while stirring. add 40 ml of a 30% aqueous NaCH solution over 30 minutes at room temperature. The mixture is stirred for an additional hour, then 18 g of chloroic acid, dissolved in 40 ml of water, are added dropwise over 30 minutes. The mixture was then heated at -550C for 24 hours. The mixture was decanted and 100 ml of 70% methanol was added to the residue. The suspension is then neutralized with 5 ml of 90% acetic acid. The mixture was filtered, washed with 70% ^m-mdha ethanol, in absolute mlthano el ^l and ^ink, under vacuum at ⁴⁰ ° C. Yield ^{24 gp} ^^ ols ^[(N-tccty - 6oOk (karbollmetiyl) -D-gjkkotalinuJ I. The infrared spectrum (KBr pellet) showed ^{U is p} p4 ^sy s 35cC. ^C · ^1. (S) 2900 (M) 1600 [Širák '· (S) J, 1400 (m), 1320 (m), llCc / wide (i. ^e to the pattern ^of iitroeá zjiet .a ^ o -se ^{-4, 0>} ^ ³ -meq those Kny / g, CO ^from the melting point ^{of 10} ^ 0% torboxylacl it. Films easily removed from - glass were cast -of aqueous solution and be transparent, flexible and tough.

207 000

Example 3

Preparation of poly (D-glucosamine)

A method similar to that described by P. Brouseignoc, Chemie and Industrie, 99 (9) (68), 1243% of a solution of 180 g of 96% ethanol and 160 g of ethylene glycol was added while stirring 360 g of CO 2. then 54 g of poly (N-acetyl-D-glucoaamine) (purified chitin) according to Example 1 are added and the mixture is heated at 120 ° C for 6 hours. After cooling, an equal volume of water was added to the mixture. The mixture is filtered and washed several times with water until neutral, then twice with acetone and dried under vacuum (yield 42.6 g of poly (D-glucosamine)), sometimes called chitosan. The infrared spectrum (KBr tablets) shows the bands at 3450 cm @ ^-1 (S), 2900 (M), 1620 (S), 1600 (S), 1370 [W (S)], 1050 [W (S)]. Potentiometric titration of the sample showed 81.4% deacylation. The product is soluble in 3% acetic acid. It forms a clear, flexible, solid film from the solution. It is not enzymatically biodegradable by lysozyme.

Example 4

Film from a mixture of poly (D-glucosamine) and pilocarpine

0.25 g of poly (D-glucosamine) from Example 3 is added to 5 ml of 3% acetic acid. 50 mg of free full-carboxylic acid and 100 µl of tritiated pilocarpine are then added to the solution thus obtained and the mixture is drained as a film (1, (16 ml wet thickness) on glass · This film is solidified by immersion in a 37% formaldehyde solution for 5 hours. This film exhibits a zero order release during 3 days, during which time pilocarpine is still released at zero order. · After 3 days about 70% of pilocarpine remains in the film matrix. The use of tritiated pilocarpine allows the liquid scintillation counter to be used to accurately and appropriately control the release rate. When treating humans there is a radiological hazard associated with tritrated material, so it is advantageous to perform release rate tests on test animals.

Example 5

Film of a mixture of poly [N-acetyl-6-O- (carboxymethyl) -D-glucosamine3 and pilocarpine

To a 5% solution of poly [N-acetyl-6-O- (carboxymethyl) -D-glucosamineJ (0.95 g) in water is added 50 mg pilocarpine nitrate and 1C0 µl tritiated pilocarpine · Film 1.016 ml thickness is poured onto glass plate and allow to dry. The film is solidified by immersion in alum for 5 hours. The release of pilocarpine from this film in an aqueous solution of similar composition to human tears is essentially first order, 90% of pilocarpine is released within 5 hours.

Example 6

Poly (N-acetyl-D-glucosemine) matrix

Poly (N-acetyl-D-glucosamine) membranes were prepared by dissolving poly (N-acetyl-D-glucosamine) in hexafluoroacetone sosquihydrate (1.4% solution) and hexafluorolaopropanol (2% solution). The films are rigid, transparent, non-sticky, flexible and completely flexible in hydration, while maintaining sufficient strength to resist handling. The membranes do not hydrolyze when exposed to water for five days · However, in the presence of lysozyme, the films slowly break down · Eroded

2 · 7 ··· filesy slow release drug in film ·

Example 7

Biodegradable poly [N-acetyl-6-O- (carboxymethyl) -D-glucosamine]

After 24 hours incubation 37 pM in fosOorennanovém buffer pH 7.2 containing 1,500 units / ml tysozymu is ^H ydrol We observe ^y ^ L ^ ccetyl N-O-O-CtebboxymethylJ-D-glucosamine ³ nc oligomeiry as determined by Gel The permeate-free control sample without the enzyme under the same conditions does not.

Example 8

In vivo results using a mixture of poly-N-acetyl-6-O- (cocoxymethyl) -D-glococamine] and pilocarpine

Membranes polyjjJ and platoon-1-6-0- (karboxymethyD-B-glucosamine were evaluated in vivo for sustained pharmacological effect and excite the eye · Bo right eye of three rabbits was umíítí ^p Rouz ^{to 1} mm film of poly mm £ ^ - ^acetyl L-6-0- ^(C abboxyme ^t hy ^{l lo} -Dg to ^about ocaminlJ (0.25 g of poly-N £ ccetyl O Ok (karOoxmπlethytoBoglukoscminuJ (0.64 · g pilokcapinu). Within 15 minutes after implantation A significant narrowing of the pupil of approximately 6 hours is observed in the film strip ·· The mercenaries were well tolerated and slowly eroded in the eye · This prolonged effect in rabbits may be extrapolated to a 24-hour effect in humans since the rabbit meetsaooizes pilocarpine much faster than humans.

Example 9

Poly ^[N-6 acety1- -0- (2'O ^h ydroxyethyl) -Boglu ^c oscminJ

Place 13.6 g of purified PAG in a screw capped flask, ground through a 1 mm sieve. 200 ml of cold (0-5 ° C) aqueous 43% NaOH solution was added to the flask and the mixture was stirred under nitrogen for 2 hours and then kept at 0-5 ° C for 10 hours. The swelling alkaline derivatives were then pressed in a funnel. with a fraction of three times the original weight, grind and freeze for 1 hour under nitrogen at -20 ° C and then thaw for 1 hour at room temperature. The freezing-thawing cycle is repeated. The child derivative is then treated with 120 ml of dieethysulfooid and the slurry is immediately added to the stirred liquor. The autoclave is purged several times with nitrogen and 53.2 ml of ethylene oxide (16 equivalents) is added. The mixture is kept at 50 ° C for 18 hours. The solution is then carefully neutralized with glacial acetic acid, dialyzed and then lyof 111x ^ 1.

· Hydroooothylový derivative can be further purified by precipitating the polymer from the aqueous solution 01¼ ^ ^^ ^{e t} ers in vysrdený sample ^of poly ^[N-6 acety1- -0- (2'-hydroxyethyl ^ B ^ ukosaminuJ rozpudí readily in water, 5 The samples analyzed for C, H and N have a composition in which the ratio of the succulent hydroxyethyl groups to the glucose residue is 1.5 ·% by weight of aqueous sodium hydroxide and 3% by weight of acetic acid.

Example 10.

Poly £ ^ - acety1-6-0- (etly1) oD-gllkotcminJ

The procedure of Example 9 is repeated except that 75 ml of ethyl ethyl chloride is used in place of ethylene oxide and the reaction is carried out for 15 hours at 50 ° C. A water-soluble derivative is obtained.

207 · 0β

To obtain a derivative soluble in an organic solvent, ethyl chloride is mixed with benzene (75% of the amount of ethyl chloride). The reaction time is 10 hours and the ee temperature is regulated as follows; Heat at 60 ° C for 1 hour, at 80 ° C for 1 hour, at 130 ° C for 1 hour, and at 130 ° C for 7 hours. An organic solvent soluble product is obtained. The following solvents may be used to dissolve (5%) the polymer at room temperature; o-xylene, benzene, toluene, methylethylketone, 1: 4 alcohol / benzene, chloroform and alcohols ·

In the following example, using pilocarpine free base, the drug is attached to the polymer by ionic bonding. An extraordinary advantage of this system is the slower drug release and the ability to release pilocarpine as the free base, which as such has a higher efficacy. Until now, it has not been possible to release pilocarpine as the free base because it is unstable in this form and is usually used as the hydrochloride or nitrate salt.

Example 11

Inserts containing pilocarpine and poly [N-acetyl-6-O- (carboxymethyl) -D-glucosamine]

Prepare a 5% solution of [, Ν- and platoon 1-6-O- (carboxymethyl) -D-glucosamine] in deionized science. The solution is acidified with acetic acid and the polymer is precipitated by slowly adding this solution to acetone. The polymer was dried overnight under vacuum at 40 ° C. Films were prepared from 5% aqueous solutions containing the following relative weights of the components:

Pilokarpin Poly [N-acetyl-6-O- (carboxymethyl) -D-glucosamine] dose of drug per 1.5 mg strip 9.1 mg 90.0 mg 0,10 mg 19.4 mg 80.6 mg 0.24 mg 33.3 mg 66.6 mg 0.50 mg

The films were cut into strips of approximately 1 mm x 10 mm weighing 1.5 mg · When placed in the eye, a dose of drug is released from each strip ·

Claims (2)

A matrix which is adapted for insertion into the conjunctival sac of the eye for drug release and which is shaped according to the eye, characterized in that it consists of an enzymatically degradable form of poly-N-acetyl-6-O- (carboxymethyl) -D-glucoamine having an average molecular weight of 40,000 to 50,000 and a dispersed and ion-bound free base of a poorly water-soluble ophthalmic drug. 2. Matrix according to claim 1, characterized in that the medicament is pilocarpine.