DK166344B - Biodegradable ortho-ester polymers - for enclosing active agents to be liberated therefrom e.g. steroid implants - Google Patents

Abstract

Polymers contain the repeating unit of formula (I) (where R1 is a polyvalent racical of (a) 2-10C alkylene or alkenylene; (b) 2-6C oxa-alkylene with one or two internal oxa gps.; (c cycloalkylene contg. 3-7 cyclic C atoms and opt. substd. by 1-7C alkyl or alkoxy or 2-7C alkinyl; (d) cycloalkenylene contg. 4-7 cyclic C atoms and opt. substd. as in (c); (e) cycloalkene-di(aliphatic hydrocarbylene) contg. 3-7 cylic C atoms, the hydrocarbylene gps. contg. 1-7C atoms and the ring being opt. substd. as in (c); (f) cycloalkane-di(aliphatic hydrocarbylene) contg. 4-7 cyclic C atoms. Matl. is used e.g. as a biodegradable polymer enclosing an active agent which is liberated therefrom, e.g. pesticides, herbicides, biocides, algicides, rodenticides, fungicides, insecticides, cosmetic prods., medicaments, fertility inhibitors and activators, air purifiers, nutritive substances, etc. The active substance may be liberated at constant or variable rates depending on the compsn. and m. wt. of the polymers. The polymers are esp. suitable for the prepn. of steroid implants for the treatment of inflammations.

Description

in

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The present invention relates to a controlled release drug composition comprising a pharmaceutically active agent enclosed in a biodegradable polyester which is biodegraded using the active agent release composition.

The reaction of ortho esters with glycols leading to non-polymeric products and various other products is known and described e.g. in Ind. J. Appl. Chem., Vol. 28, No. 2, pages 53-58, 1965, in which Mehrota et al. obtained monoethoxymonoglycolate and tri g of 1ycoxybisorthoform in that by reacting orthoformate with hexamethylene glycol in molar ratios of 1: 1 and 2: 3. Crank et al. also indicates in Aust. J. Chem., Volume 17, pages 1392 - 1394, 1964, the reaction of triols with orthoesters including ethyl orthoformate with butane-1,2,4-triol, pentane-1,2,5-triol and pentane-1,3,5 -triol for the preparation of monomeric bicyclic compounds. During the preparation of the bicyclic orthoesters by reaction of ethyl orthoformate with triols, Crank et al. Found that compounds prepared from gait materials with a 1,2-diol structure also contained compounds with ethylene bonds. You are. subsequent article developed Crank et al., Aust. J. Chem., Vol. 17, pages 1934-1938, 1964, this reaction to a synthesis method for converting 1,2-diols to olefins. Later, DeWolfe, in Carboxylic Ortho Acid Derivatives, 1970, published by Academic Press, Inc., New York, pp. 134-135, noted that carboxylic orthoesters are more reactive to acid hydrolysis than almost any other group of compounds, Drolytic reactivity complicates their synthesis and storage. Said DeWolf, in said book, page 136, states that the conversion of diesels to cycles into spherical orthoesters including all oxide in oxolane or alkoxydioxane followed by acid hydrolysis led to a process for monoacylation of diols. Later, Bailey indicated in Polym. Prepr. Amer. Chem. Soc. Div. Polym. Chem., Vol. 13, no.

1, pages 281 - 286, 1972, that the polymerization of spiroor thoesters at ambient temperature and elevated temperature ranges led to polyesters and polycarbonates with the repeating units - £ θΗ2θΗ2ΟΗ2θΟΟΰΗ2θΗ2θ · 3 and fOCH2OCOOCH2CH2CH2l · ·

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2

Furthermore, DK patent patent 134,465 discloses an eye insert for controlled continuous administration of a predetermined dose of drug to the eye. This known eye insert is characterized in that it comprises one or more reservoirs 5 of drug enclosed in a biodegradable, eye-harmless material which is cross-linked gelatin or a polyes- CH3 ter of the formula -fO-C fO-CH-CO + γ, as defined in claim 6.

10

The composition of the invention is characterized in that the polymer is an ortho ester polymer consisting of repeating units of the general formula - R 1 -O-C-O-τ 3τ FT Fr \ /% ✓ t - n 20 wherein R 1 is an alkylene group of 2- 10 carbon atoms, an alkenylene group of 2-10 carbon atoms, an oxaalkylene group of 2-6 carbon atoms and 1 or 2 internal oxa groups, one of methyl substituted cycloalkylene group of 3-7 ring carbon atoms, or a cycloalkanalkanedipate group of 3 -7 ring carbon atoms and 1-7 carbon atoms in the alkylene residue, the cycloalkane ring being optionally substituted with alkyl groups of 1-7 carbon atoms or with alkenyl groups of 2-7 carbon atoms, and R2 and R3 together with the polymer backbone's dioxycarbon atom forming a heteromonocyclic group of 5- 8 ring links having 1 or 2 oxygen hetero atoms bonded to the polymer backbone's dioxycarbon atom and the remaining ring link being carbon atoms optionally substituted by alkyl groups of 1-7 carbon atoms, alkox y groups having 1-7 carbon atoms or 35 alkenyl groups having 2-7 carbon atoms, or a phenyl ring are fused to 2 neighboring carbon atoms and n is an integer from 10 to 1000.

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The medical composition of the present invention differs substantially from the eye insert known from DK patent 134,465, in that the polymer contained in the composition differs substantially from the crosslinked gelatin or polyester which encloses the drug reservoir or drug reservoir in the prior art. eye insert, wherein the composition of the invention has more general applicability and thus is not limited to the use as an eye insert, but may be available in various forms of preparation, such as solutions, dispersions, 10 pastes, creams and microcapsules 1, from which, in addition to drugs, a long dispensing can be dispensed. range of other active substances such as preservatives, cosmetics and contraceptives.

The polymers included in the composition of the invention comprise homopolymers, statistical distribution copolymers and block copolymers obtained by reacting monomers or mixtures of pre-prepared homopolymers and / or copolymers. The polymers are thermoplastic linear polymers.

20

Preferred polymers are homo, co and terpolymers wherein R 1 is divalent and is a cycloalkanedialkylene group having 4-6 ring carbon atoms wherein the alkylene groups have 1-4 carbon atoms, an alkylene group as mentioned above or an oxaalkylene group 25 as mentioned above and R 2 and R3 together with the polymer skeleton's dioxycarbon atom forms a 5-6 membered heteromonocyclic ring with 1 oxygen heteroatom attached to the dioxycarbon atom of the polymer backbone, and the remaining members of the ring are carbon atoms.

The term alkylene used for R 1 in the present specification refers to straight or branched divalent groups such as 1,2-ethylene, 1,2-propylene, 1,7-heptylene, 2,3,5-trimethylene, 1,7-heptylene and 1,10-decylene. The term alkylene group used for R * denotes unsaturated straight or branched divalent groups such as vinylene, 2,5-dimethyl-1,8-oct-3-enylene and 1,10-dec-3-enylene. The term cycloalkylene groups used for R 1 includes monocyclic groups such as cyclopropylene

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4 and cycloheptylene. Examples of cycloalkanedialkylene, cycloalkanedialkenylene, cycloalkendialkylene and cycloalkendialkenylene groups represented by R 1 are cyclopropanedimethylene, 1,4-cycloheptanedheptylene, cyclopropanedivinylene, 1,5-cycloheptenedhylene-4-en-4 -endimethylene, 1,3-cyclohept-5-endiheptylene, 1,3-cyclobut-2-endylene and 1,4-cyclohept-6-ene-dihept-4-enylene. Oxaa1 chylene groups represented by R 1 are e.g. oxaethylene, 3-oxahexylene and 2,4-dioxahexylene.

The term alkyl groups occurring in the definition of any substituents on R 1 groups and heteromonocyclic groups represented by the combination of R 2, R 3 and the dioxycarbon atom in the polymer backbone comprises straight and branched groups such as methyl, n-heptyl, isopropyl and t heptyl. Eczema I5 piers of α1 kenyl groups designated for R2 and R3 and optionally substituent on R1 and heteromonocyclic groups formed from a combination of R2, R3 and the dioxycarbon atom in the polymer backbone include the straight and branched groups such as vinyl, 2-propenyl, 1-heptenyl and 3-methyl-4-hexenyl. The expressed alkoxy groups used for R 2 and R 3 and heteromonocyclic groups formed from a combination of R 2, R 3 and the dioxycarbon atom in the polymer backbone include the straight and branched groups such as methoxy, n-heptoxy, isopropoxy and 2-methylhexoxy. Heteromonocyclic rings represented by the combination of R 2, R 3 and the dioxycarbon atom in the polymer backbone are e.g. the furyl group and its hydro derivatives, the dioxola-ny1 group, the oxoci ny1 group and its hydro derivatives and the dioxocinyl group and its hydro derivatives. Condensed heteropoycyclic rings represented by the combination of R 2, R 3 and the dioxycarbon atom in the polymer backbone are those wherein a heterocyclic ring and a phenyl ring have 2 common carbon atoms, e.g. the benzfuryl group and its hydro derivatives, the 4,5-benz-1,3-dioxo-1anyl group, the 4,5-benz-1,3-dioxocinyl group and their ligand isomers and hydro derivatives thereof, and the 4,5-benzoxacinyl group and the pathway isomers and hydro derivatives.

Alkyl groups represented by R 1 may be straight or branched chain and are e.g. methyl, isopropyl, butyl, heptyl and

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3-methyl hexyl. R 2 is preferably an alkyl group of 1-4 carbon atoms, i.e. a methyl to buty 1 groupThe individual groups R® may be the same or different.

The term repeat unit is used herein to denote the monomeric unit of the polymer. In a homopolymer, the repeating units are similar. In a copolymer, the repeating units are different and may be arranged statistically in the polymer chain when the original copolymer units are viewed in a common reaction vessel, or they may be arranged in block form when the polymers are formed one after the other, with a homopolymerization of each of the individual monomer units found place to begin with. A terpolymer is a copolymer consisting of three different repeating units.

15

As indicated above, the polymers can be synthesized by reaction of the polyol monomer with the ester or carbonate monomer. The polymerization reaction is carried out by reacting stoichiometric amounts of the monomers or an excess of the polyol, i.e. ca. 1 to 10 moles of polyol to 1 mole of ester or carbon monomer.

The polymerization of the monomers can be carried out in a single reaction vessel equipped with a stirrer and vacuum connection, 9 c, with continuous mixing of the monomers in the presence of an transesterification catalyst. The polymerization comprises an initial transesterification reaction followed by a polycondensation reaction, the total polymerization being carried out at a temperature of 50 ° C to 220 ° C and during a reaction time of 1 to 96 hours. The transesterification step of the reaction consists of mixing the monomers with the catalyst while continuously stirring the mixture and gradually increasing the temperature to 180 ° C. The transesterification reaction occurs for most monomers at 75 - 180 ° C over a reaction time 35 of 1 - 12 hours and at normal atmospheric pressure with continuous evaporation in 11 oz of the alcohol, the Polycondensation reaction ion is started by reducing the pressure to 13.33 - 0.01333 Pa, with

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6 the elevated temperature and the reduced pressure are maintained and the reactants are continuously mixed for 12 - 96 hours.

The polymer can be recovered under anhydrous conditions from the reactor in the reaction vessel by conventional isolation and recovery methods. The polymer can e.g. is recovered in hot state by extruding or pouring, or the polymer can be isolated after cooling by dissolving in a dry organic solvent such as benzene, carbon tetrachloride, methylene chloride, dioxane, toluene or xylene, followed by the addition of an organic liquid in which the polymer is insoluble or has limited solubility, to precipitate the polymer. Organic solvents for the latter purpose include ether, hexane, pentane, petroleum ether and mixtures of hexane and heptane. The polymer is isolated by filtration and drying under anhydrous conditions. Other methods for recovering the polymer include lyophilization from a solvent.

Typical transesterification catalysts for conducting polymerization in the ion reaction are Lewis acids such as boron trifluoride, boron trichloride, boron trichloride etherate, boron fluorine detherate, stannous oxychloride, phosphorus oxychloride, zinc chloride, phosphorus pentachloride, calcium acetate, antimony oxide mixture, antimony pentafluoride, stannous octoate, stannous chloride, diethyl zinc, n-butyl1 in thium and mixtures thereof, succinic acid catalysts such as p-toluenesulfonic acid, polyphosphoric acid, cross-linked polystyrene sulfonic acid, acid silica gel tetrahydrate hexane and mixtures thereof, organotitanates, , oxides, carbonates and acetates of 30 zinc, calcium, lead, magnesium, manganese and cobalt, alkanoates, hydrides and alkoxides of sodium, lithium, zinc, calcium, magnesium and aluminum, antimony trioxide, complex alkoxides and organomagnesium halides. The preferred amount of catalyst is approx. 1 part catalyst to approx. 500 parts ester or carbonate monomer. Smaller or larger amounts can also be used,

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7 as 0.005% to approx. 2.0% by weight of ester or carbonate monomer

The polymerization may optionally be carried out in the presence of an added inert organic solvent which does not adversely affect the reaction. When no additional solvent is used, one of the reactants, e.g. polyol, to begin with, serve as a solvent. As the polymerization proceeds, the solvent by-product is removed from the reaction mixture by customary distillation at 11 at on, azeotropic distilled at 11 at on, or by distillation under vacuum. Suitable azeotropic solvents include toluene, benzene, m-xylene, cumene, pyridine and n-heptane.

The following examples illustrate the polymers contained in the composition of the invention and their synthesis.

Example 1 To 45 g (0.312 mole) of anhydrous trans-1,4-cyclohexanedicarbinol and 0.05 g of polyphosphoric acid in a commercially available polymerization reactor, 50 g (0.312 mole) of anhydrous was added with constant stirring under an inert nitrogen atmosphere and normal atmospheric pressure. . 2,2-diethoxytetrahydrofuran. The mixture 25 was then heated to 110 - 115 ° C and maintained at this temperature for 1% - 2 hours with slow distillation of any liquid formed. While maintaining the temperature, the pressure was then gradually reduced to 1,333 Pa, and at this reduced pressure the temperature was slowly raised to 180 ° C. Reaction 30 was continued at this temperature for 14 hours. The polymer was isolated by extrusion from the reactor. The polymer had the following structure, where n is the degree of polymerization.

- · -36 · γ ^ Γ®-®τ · [_?

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8

The polymer prepared according to Example 1 is a clear, transparent glassy polymer with a Tg value of 34 ° C and a molecular weight (Mw) of 38,160.

Examples 2-4

The procedure of Example 1 is followed, but by replacing trans-1,4-cyclohexanedicarbanol and 2,2-di ethoxytetrahydrofuran with trans-2-methyl-1,4-cyclohexanediethanol and 2,2-dimethoxyte-tetrahydrofuran, trans. 2-methyl-1,4-cyclohexanedipropanol and 2,2-dibutoxytetrahydrofuran and trans-2-ethyl-1,4-cyclohexanedicarbinol and 2,2-diethoxy-5-methyl-3,4-dihydrofuran form the following polymers: 15 - 0N / 0— (CB ^^ - - ^ Sy (CHg ^ _L_? \ H3 in _ ·%, 1 - ° V / ° -CH2 - - CH2 - _L-0 \ h5 Jn 30 where n is from 10 - 1000 with an average value of 40 - 300. Example 5

The procedure of Example 1 is repeated, but by replacing 2,2-diethoxytetrahydrofuran with a 2,2-dialkoxytetrahydrofuran

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9 selected from the group of 2,2-dimethoxytetrahydrofuran, 2,2-dipropoxytetrahydrofuran and 2,2-dibutoxytetrahydrofuran and the dicarbinanol with 1,6-hexanediol gives the corresponding polymer of the following formula 5 - η ) 6--

Cs - Jn 10

A polymer prepared according to Example 5 is a clear, transparent polymer having an average molecular weight (Mw) of 47,520 - 50,120.

Example 6

To 45 g (0.312 mole) of dry cis-trans-1,4-cyclohexanedicarbinol and 0.05 g of p-toluenesulfonic acid are added with constant stirring 50.5 g (0.312 mole) of 2,2-dimethoxy-5-methyl-1, 3-dioxolane and polymer in the reaction reaction ion of Example 1 were repeated to prepare the polymer T w • - 0 O-CH 2 - {S \ -CH 2 / V '' up 25 V- / CH3 Jn

The polymer prepared according to Example 6 is a clear, transparent glassy polymer with a Tg value of 26 ± 5 * 0 and a molecular weight (Mw) of 30,100.

Example 7

To 54.7 g (0.312 mole) of 1,10-decanediol and 0.05 g of polyphosphoric acid in a reaction vessel under a nitrogen atmosphere and at atmospheric pressure, 50.0 g (0.312 mole) of 2.2 g. diethoxytetrahydrofuran. The mixture then became

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10 heated to 110 - 115 ° C and maintained at this temperature for 1 temperatur2 hours while ethanol was gently distilled from the reactor. While maintaining this temperature, the pressure was then reduced to 1.333 Pa and at this reduced pressure the temperature was raised to 180 ° C. The polycondensation was continued for 24 hours to prepare the polymer having the structure given below - · ~ 10 --η ° - (ΟΗ2) ιο-

LJ

L Jn

The polymer prepared according to Example 7 is a clear, viscous polymer having a molecular weight (Mw) of 42,630.

Example 8

To 7.38 g (0.625 mol) of 1,6-hexanediol and 0.10 g of polyphosphoric acid were added 100.0 g (0.625 mol) of 2,2-diethoxytetrahydrofuran and 81.0 g (0.562 mol) of trans-cyclohexanedicarbinol. and the polymerization was carried out according to the procedure of Example 1. The random copolymer obtained had a molecular weight (Mw) of 11,500 and the following structure 25 -0 ^ .0-CH2-CH2 - · On ^ / O— (CH2) 6

Cs ώ -> n 30

Example 9

The procedure of Example 8 was repeated in this example, and all conditions and reagents were as described in Example 35 except that in this case 1,7-hepandiol was used instead of 1,6-hexanediol. The recovered random copolymer had the indicated structure in which n = 10 - 1000 with an average value of 40 - 300.

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-o ^ o-ch2 ~ - (n - cH2-o o- (ch2)? -

Cs ό L Jn 5

Example 10

To 66.3 g (0.625 mole) of diethylene glycol and 0.1 g of polyphosphoric acid in a stainless steel polymerization reactor was added 10 100 g (0.625 mole) of 2,2-diethoxytetrahydrofuran with constant stirring under an argon reflux and the reactants heated to 110 ° C. 115 ° C for 2 hours while distilling off the ethanol formed during the transesterification step. While maintaining the temperature constant, the pressure was reduced from atmospheric pressure to 1,333 Pa and maintained there, slowly raising the temperature to 180 ° C. The polycondensation was allowed to proceed for 24 hours under these conditions to prepare the polymer shown below - 20 o - ch 9 ch 7 and 7 ch 2 - C / C.

The polymer prepared according to Example 10 is a clear, transparent transparent polymer having a Tg value of 17+ 8 ° C and a molecular weight (Mw) of 42,000.

Examples 11 - 15 30

The procedure of Example 10 was followed in these Examples with all the reaction conditions as described in Example 10 except that the monomers of the previous Example were replaced with stoichiometric amounts of the following monomers:

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12 a) 1,5-pentylene Tyco 1 and 2,2-di propoxy-4-methyltetrahydrofuran, b) 2,3-dimethyl-1,6-hexylene glycol and 2,2-dipropoxy-5-heptyl 5) tetrahydrofuran, c) 3,6-dimethyl-1,9-nonionic Tyco 1 and 2,2-dipropoxy-5-ethoxy-tetrahydrofuran, 10 d) 1 -dihydrofuran, and e) 1,6-hexylene glycol and 2,2-diethoxy-5-vinyl-3,4-dihydrofuran to prepare the following polymers (n is in each case 10 - 1000 with an average value of 40 - 300): - 20 a) j / y -c% in 25 -1D O-OH 2 CH (CH 2) CH (CH 2) (OH 2) 3- o c 7 H 15 in - -, Λ - (CH 2) 2 CH (CH 2) (CH2) 2CH (CH3) (CH2) 3-- ·> L5 L * J -in 13

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- ° v // ° ~ (CH2) 6- "·" b L -Jn 5 - 0 ^, 0— (oh2) 5—

S

XCH = CH, 10 L 2 Jn

Examples 16 - 18

The procedure used in Example 10 was followed in these 15 Examples with all the reaction conditions as previously described. The starting monomers listed below were used in amounts equivalent to those used in Example 10.

2,2 / 4,4-tetramethylcyclobutane-1,3-diol and 2,2-diethoxytetrahydrofuran, triethylene glycol and 2,2-diethoxy-5,5-dimethyltetrahydrofuran, triethylene glycol and 2,2-diethoxy-4 -methoxytetrahy-drofuran.

He thus obtained the following polymers in which n is 10 - 1000 with an average value of 40 - 300.

CH ". CH, 3y 5 30

Xx ~ [_j ca, nch3 35

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14 -O- (O-CH 2 CH 2) 3-l · 0 L-L (CH 2) L 5 Jn --0. (O-CHoCHo) -D- Λ 10 AND -z 5 Jn

Example 19 To a mixture of polyol monomers consisting of 41.58 g (0.284 mol) of trans-cyclohexanedicarbinol, 7.53 g (0.071 mol) of the oxyalkylene glycol, diethylene glycol and 0.057 g of polyphosphoric acid was added 56.7 g (0.355 mol) ) diethoxytetrahydrofuran under the inert gas argon, and the mixture was heated to 20 115 ° C for 2 hours with continuous distillation of the liquid organic by-product. While keeping the temperature constant, the pressure was then reduced to 1.333 Pa, and at this reduced pressure the temperature was raised to 180 ° C. The reaction was continued at this temperature and vacuum for 24 hours. The random co-25 polymer was isolated by extrusion from the reactor and it had the following configuration - -o o -ch2ch2och2ch2-o .o-ch2-0-cii2- -

30 rS "cS

The polymer prepared according to Example 19 is a clear, transparent polymer having a molecular weight (Mw) of 28,000.

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Example 20

The procedure used for the preparation of the copolymer of Example 19 was repeated in this polymerization; 5 all conditions were as described. The monomers used in this example were 2,2-diethoxytetrahydrofuran, 1,6-hexanediol and a mixture of cis-trans-1,4-cyclohexanedicarbinol. The structure of the copolymer obtained is as follows: -o v / O - (ch 2) 6-o o ^ h 2_ (s> -ch 2 - - ά ώ L Jn 15 The polymer prepared according to Example 20 has a molecular weight (Mw) of 41,200.

Example 21 20 To 14.77 g (0.125 mol) of 1,6-hexanediol was added 20.0 g (0.125 mol) of 2,2-diethoxytetrahydrofuran and 20 mg of p-toluenesulfonic acid, and the monomers were reacted by the procedure of Example 1. 1 for the preparation of poly (2,2-dioxohexamethylene-tetrahydrofuran) having a molecular weight of 15,700. 45 g (0.312 mole) of cistrans-1,4-cyclohexanedicarbinol and 0.05 g of p-toluenesulfonic acid were separately added to 50 g (0.312 mole) of 2,2-diethoxytetrahydrofuran and the monomer was reacted by the procedure of Example 1 to preparation of poly- (2,2-dioxo-cis, trans-cyclohexanedimethylenetetrahydrofuran) having a molecular weight of 24,700.

Then 9.5 g (0.051 mole) of the poly (2,2-dioxohexamethylene tetrahydrofuran) was copolymerized with 10.76 g (0.051 mole) of poly (2,2-dioxo cis, trans-cyclohexanedimethylene tetrahydrofuran) in 43 hours at 180 ° C under a pressure of 1,333 Pa in the presence of trace amounts of acidic catalyst to produce the block copolymer of the following formula, wherein the ratio m: n is 1: 1.

16

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-island. .o-ch 2 - (s) -ch 2

6. ώ. IN

Jm L -Jia 5

The polymer prepared according to Example 21 has a molecular weight (Mw) of 38,200.

Example 22 13.26 g (0.125 mole) of diethylene glycol was added to 20.0 g (0.125 mole) of 2,2-diethoxytetrahydrofuran and the monomers were reacted in the presence of a Lewis acid catalyst in the form of polyphosphoric acid for 42 hours according to the general process described in Examples 10 and 11 for the preparation of a polymer having a molecular weight of approx. 20,000. 50.0 g (0.312 mole) of trans 1,4-cyclohexanedicarbinol and 50 g (0.312 mole) of 2,2-diethoxytetrahydro uranium were separately reacted by the procedure of Example 1 to prepare another polymer. Then, 5.94 g (0.341 mol) of the polymer formed was mixed with 14.5 g (0.0682 mol) of the latter polymer and the reaction was carried out at 180 ° C and under a pressure of 1,333 Pa for 4 days to prepare of a block copolymer. The copolymer was dissolved in benzene and lyophil 1 in the sera for later use. The structure of the copolymer, where the ratio m: n is 2: 1, is as follows: -0v .0 — CHp— (S) —CirJ — t-0v, Q — CH9CH90CHoCKo— ώ w & «- Jm L - n

The polymer prepared according to Example 22 has a Tg value of 22 ° C and a molecular weight (Mw) of 43,200.

35 17

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Examples 23 - 25

The procedure of Example 1 was followed in this example, all reaction conditions being identical to the previous ones, but the monomers of Example 1 were replaced with the monomers listed below: a) 2,2-dimethoxy-4,5 1,3-dioxolane (61.5 g, 0.3 mol) and 1,6-hexamethylenediol (39.5 g, 0.3 mol), b) 2,2-dimethoxy-4,5-benz-1 3-dioxane (66.3 g, 0.3 mol) and 3-hexenylene-1,6-diol (48.3 g, 0.3 mol), and c) 2,2-diethoxy-4,5- benz-1,3-dioxolane (106 g, 0.5 mole) and diethylene glycol (41 g, 0.5 mole) to produce the following polymers (n = 10 - 1000 with an average value of 40 - 300 ): 20 r- -i - ° N / ° - (CH2) 6—, O ^ N) u 25 \ _ / L Jn - 0 O— (CH 2) 2 — oh = ch— (ch 2) 2 - 30 crv L Jn 35

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18 - ° v / 0CH2CH20CH2GK2— w s' ® -> n

Examples 26 - 28 10 follow the procedure of Example 21 with all the reaction conditions as described except that the polyol and heterocyclic ester of Example 21 are replaced by the following monomers: 15 a) 174 g of 1,10-decanediol and 180 g of 2, 2-diethoxy-5-triethyl-1,3-dioxane; b) 174 g of 1,10-decanediol and 178 g of 2,2-diethoxy-1,3-dioxepane; hexanediol and 218 g of 2,2-diethoxy-1,3-dioxocane, the following polymers are prepared (n = 10-1000 with an average value of 40-300): 25 -oo- (ce2) 10- ~ a) <Q> 0Έ-Ζ 30 LJ Jn —0 \ y ° (CH2 ^ X0 0X0 U i

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19 • ίο

Examples 29 - 32

The procedure of Example 21 is repeated. The transesterification and polycondensation steps are repeated with the following reactive monomers: a) 122 g of 1,6-hexanediol and 174 g of 2,2-di ethoxytetrahydropyran, b) 122 g of 1,6-hexanediol and 202 g of 2,2-diethoxy -5,5-dimethyltte trahydropyran, c) 122 g of 1,6-hexanediol and 188 g of 2,2-diethoxy-1-oxepane, and 20 d) 122 g of 1,6-hexanediol and 172 g of 2,2-diethoxydiol. A 3-oxyepine, to produce the following polymers, where n = 10 - 1000 with an average value of 40 - 300: 25 r - -0 0 - (ch 2) 5- - * 15 15 30. .0 (CH2

Q

35 h7c cii, _ D-th.

20

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--OvO (CH2) g. · 5 1 - - ° \ / 0 "(CH2) 6" "* 'ό -in

The polymer prepared according to Example 29 has a molecular weight 15 (Mw) of 15,000.

Examples 33 - 37 In Table 1 below, the structure of copolymers prepared according to the general procedure of Example 21 is given. In the table, "No." to the polymer; "Relationship" to the relationship between "m" and "n"; type "B" refers to block copolymer and type "R" to random copolymer; and the degree of polymerization is 10 - 1000 with an average value of 40 - 300.

25 30 35

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21

Table 1

No. Ratio Type___Polymer_______ 33 1: 1 B —0. 0 — CH2— / s GH2 --- Q \ / ° —CH2CH20CH2CH2-1 5 ts in L Jin «- 34 1: 2 B —0 0 — CHP— \ S \ —CH? J — U) (0-— CHpClip) p— -a L Yes 35 4: 1 R ~ r-0s .0 — CII9 — ί S) —CKP - 0. .0 ~ CHpCHp0CIIoCHP- x w. (X0 - 36 4: 1 R - 0 JD - CH 2 - / S \ --- ° \ / ° - CHgCHgOCHgCHg- 6 &

_ Jjl L J

37 4: 1 R - 0 O— (CH 2) 6 --- Ο, Ό — CK 2— (TO / o \ _ / I-- 'L 4 L -In

Examples 38 - 40 In Table 2, polymers prepared according to Example 1 are illustrated from the monomers 2,2-diethoxytetrahydropyran, 2,2-diethoxyoxepane, 2,2-diethoxyoxecane and trans-cyclohexanedicarbinol (n = 10 - 1000 with an average value of 40 - 300).

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22 I ri I si I ri i I-1 i i - 1 i — i --- 1

C \! C \ in CM

KW W

o o c3

III

Θ 0 · 0.

I I I I

S, CM CM CM

H K W W

0 O O O

"Q: o> 0

I —__ I I__I

KW K

o o o

CM CM CM

KW K

o o o: 1 i i i i i Θ Θ Θ

g I I I

o o o

CM CM CM

KW w o o o

K K K

tr \ ir \ irv

K K K

CM CM CM

u o O / V O

ø O O - v O O \, O

1 X> XJ ^ Λ

g CM CM CM V J

o o o ^ ir> ir \ irv

KW W

b. CO σι O

n ro

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23

Example 41 50 g of 2,2-diethoxytetrahydrofuran and 28.1 g of 1,4-butanediol pre-mixed with 0.05 g of polyphosphoric acid were reacted for 3.25 hours at a temperature increasing from 70 to 130 ° C and under atmospheric pressure. of Example 1. The reactants were then heated under a reduced pressure of 16000 - 320 Pa for 4 hours at 110 -125 ° C to produce 1,6,8-trioxa-spiro (4.6) undecane. The spiro compound was polymerized in a sealed tube at 125 ° C in the presence of a Lewis acid catalyst in the form of polyphosphoric acid to produce the polymer, where n = 10 - 1000 having an average value of 40 - 300, as illustrated below .

". D

V

h5C20 ° C2h5 + H0 (CH2) 40H η— (0Η2) + - o>. c ° 20 Λ

Example 42

The polycondensation of 2,2-diethoxytetrahydrofuran and 30/70 cis / transcyclohexanedimethanol with polyphosphoric acid was carried out as follows: The weight ratio of catalyst to diethoxytetrahydrofuran was 1/500; the needle was introduced into the reactor as a 68% by weight solution in methanol. The methanol was distilled from the diol in situ and toluene was added to azeotropically remove water from the system. The tetrahydrofuran was then added and transesterification and polycondensation were carried out at 180 ° C and a vacuum of 3200 Pa over a 24 hour period. The yield obtained was 82%. Gas-35 phase chromatographic analysis (GPC analysis) was as follows: Mw = 36,000, Mn = 8,500, Mw / Mn = 4.3. The polymer had the following formula:

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24 —Ον O — GHp— / S) —CH2- ~ 5 L Jn 5

Examples 43 - 45

The procedure set forth in Example I is repeated in these Examples, and all reaction conditions are as previously described except that instead of the monomers previously mentioned, the following are used: 2.2-Diethoxytetrahydrofuran and 5-methyl1,6 -cyclohex-A2-endi-carbinol 2.2-dipropoxy-1,3-dioxolane and 2-vinyl-1,6-cyclohexanedipropanol, and 2,2-diethoxy-5-methyl-1,3-dioxolane and 3-methyl 1,5-cyclopentanediethanol.

Hereby the following polymers are prepared, respectively: - Ml 25 -0X ° - = H2-Q-.H2- W H3 °

Jn 30 h2c = ch - -0 ^ 0 - ch2ch2ch2 - GH2CH2CH2- - w

3 5 L

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25 -CL .0-CHo0 £ U-7-t-CHpCHp- »x, CHs CHj Jn where n = 10 - 1000 with an average value of 40 - 300.

Example 46 10 13.26 g (0.125 mol) of diethylene glycol was added to 20.0 g (0.125 mol) of 2,2-diethoxytetrahydrofuran and the monomers were reacted in the presence of a Lewis acid in the form of polyphosphoric acid for 42 hours according to Example 10 for the preparation of poly- (2,2-dioxo diethylene glycol tetrahydrofuran). 50.0 g (0.312 mole) of trans-1,4-cyclohexanedicarbinol and 50.0 g (0.312 mole) of 2,2-diethoxytetrahydrofuran were reacted separately according to Example 1 to prepare poly- (2,2-dioxo-trans-cyclohexanedimethylenetetrahydro furan). 14.77 g (0.125 mole) of 1,6-hexanediol were separately added 20 to 20.0 g (0.125 mole) of 2,2-diethoxytetrahydrofuran and 20 mg of p-toluenesulfonic acid, and the monomers were reacted according to Example 5 to prepare (2,2-dioxohexamethylentetrahydrofu-RAN). Then 0.51 moles of poly (2,2-dioxodiethylene glycol tetrahydrofuran), 0.51 moles of poly- (2,2-dioxo-trans-cyclohexanedimethyl-1-tetetrahydrofuran) and 0.51 moles of poly- (2.2 dioxohexamethylene terahydrofuran) polymerized for 50 hours at 180 ° C under a pressure of 1.333 Pa in the presence of trace amounts of polyphosphoric acid to produce the terpol ymer, where the m: n: p ratio was 1: 1: 1.

30 - -o o -ch 2 -O-ck 2 --- CL 0 - CH 2 CH 2 CH 2 --- 0. 0- (CH 2) r

35 L Jm L Jn L

The terpolymer prepared according to Example 46 was synthesized with a molecular weight (Mw) of 27,000.

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Example 47 68.2 g of trans-cyclohexanedicarbinol and 0.1 g of polyphosphoric acid were added to 50 g of 5-methyl-2,2-diethoxytetrahydrofuran, which was pre-treated with sodium to remove any ethanol traces, and the polymer was polymerized according to Example 1. to produce 46.2 g of polymer. The polymer had Mn of 10,000, an Mw of 36,000, an Mw / Mn of 3.6, and the following structural formula: 10 - ——CH2— (7) —CH2 O.

CH, J Jn

Examples of other polymers which can be prepared by the above methods are: 20 poly- (2,2-dioxohexamethylene-1,3-dioxolane), poly- (2,2-dioxo-2-methyl-cis, trans-1,6-cyclohexanedipropylene-1,3-dioxepane), poly- (2,2-di oxo-3-ethyl-1,5-cyclopentanediethylene-1,3-dioxocane), poly- (2,2- dioxo-1,6-hex-3-enene-1,3-dioxolane), poly (2,2-dioxo-1,6-cyclohexanedibut-2-enylene-1,3-dioxolane), and poly ( methyl orthoacetate-1,6-hexylene).

The polymers included in the composition of the invention are suitable for the preparation of products and materials for dispensing an active agent into an aqueous biological environment, i.e. an animal or a human as they have an adjustable hydro-

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27 phobicity in such environments, and because they continuously erode therein into harmless products which do not produce any known adverse effects. In the present context, the term products encompasses objects having a unitary structure as well as other product forms, such as ointments which do not have a unitary structure. The polymers can be processed into such products and coated on an agent by standard methods. The polymers may e.g. extruded into filaments, spun into fibers, pressed into shaped articles, solvent film casted, coated on a solvent by solvent evaporation, coated using a fluidized bed, or molded and squeezed and processed by similar standard methods.

The term hydrophobicity used above denotes here and in the other description the ability of polymers not to absorb substantial amounts of water. The hydrophobic polymers do not absorb water in an amount exceeding 5% of their dry weight.

20

The terms degradable and biodegradable are used to define the ability of polymers to degrade over a period of time as a unit in an aqueous, biological environment or to be completely degraded. The terms erosion, degradation, biodegradation and bioerosion generally define the method by which degradation of the polymer takes place.

In the present specification, the term pharmaceutically active agent comprises e.g. medicines, contraceptives or contraceptives. The term drug includes physiologically or pharmacologically active substances to induce a local or systemic effect or local or systemic effects in mammals.

The present composition may be in various forms, such as solutions, dispersions, pastes, creams, particles, microcapsules, emulsions and suspensions.

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28

The composition may be prepared to release an active agent at a zero order rate or at a variable rate depending on the molecular weight and composition of the polymer, the concentration of the active agent in the polymer and the surface area of the composition subjected to environmental influence. Variable release or release rate compositions can also be prepared by using different polymers which are biodegraded at different rates, or by using different structures such as laminates of different polymer drug contents.

Examples of such compositions for dispensing active agents are described below.

A parallelepiped-shaped blank (7.5 cm x 7.5 cm x 250 µm) for dispensing hydrocortisone was prepared by mixing hydrocortisone in poly- (2,2-dioxo-trans-1,4-cyclohexanedimethyl-1-tetetrahydrofuran) as follows. way: 2.375 g of the polymer was heated as a solid in a laboratory pan to ca.

20 ° C, whereby the polymer melted to give a syrupy consistency, after which 0.125 g of micronized hydrocortisone was added to the polymer. The polymer and hydrocortisone were then carefully mixed to produce a good dispersion of the drug in the polymer. After cooling the pan to room temperature 25, the polymer-drug mixture was removed from it and a blank was prepared by pressing at 121 ° C, 700 kg / cm 2 for 5 minutes with a 250 micron, 7.5 cm x 7, 5 cm spacer placed between "Teflon" plates. The blank was prepared under a substantially dry inert atmosphere using an oven-dried apparatus. The surface of this subject is biodegraded in an aqueous environment at a controlled and continuous rate of approx. 2 microns depth per hour. At the same time, hydrocortisone is released at a similarly regulated and continuous but proportional rate. This item can be used to treat inflammation and bursitis when applied to the skin or mucosa.

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29

A drug dispensing ointment was prepared as follows: To 2.375 g of the viscous polymer poly- (2,2-dioxo-1,6-hexamethylenetetrahydrofuran) having a molecular weight of approx. 25,000 0.125 g of hydrocortisone was added and the ingredients were mixed thoroughly for 5 minutes. The mixture was made with standard laboratory mixing equipment at room temperature and in a dry, inert atmosphere. The ointment is useful as a topically used anti-inflammatory agent.

The composition may be in the form of a solid implanted subject, such as an implanted subject delivering an analgesic substance, and used in connection with surgical procedures accompanied by severe post-operative pain. In these cases, once the body has been opened for surgery, an implantable device containing an analgesic may be implanted into the body during surgery to reduce pain as the implanted device is biodegraded and releases the analgesic during the healing period. Injectable (e.g. by trocar injection) implantable units may also be manufactured. An injectable, implantable unit comprising a polymer with an erosion rate of approx. 2 mi per kr. was prepared as follows: To 2.375 g of poly (2,2-dioxo-trans-1,4-cyclohexanedimethylenetetrahydrofuran) was added 25 was added 0.125 g of hydrocortisone and the ingredients were heated to 150 ° C to prepare a melt. The drug was dispersed throughout the melt by mixing the ingredients for 5 minutes to obtain a good dispersion. The mixture was carried out in a dry, inert environment at atmospheric pressure and with a dry equipment. After cooling the polymer to room temperature, it was then transferred to a press and injection molded into a fixed, cylindrical, implantable unit 3 mm in diameter and 8 mm in length. The implantable end was placed in a muscle of an animal by trocar injection and biodegraded here, releasing steroid to treat inflammation.

A similar implantable unit containing 20% progesterone in poly (2,2-dioxo-trans-1,4-cyclohexanedimethylenetetrahydrofuran)

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30 with an initial weight of approx. 114 mg had an in vivo progesterone release rate expressed in mg / day over a 7 day period as follows: 3.7, 3.2, 2.9, 2.2, 2.5 and 3.8, respectively.

Another injectable, implantable substance containing norethesterone was prepared by dispensing the drug into poly- (2,2-dioxo-trans-1,4-cyclohexanedial methyl entetrahydrofuran) in accordance with the method set forth above except that drug and polymer was mixed at 130 ° C in a dry helium atmosphere. The 10 implantable unit formed had a drug concentration of 20% and cylindrical shape. The implantable unit was placed bilaterally in the paravertebral muscles of rabbits by trocar injection and was biodegraded at a controlled and continuous rate at the same time as the release of norethistone at 600 pg / day.

Eye inserts in such forms as an 8 mm disc and a 6 mm x 12 mm ellipsoid, each 0.4 mm thick, were also prepared by dissolving both the drug and the polymer in a dry solvent, benzene or 1.4 dioxane and the mixture was lyophilized in the sera. The dry mixture was then pressed at 100 ° C and 1050 kg / cm 2 to produce a drug-containing polymer plate. Eye inserts prepared by this method include 10% pilocarpine nitrate and poly- (2,2-dioxo-trans-1,4-cyclohexanedimethylenetetrahydrofuran), 5% pilocarpine-free base and poly- (2,2-dioxo-trans-1 , 4-cyclohexanedimethylenetetrahydrofuran), 10% hydrocortisone alcohol and poly (2,2-dioxo-trans-1,4-cyclohexanedimethylenetetrahydrofuran), 10% idoxuridine and poly (2,2-dioxo-trans-1,4-cyclohexanedimethylenetetrahydrofuran) -2,2-30 dioxo-oxadimethylenetetrahydrofuran), and 10% chloramphenicol and poly (2,2-dioxo-trans-1,4-cyclohexanedimethylenetetrahydrofuran-2,2-dioxo-oxadimethylenetetrahydrofuran). These eye insertions are biodegraded continuously, delivering a measured amount of eye drug or drug to the eye and its surrounding tissue over a prolonged period of time.

Additional ocular products comprising zinc bacitracin and the random copolymer poly- (2,2-dioxo-trans-1,4-cyclohexanedimethyl)

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31 lentetrahydrofuran-2,2-dioxo-1,6-hexamethylenetetrahydro uranium) was prepared by mixing and dispersing at 120 ° C for 5 minutes of bacitracin in the hot melt of the polymer. After cooling to room temperature, the drug-polymer product 5 was pressed into a film at 120 ° C under 700 kg / cm 2 for 5 minutes and then cut to eye insert. The release rate for 3-day eye insert made from the above-mentioned drug-polymer product is given in the following table: 10 Surface-Zinc Baci area tracin input pg / h in

Dimension and shape_ (cm2) _hold (mg) _72 h_ 6 mm circular 0.56 1.5 21 15 5 x 8 mm ellipse 0.62 1.6 22 5.6 x 12.7 mm ellipse 1.1 2.9 40

Compounds of active agent and polymer compositions, such as those used for burns and wound treatment, can be made by incorporating the composition into an absorbent carrier. Carriers such as textile fabric, plastic fibers, a piece of porous foamed gum or paper can be used. Typical active agents which can be used in such compounds are the various sulfal drugs, salicylic acid derivatives and other antibiotic agents. For example, a circular piece of double-knit polyester fabric is provided. with 4 g of poly (2,2-dioxohexamethylenetetrahydrofuran) containing 0.1-30%, usually 2-15% α-amino-p-toluenesulfonamide by incorporating 30 polymeric agent into the fabric with a laboratory spatula. The hydrophobic polymer can also be charged with other agents, such as 1 - 1¾% silver nitrate in poly (2,2-dioxohexamethylenetetrahydrofuran), from 0.001% - 2% by weight collagenase mixed with 1-1¾% by weight silver nitrate in poly ( 2,2-dioxohexamethylenetetrahydrofuran) .35 and 1 g poly (2,2-dioxohexamethylenetetrahydrofuran) containing 82 x 1θ3 casein units of a protease such as streptokinase or otherwise.

Claims (9)

A controlled release medical composition 5 comprising a pharmaceutically active agent enclosed in a biodegradable polyester which is biodegraded using the active agent release composition, characterized in that the polymer is an orthoester polymer of repeating units of the general formula 10 - R 1 -O-C-O-Λ, IT Fr 1/15 * - n wherein R 1 is an alkylene group of 2-10 carbon atoms, an alkenylene group of 2-10 carbon atoms, an oxaalkylene group of 2-6 carbon atoms and 1 or 2 internal oxa groups, a red methyl group substituted cycloalkylene group having 3-7 ring carbon atoms or a cycloalkanedialiphatic group having 3-7 ring carbon atoms and 1-7 carbon atoms in the alkylene residue, the cycloalkane ring being optionally substituted with alkyl groups having 1-7 carbon atoms or with alkenyl groups of 2-7 carbon atoms, and r2 and r3 together with the polymer backbone's dioxycarbon atom form a 5- to 8-ring heteromonocyclic group with 1 el clay 2 oxygen hetero atoms bonded to the polymer backbone dioxycarbon atom and the remaining ring link being carbon atoms optionally substituted with alkyl groups of 1-7 carbon atoms, alkoxy groups of 1-7 carbon atoms or alkenyl groups of 2-7 carbon atoms, or a phenyl ring condensed to 2 neighboring carbon atoms, and n is an integer from 10 to 1000. Composition according to claim 1, characterized in that the polymer is a homopolymer, copolymer or terpolymer, R * is divalent and is the cycloalkyl dialkylene having 4-6 ring carbon atoms, wherein the alkylene groups have 1-4 carbon atoms, the alkylene having 2 to 10 carbon atoms or the oxa alkyl of 2-6 carbon atoms and 1 or 2 internal oxa groups, and R 2 and R 3 together with the diocycarbon atom of the polymer backbone form a 5 or 6 membered heteromonocyclic ring with an oxygen hetero atom attached to the dioxycarbon atom of the polymer backbone, the remaining members of the ring being carbon atoms. Composition according to claim 1, characterized in that the polymer is a homopolymer, R 1 is tetramethylene, hexamethylene, decamethylene, 1,4-cyclohexadimethylene, 2,2,4,4-tetramethyl-1,3-cyclobutylene or 2-oxa-1,4-butyl one, and R 2 and R 3 together with the deoxycarbon atom in the polymer backbone form a tetrahydrofuryl group. 15 Composition according to claim 1, characterized in that the polymer is a random copolymer of two units, that R 2 and R 3 together with the dioxycarbon atom in each unit in the polymer backbone form a tetrahydrofuryl group, that R 2 is clohexanedimethylene and that R * in the other unit is hexamethylene or 2-oxa-1,4-butylene. Composition according to claim 1, characterized in that the polymer is a block copolymer of two units, that R 2 and R 3 together with the dioxycarbon atom of each unit in the polymer backbone form a tetrahydrofuryl group, that R 1 in one unit is 1,4-cyclohexanedimethylene. and that R 1 in the other unit is hexamethylene or 2-oxa-1,4-butylene. Composition according to claim 1, characterized in that the polymer is a block polymer, that R 2 and R 3 together with the dioxycarbon atom in each unit in the polymer backbone form a tetrahydro-uryl group, that R 1 in one unit is 1,4-cyclohexanedimethylene. R 1 in the second unit is hexamethylene and that R 1 in the third unit is 2-oxa-1,4-butylene. Composition according to claim 1, characterized in that the polymer is a homopolymer, that R 1 is 1,4-cyclohexanedimethylene, DK 166344 B and that R 2 and R 3 together with the dioxycarbon atom in the polymer backbone form a tetrahydropyranyl group. Composition according to claim 1, characterized in that the polymer is a homopolymer, that R 1 is 1,4-cyclohexanedimethylene and that R 2 and R 3 together with the dioxycarbon atom in the polymer backbone form a 5-methyl tetrahydrofury group. A composition according to claims 1-8, characterized in that the active agent is a drug. 15 20 25 30 35