WO1981003278A1 - Polymers of polyketene acetals and polyols - Google Patents

Polymers of polyketene acetals and polyols Download PDF

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WO1981003278A1
WO1981003278A1 PCT/US1981/000621 US8100621W WO8103278A1 WO 1981003278 A1 WO1981003278 A1 WO 1981003278A1 US 8100621 W US8100621 W US 8100621W WO 8103278 A1 WO8103278 A1 WO 8103278A1
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polymers
functionality
polyol
polymers according
groups
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PCT/US1981/000621
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French (fr)
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J Heller
R Helwing
D Penhale
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Stanford Res Inst Int
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Priority to DK16082A priority patent/DK16082A/en

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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/34—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from hydroxy compounds or their metallic derivatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • A61K9/204—Polyesters, e.g. poly(lactide-co-glycolide)
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
    • C08G63/66—Polyesters containing oxygen in the form of ether groups

Definitions

  • This invention relates to polymers which are bioerodible and are suitable as carriers or matrices for drugs and other beneficial agents used for therapeutic purposes and which, upon contact with the environment in which they are used, degrade and release the drug or other biologically active agent.
  • the invention also relates to methods of preparing such polymers, to compositions of matter comprising the polymer and biologically active agents and to fabricated articles such as implants in which the polymer constitutes the matrix and contains a biologically active material.
  • Patent is a polymer prepared from trans-1, 4-cyclohexane dicarbinol and 2,2-diethoxytetrahydrofuran.
  • the polymer has the formula
  • n is an integer from 10 to 1000.
  • this polymer is prepared by heating a mixture of the monomers and polyphosphoric acid, first at 110-115°C for 1-1/2 to 2 hours with slow distillation of any liquid formed, then at 0.01 millimeter of mercury while the temperature is slowly increased to 180°C. The reaction is allowed to continue at 180°C for 24 hours.
  • the reaction takes a considerable period of time, in this particular instance in excess of 24 hours. Furthermore, it is necessary to remove by distillation under high vacuum the volatile products formed as a result of condensation. The necessity to remove the volatile material precludes formation of nonporous, dense crosslinked products obtained by using alcohols having functionalities greater than two.
  • a further disadvantage of this procedure is the difficulty in achieving very high molecular weights. It is well known, that typical polymers prepared by condensation reactions involving a transesterification reaction have molecular weights of about 30,000. Since this is an average molecular weight, it is apparent that the product contains a considerable proportion of polymer of much lower molecular weight. In many instances the presence of low molecular weight polymer chains adversely affects mechanical properties.
  • a yet further disadvantage is the fact that a transesterification reaction is an equilibrium reaction which is driven to high polymer molecular weight by removal of a volatile by-product with a consequent shift of equilibrium. However, it is usually not possible to completely remove the diol by-product and varying amounts of this diol are very often found in the final polymer product.
  • Still another disadvantage is the fact that because of the high reaction temperatures are long reaction times, side-reactions can occur and the product is usually not pure because extraneous linkages can be formed.
  • a particular object is to provide polymers which can be made by a process which proceeds rapidly at low temperatures, usually below 40°C, without the evolution of any by-products. Therefore, either linear or dense, crosslinked matrices can be readily produced.
  • Another particular object is to provide a process of polymerization which is not an equilibrium reaction and whereby molecular weights as high as 200,000 can be routinely achieved.
  • Another object is to provide polymer structures having no significant amounts of unreacted monomers or extraneous linkages.
  • a further object is to provide a process in which there is no limitation on the number of carbon atoms in the diol whereby polyols having fewer than five carbon atoms may be employed, and such diols do not form monomeric spiro structures.
  • a ketene acetal having a functionality of two or more is reacted with a polyol, which term includes alcohols and phenols.
  • a diketene acetal has a functionality of two
  • a triketene acetal has a functionality of three
  • the term "functionality" is used in connection with a polyol, it refers to the hydroxyl groups.
  • Such polymers have a number of advantages as matrices or carriers for drugs as explained below.
  • the monomeric polyols can be represented generally by the formula wherein y is zero or a positive integer. These are described below.
  • the monomeric ketene acetals are of two types as follows:
  • terminal R groups are the same or different, and can be H or essentially hydrocarbon groups, primarily alkyl, aryl, cycloaliphatic or aralkyl groups, and may be saturated or unsaturated, and ® is a quadrivalent grouping or atom.
  • Type I monomer may be a spiro structure or it may be a non-spiro grouping.
  • a subgroup of Type I monomer is exemplified by Compounds XIII through XVIII in Table II below.
  • essentially hydrocarbon is meant that the groups R may contain hetero atoms provided they do not inhibit polymerization with a polyol to an unacceptable degree, do not inhibit degradation of the polymer to an unacceptable degree and do not give rise to toxic or difficultly metabolizable degradation products.
  • the formulation R—R indicates that the two R groups may be joined together to form a cyclic group or may be separate, unconnected groups .
  • terminal R groups are the same or different essentially hydrocarbon groups
  • the R' groups are hydrogen or essentially hydrocarbon groups (defined as above) and R" is a bivalent organic grouping which is also essentially hydrocarbon (similarly defined).
  • R being an essentially hydrocarbon (similarly defined) bivalent group to produce linear polymers as follows :
  • R is derived from the polyol and n is an integer greater than one and usually 100 to 300 or greater.
  • the Type II monomers polymerize with diols HO-- OH (defined as above) to produce linear polymers as follows:
  • R and n are similarly defined.
  • crosslinked polymers will result. As noted below crosslinking may also be achieved by other crosslinking agents.
  • Exemplary polyols suitable as reactants include diols, triols and the like that can enter into the polymerization reaction without adversely effecting it or the polymeric products.
  • the polyols are known to the art in reported synthesis and they are commercially available. Generally, they include ⁇ , ⁇ -aliphatic diols, triols and the like of the straight or branched chain type.
  • Representative polyols are alkane polyols having a terminal hydroxyl group at the terminus of an alkylene chain of the formula
  • R is an alkylene chain of 2 to 12 carbon atoms and y is 0 to 6.
  • Typical diols named as the glycols, include 1,5 pentylene glycols; 1,6-hexylene glycol; 1,7-heptylene glycol; 1,9-nonylene glycol; 2,3-dimethyl-1,6- hexylene glycol; 3,6-diethyl-1,9-nonylene glycol; 1,12-dodecamethylene glycol; and the like.
  • Polyols containing more than 2 reactive hydroxyl radicals suitable for use herein include polyhydroxyl compounds such as 1,2,3,4,5,6-hexanehexol; 1,2,3-propanetriol; 1,2,5-pentanetriol; 1,3,5-pentanetriol; 1,2,4-butanetriol; 2-methyl-1,2,3-propanetriol; 2-methyl-2(hydroxymethyl) 1,2-propanediol; 1,4,7-heptanetriol; 1,5,10-decanetriol; 1,5,12-dodecanetriol; and the like.
  • polyhydroxyl compounds such as 1,2,3,4,5,6-hexanehexol; 1,2,3-propanetriol; 1,2,5-pentanetriol; 1,3,5-pentanetriol; 1,2,4-butanetriol; 2-methyl-1,2,3-propanetriol; 2-methyl-2(hydroxymethyl) 1,2-propanediol; 1,4,7-heptanetriol; 1,5,10-decanetriol;
  • polystyrene resins suitable for synthesizing the polymers include polyglycols containing a repeating glycol monoether moiety—OCH 2 (CH 2 ) OH wherein p is 1 to 5, and the polyglycols are diglycols, triglycols, tetraglycols, and the like.
  • Typical polyglycols include diethylene glycol, triethylene glycol, tetraethylene glycol, bis(4-hydroxybutyl) ether, bis (3-hydroxypropyl) ether, and the like.
  • polyhydroxyl compounds having 2 or more reactive hydroxyl groups such as pentaerythritol; dipentaerythritol; ⁇ -methylglycerol; 1,4-cyclohexane dicarbinol in the cis, transisomeric configuration or mixtures thereof; 2,2,4-4-tetramethyl cyclobutane 1,3-diol; adonitol; mannitol; 2,5-di ⁇ ropyl-1,4-phenyldipro ⁇ anol;
  • 1,3-cyclopropanol 2-propenyl-1,4-cyclohexane dipropanol; trimethylol propane; sorbitol; penacol; 2-methyl-1,4-cyclohexane dicarbinol; 3-isdpropoxy-1,4-cyclohexane dipropanol; 2-ethenyl-1,3-cyclopentane dicarbinol; 1,4-phenyldicarbinol; 2-propyl-1,4-phenyldiethanol; 3-butoxy-1,-4,-phenyldibutanol; and the like.
  • the preparation of the above polyols is known to the art in Acta Pharm. Jugaslav. Vol.
  • phenolic polyols two or more phenolic hydroxyl groups
  • mixed phenolic-alcoholic polyols may be employed.
  • mixtures of two or more polyols may be employed. Examples of polyols and of mixed phenolic-alcoholic polyols are as follows : 4,4'-isopropylidenediphenol (bisphenol A);
  • 3,4-dihydroxymethylc lamate also non-phenolic polyols having aromatic linking groups between the hydroxyl groups, e.g. 1,4-dihydroxymethylbenzene.
  • tri- (and higher) hydric phenols may be used such as pyrogallol; hydroxyhydroquinone; phloruglucinol; and propyl gallate.
  • Table I immediately following identifies the ketene acetals of the Examples (Compounds I through XII) and it also identifies ketene acetals of a sub-group of Type I which may be used.
  • the high molecular weight poly (ortho ester) was isolated by either precipitation into n-hexane which contained a small amount of triethylamine followed by filtration of the white solid, or by evaporation of the tetrahydrofuran in a Teflon coated pan placed in a vacuum chamber.
  • the polymer had the following structure
  • Example 1 Using the same conditions as in Example 1, 15.00 grams (0.0781 moles) of compound II and 9.22 grams (0.0781 moles) of 1.6-hexanediol are dissolved in 90 ml of tetrahydrofuran and 3 ml of a solution containing 1 x 10 -6 moles of iodine per ml of pyridine are added. There is an immediate temperature rise to 52°C after which it gradually returns to room temperature. After stirring at room temperature for about one hour, the polymer is isolated as described in Example 1, and has the following structure where n is 10 to 1000.
  • Example 2 Using the same conditions as in Example 1, 42.00 grams (0.1567 moles) of Compound V and 14.10 grams (0.1567 moles) of 1,4-butanediol are dissolved in 200 ml of 1,2-dimethoxyethane and 1 ml of solution containing 1 x 10 -4 mole of p-toluenesulfunic acid monohydrate per ml of tetrahydrofuran is added. After the slight temperature rise subsides, the mixture is stirred at room temperature for about one hour and the polymer is isolated as described in Example 1. The polymer has the following structure where is 196,000 and the is 1.48.
  • the polymer has the following structure:
  • the two diol residues are randomly located in the chain and are shown as alternating merely for convenience.
  • Example 7 The procedure of Example 7 is repeated except that no solvent is used and instead the reaction mixture is heated to 70°C in order to achieve a homogeneous solution.
  • Compound V and 1,4-butanediol used in Example 7 are replaced with 33.06 grams (0.1333 moles) of Compound IV and a mixture of 9.60 grams (0.1000 moles) grams 1,4-butanediol and 5.39 grams (0.0333 moles) of 1,2,6-hexanetriol.
  • the following crosslinked polymer is obtained:
  • Example 6 The procedure of Example 6 is repeated except that no solvent is used and instead the reaction mixture is heated to 65°C in order to achieve a homogeneous solution.
  • Compound II are 1,6-hexanediol used in Example 6 are replaced with 25.00 grams (0.1263 moles) of Compound III and 16.92 grams (0.1263 moles) of trimethylolpropane.
  • the following crosslinked polymer is obtained:
  • Example 6 The procedure of Example 6 is repeated except that no solvent is used and instead the mixture is heated to 60°C in order to achieve a homogeneous solution.
  • Compound II and 1, 6-hexanediol are replaced with 10.00 grams (0.0794 moles) of Compound XI and 7.38 grams (0.1191 moles) of ethylene glycol.
  • the following polymer is obtained:
  • Example 6 The procedure of Example 6 is repeated except that no solvent is used and instead the mixture is heated to 85oC in order to achieve homogeneous solution.
  • Compound II and 1,6-hexanediol are replaced with 15.00 grams (0.0490 moles) of Compound XII and 6.62 grams (0.0731 moles) of 1,4- butanediol.
  • the following polymer is obtained:
  • Delivery devices were prepared by putting 7.2 grams of the polymer of Example 1 on a Teflon coated pan heated to a surface temperature of about 150°C to provide a melt consistency permitting mixing to produce a thorough dispersion of 0.8 grams of micronized Na 2 CO 3 and 2.0 grams of micronized norethindrone into the polymer melt. Sheets of the polymer mixture 20 mil and 40 mil in thickness 3" x 3" square were pressed at 135°C (275°F), and 10,000 psi between sheets of Teflon covered foil using the appropriate thickness mold spacers. 1/4" discs were punched from these sheets. These discs are suitable as implants.
  • the drug may be incorporated in the mixture of monomers before polymerization.
  • crosslinked polymers such as those of Examples 18 to 21 this will be done because the polymers are infusible and insoluble in solvents.
  • drugs may be similarly incorporated in the polymers of the invention.
  • these drugs or beneifical agents may include any of those mentioned in Choi and Heller U.S. Patent 4,093,209 column 29, line 45 to column 30, line 37; also insecticides and other biologically active agents.
  • Examples 18 and 19 illustrate the use of polyols having a functionality greater than two and Examples 20 and 21 illustrate the use of ketene acetals having a functionality greater than two.
  • examples 20 and 21 illustrate the use of ketene acetals having a functionality greater than two.
  • crosslinking it is preferred to use tri- and higher functionality polyols because of their greater availability.
  • Mixtures of polyols of different functionality, e.g. 2 and 3 and/or mixtures of ketene acetals of different functionality, e.g. 2 and 3 may be used.
  • a mixture of diol and triol the density of crosslinking can be controlled by the ratio of diol to triol.
  • Type I polymers are derived from ketene acetals of the formula:
  • the group ® may contain no single radical as in Compound I to which all four of the interior acetal oxygen atoms are attached.
  • Examples of such Type I ketene acetals and resulting polymers are as follows:
  • crosslinked polymers of Compounds XIII through XVII may be produced by using tri- and higher functionality polyols, and/or by using ketene acetals of tri- or higher functionality.
  • my novel polymers Being prepared by a reaction between a ketene acetal and polyol, they do not require removal by heat and distillation of small molecules. Also, the reaction proceeds to a high degree of polymerization at low temperatures. Therefore, a drug, even one that is sensitive to elevated temperatures, can be incorporated in the mixture of monomers and will appear in the polymer without degradation. This is especially advantageous in the case of crosslinked polymers.
  • Suitable solvents are polar aprotic solvents, e.g. glyme, diglyme, dimethylacetamide, dimethyl, sulfoxide, dimethyl-formamide, acetonitrile, pyrrolidone, and methylbutyl ether. When crosslinking occurs, solvents are not used.
  • Catalysts are not required but when used, suitable catalysts are iodine in pyridine, p-toluensulfonic acid; also Lewis acids such as boron trichloride, boron trifluoride, boron trichloride etherate, boron trifluoride etherate, stannic oxychloride, phosphorous oxychloride, zinc chloride, phosphorous pentachloride, antimony pentafluoride, stannous octoate, stannic chloride, diethylzinc, and mixtures thereof; also, Bronsted catalysts in addition to p-toluene sulfonic acid such as poly-phosphoric acid, crosslinked polystyrene sulfonic acid, acidic silica gel, and mixtures thereof.
  • the amount of catalyst used may be about one part catalyst to about 500 parts of the ketene acetal monomer. Smaller or larger amounts can also be used, such as 0.00
  • Type I and Type II polymers there are various organic groups such as those in the R-O- groups, those forming parts of pendant groups such as
  • linking groups those forming linking groups or parts of linking groups such as ® and
  • R groups may be hydrogen. Where they are not hydrogen, they are essentially hydrocarbon groups as defined above; i.e., they do not exclude groups containing hetero atoms provided the presence of the hetero atom or atoms is not incompatible with the intended use and with bioerodibility, and do not give rise to toxic or non-metabolizable degradation products.
  • R the polyol residue
  • R is derived from a polymer of an alkylene oxide (e.g. ethylene oxide, propylene oxide, butylene oxide, tetrahydrofuran and the like) in which case R has the formula
  • polyesters are the glycolides and lactides.
  • the "R groups" as defined above may be of low molecular weight, e.g. methyl, ethyl, -CH 2 -CH 2 - , etc., or they may be of high or intermediate molecular weight. Practical considerations will influence the choice of molecular weight. For example, "R groups" of high molecular weight which are pendant groups, or which form linking groups or parts of linking groups, or are parts of R-O- groups, or which are derived from high molecular weight polyols, may be available only from expensive starting materials, or may impart less desirable characteristics to the polymer.

Abstract

Ortho ester polymers formed by condensation reaction between ketene acetals having a functionality of two or more and hydroxyl containing compounds having a functionality of two or more. The reaction proceeds without the evolution of small molecule by-products which must be removed by distillation in order to achieve high molecular weight. Hence, the process produces high molecular weight poly (ortho esters) in short reaction times, at essentially room temperature and at atmospheric pressure. Linear thermoplastic materials are produced when both the keten acetal and alcohol have functionalities of two. Because no volatile materials are produced, void-free, thermoset materials are produced when either or both the alcohol and ketene acetal have functionalities greater than two and crosslinking occurs. The polymers are bioerodible and are useful in the fabrication of devices and coatings for delivering beneficial agents.

Description

POLYMERS OF POLYKETENE ACETALS AND POLYOLS BACKGROUND OF THE INVENTION
1. Origin of Invention
This invention disclosure described herein was made in the course of or under National Institutes of Health Contract No. 1-HD-7-2826 with the United States Department of Health, Education and Welfare.
2. Technical Field of the Invention
This invention relates to polymers which are bioerodible and are suitable as carriers or matrices for drugs and other beneficial agents used for therapeutic purposes and which, upon contact with the environment in which they are used, degrade and release the drug or other biologically active agent. The invention also relates to methods of preparing such polymers, to compositions of matter comprising the polymer and biologically active agents and to fabricated articles such as implants in which the polymer constitutes the matrix and contains a biologically active material.
3. Background Art
There are available drug delivery devices such as those described in U.S. Patent 4,069,307 in which a drug is included in a polymeric matrix from which it diffuses. There are also drug delivery devices in which a drug is contained in a capsule the walls of which are permeable to water and which, upon infusion of water, generate an internal osmotic pressure such as to force the drug through an orifice. Both types are implanted and require subsequent removal.
Another approach to drug delivery devices is typified by Choi and Heller U.S. Patent 4,093,709, which employs a bioerodible polymer in which a drug is incorporated and which undergoes degradation (called bioerosion) to release the drug. Provided the degradation products are harmless, such an implant has the advantage that it does not require removal. The bioerodible polymers of that patent are poly (ortho esters) or polycarbonates.
A typical example of such a polymer and its method of synthesisis given in Example 1 of the Choi and Heller
Patent and is a polymer prepared from trans-1, 4-cyclohexane dicarbinol and 2,2-diethoxytetrahydrofuran. The polymer has the formula
Figure imgf000004_0001
wherein n is an integer from 10 to 1000. As described in Example 1, of the Choi and Heller Patent this polymer is prepared by heating a mixture of the monomers and polyphosphoric acid, first at 110-115°C for 1-1/2 to 2 hours with slow distillation of any liquid formed, then at 0.01 millimeter of mercury while the temperature is slowly increased to 180°C. The reaction is allowed to continue at 180°C for 24 hours.
There are several disadvantages to this procedure which are typical of a transesterification reaction and to the polymeric end-products resulting therefrom, among which are the following:
The reaction takes a considerable period of time, in this particular instance in excess of 24 hours. Furthermore, it is necessary to remove by distillation under high vacuum the volatile products formed as a result of condensation. The necessity to remove the volatile material precludes formation of nonporous, dense crosslinked products obtained by using alcohols having functionalities greater than two.
A further disadvantage of this procedure is the difficulty in achieving very high molecular weights. It is well known, that typical polymers prepared by condensation reactions involving a transesterification reaction have molecular weights of about 30,000. Since this is an average molecular weight, it is apparent that the product contains a considerable proportion of polymer of much lower molecular weight. In many instances the presence of low molecular weight polymer chains adversely affects mechanical properties. A yet further disadvantage is the fact that a transesterification reaction is an equilibrium reaction which is driven to high polymer molecular weight by removal of a volatile by-product with a consequent shift of equilibrium. However, it is usually not possible to completely remove the diol by-product and varying amounts of this diol are very often found in the final polymer product.
Still another disadvantage is the fact that because of the high reaction temperatures are long reaction times, side-reactions can occur and the product is usually not pure because extraneous linkages can be formed.
Yet another disadvantage is due to the propensity of diols having fewer than five carbon atoms to form monomeric spiro structures which then need to be polymerized in a separate step.
The foregoing disadvantages are typical of bioerodible polymers prepared by condensation of monomers which have been patented heretofore.
DISCLOSURE OF INVENTION AND OBJECTS
1. Object
It is an object of the present invention to provide improvements upon bioerodible polymers suitable for use as matrices for drugs and other beneficial agents.
More particularly it is an object of the present invention to provide a bioerodible polymer which is useful for such purposes and which can be made by an improved process having few or none of the aforementioned disadvantages.
A particular object is to provide polymers which can be made by a process which proceeds rapidly at low temperatures, usually below 40°C, without the evolution of any by-products. Therefore, either linear or dense, crosslinked matrices can be readily produced.
Another particular object is to provide a process of polymerization which is not an equilibrium reaction and whereby molecular weights as high as 200,000 can be routinely achieved.
Another object is to provide polymer structures having no significant amounts of unreacted monomers or extraneous linkages.
A further object is to provide a process in which there is no limitation on the number of carbon atoms in the diol whereby polyols having fewer than five carbon atoms may be employed, and such diols do not form monomeric spiro structures.
The above and other objects of the invention will be apparent from the ensuing description and the appended claims.
2. Description of Invention and Best Mode(s) for
Carrying Out In accordance with the present invention, a ketene acetal having a functionality of two or more is reacted with a polyol, which term includes alcohols and phenols.
By "functionality" as applied to a ketene acetal is meant the ketene acetal group
Figure imgf000008_0001
Thus a diketene acetal has a functionality of two, a triketene acetal has a functionality of three, etc. Similarly where the term "functionality" is used in connection with a polyol, it refers to the hydroxyl groups.
Such polymers have a number of advantages as matrices or carriers for drugs as explained below.
The monomeric polyols can be represented generally by the formula
Figure imgf000009_0002
wherein y is zero or a positive integer. These are described below.
The monomeric ketene acetals are of two types as follows:
Figure imgf000009_0001
wherein the terminal R groups are the same or different, and can be H or essentially hydrocarbon groups, primarily alkyl, aryl, cycloaliphatic or aralkyl groups, and may be saturated or unsaturated, and ® is a quadrivalent grouping or atom. The grouping
Figure imgf000010_0001
may be a spiro structure or it may be a non-spiro grouping. A subgroup of Type I monomer is exemplified by Compounds XIII through XVIII in Table II below.
By "essentially hydrocarbon" is meant that the groups R may contain hetero atoms provided they do not inhibit polymerization with a polyol to an unacceptable degree, do not inhibit degradation of the polymer to an unacceptable degree and do not give rise to toxic or difficultly metabolizable degradation products. The formulation R—R indicates that the two R groups may be joined together to form a cyclic group or may be separate, unconnected groups .
Type II Monomers
Figure imgf000011_0001
Wherein the terminal R groups are the same or different essentially hydrocarbon groups, the R' groups are hydrogen or essentially hydrocarbon groups (defined as above) and R" is a bivalent organic grouping which is also essentially hydrocarbon (similarly defined).
The Type I monomers condense with diols HO- R- OH,
R being an essentially hydrocarbon (similarly defined) bivalent group to produce linear polymers as follows :
Figure imgf000011_0002
wherein R is derived from the polyol and n is an integer greater than one and usually 100 to 300 or greater.
The Type II monomers polymerize with diols HO-- OH (defined as above) to produce linear polymers as follows:
Figure imgf000012_0001
R and n are similarly defined.
It will be understood that where the polyol and/or the ketene acetal has or have functionalities greater than two, crosslinked polymers will result. As noted below crosslinking may also be achieved by other crosslinking agents.
Certain of the diketene acetals which can be used in the present invention are described in the literature, among which are the following:
Type I Diketene Acetals
Figure imgf000012_0002
This compound and its synthesis are described in Yasnitskii et al in Zhurnal obshchei Khimii 34, 1940-45 (1964). Type II Ketene Acetals
Figure imgf000013_0001
(R = methyl, ethyl, n-butyl,
Figure imgf000013_0002
Scheeren and Aben, Tetrahedron Letters , 12, 1019-1020 (1974)
Figure imgf000013_0003
Scheeren et al., J. Royal Netherlands Chemical Society, 94, 196-8 (1975). The centrally located double bond may be employed to bring about crosslinking of linear ketene-diol polymers. Suitable crosslinking agents for this purpose are free radical type crosslinking agents such as benzoyl peroxide. Methods of preparation of other polyfunctional ketene acetals which are not described in the literature and are believed to be novel are described in the examples below. Examples of such ketene acetals and general methods of synthesis are as follows :
Figure imgf000014_0001
Figure imgf000015_0001
Figure imgf000015_0002
Figure imgf000016_0001
The condensation of a glycol with diethylbromoacetals is described by R. M. Roberts , J. Corse, R. Boschaw, D . Seymour and S . Winstein in J. Am. Chem. Soc. 80 , 1247-1254 (1958) and the dehydrohalogenation by F. Beyerstedt and S . M. McElvain in J. Am. Chem. Soc. 58, 529-53 (1936) . Isomerizatin of the double bond has been described by F. J. Corey and J. W. Suggs in J. Org. Chem. 38 , 3224 (1973) .
There is another, somewhat less satisfactory method which involves an imino ether hydrochloride intermediate.
Figure imgf000017_0001
The reaction of imino ether hydrochlorides with diols has been described by S. M. McElvain and C. C. Aldridge in J. Am. Chem. Soc. 75, 3993-3996 (1975). The dealcoholation has been described by S. M. McElvain and J. T. Venerable in J. Am. Chem. Soc. 72, 1661-1669 (1950).
The procedures thus described in the cited literature may be adapted to synthesize the diketene acetals set forth above and below.
The addition of monohydric alcohols to mono ketene acetals has been intensely studied and described in the literature by McElvain and co-workers, in J. Am. Chem. Soc. commencing in 1936, e.g. Beyerstedt and McElvain, J.A.C.S. 58, 529 (1936), McElvain and Weyna J.A.C.S. 81, 2579 (1979) and in many papers in the same Journal between those dates. Most of these studies involve the addition of a monohydric alcohol to a mono ketene acetal. Scheeren and Aben, Tetrahedron Letters 12, 1019-1020 (1974) describe the addition of several monohydric alcohols to diketene acetals; see above. No description of polymers of polyols and polyfunctional ketene acetals is known and such are believed to be broadly novel.
Exemplary polyols suitable as reactants include diols, triols and the like that can enter into the polymerization reaction without adversely effecting it or the polymeric products. The polyols are known to the art in reported synthesis and they are commercially available. Generally, they include α,ω-aliphatic diols, triols and the like of the straight or branched chain type. Representative polyols are alkane polyols having a terminal hydroxyl group at the terminus of an alkylene chain of the formula
Figure imgf000019_0001
Wherein R is an alkylene chain of 2 to 12 carbon atoms and y is 0 to 6. Typical diols, named as the glycols, include 1,5 pentylene glycols; 1,6-hexylene glycol; 1,7-heptylene glycol; 1,9-nonylene glycol; 2,3-dimethyl-1,6- hexylene glycol; 3,6-diethyl-1,9-nonylene glycol; 1,12-dodecamethylene glycol; and the like.
Polyols containing more than 2 reactive hydroxyl radicals suitable for use herein include polyhydroxyl compounds such as 1,2,3,4,5,6-hexanehexol; 1,2,3-propanetriol; 1,2,5-pentanetriol; 1,3,5-pentanetriol; 1,2,4-butanetriol; 2-methyl-1,2,3-propanetriol; 2-methyl-2(hydroxymethyl) 1,2-propanediol; 1,4,7-heptanetriol; 1,5,10-decanetriol; 1,5,12-dodecanetriol; and the like.
Other polyols suitable for synthesizing the polymers include polyglycols containing a repeating glycol monoether moiety—OCH2(CH2) OH wherein p is 1 to 5, and the polyglycols are diglycols, triglycols, tetraglycols, and the like. Typical polyglycols include diethylene glycol, triethylene glycol, tetraethylene glycol, bis(4-hydroxybutyl) ether, bis (3-hydroxypropyl) ether, and the like.
Additional polyols that can be used in accordance with the invention are polyhydroxyl compounds having 2 or more reactive hydroxyl groups such as pentaerythritol; dipentaerythritol; β-methylglycerol; 1,4-cyclohexane dicarbinol in the cis, transisomeric configuration or mixtures thereof; 2,2,4-4-tetramethyl cyclobutane 1,3-diol; adonitol; mannitol; 2,5-diρropyl-1,4-phenyldiproρanol;
1,3-cyclopropanol; 2-propenyl-1,4-cyclohexane dipropanol; trimethylol propane; sorbitol; penacol; 2-methyl-1,4-cyclohexane dicarbinol; 3-isdpropoxy-1,4-cyclohexane dipropanol; 2-ethenyl-1,3-cyclopentane dicarbinol; 1,4-phenyldicarbinol; 2-propyl-1,4-phenyldiethanol; 3-butoxy-1,-4,-phenyldibutanol; and the like. The preparation of the above polyols is known to the art in Acta Pharm. Jugaslav. Vol. 2 pages 134 to 139, 1952; Ann. Vol. 594, pages 76 to 88, 1955; J. Am. Chem. Soc. Vol. 71, pages 3618 to 3621, 1949; ibid., Vol. 74, pages 2674 to 2675, 1952; Chem. Abst., Vol. 42, pages 8774 to 8775, 1948; ibid., Vol. 43 pages 571 to 573 and 6652, 1949; ibid; Vol. 44, pages 2554 and 7231, 1950; ibid., Vol. 46, page 9585, 1952; ibid., Vol. 47, page 7575, 1953; ibid., Vol. 48, page 106, 1954, ibid., Vol. 49, pages 6098 to 6099, 1955; Encyclopedia of Chemical Technology, Kirk-Othmer, Vol. 10, pages 638 to 678, 1966, published by Interscience Publishers, New York.
Also, phenolic polyols (two or more phenolic hydroxyl groups) and mixed phenolic-alcoholic polyols may be employed. Also mixtures of two or more polyols may be employed. Examples of polyols and of mixed phenolic-alcoholic polyols are as follows : 4,4'-isopropylidenediphenol (bisphenol A);
4-hydroxybenzylalcohol;
4-hydroxy-3-methoxybenzylalcohol; p-hydroxyphenethylalcolhol;
4,4'-dihydroxydiphenyl;
4,4'-dihydroxydiphenylmethane;
2,4-dihydroxybenzaldehyde; catechol; resorcinol; hydroquinone;
2,2'-dihydroxybenzophenone;
2 ,4-dihydroxybenzophenone; and
3,4-dihydroxymethylc lamate; also non-phenolic polyols having aromatic linking groups between the hydroxyl groups, e.g. 1,4-dihydroxymethylbenzene.
Furthermore, tri- (and higher) hydric phenols may be used such as pyrogallol; hydroxyhydroquinone; phloruglucinol; and propyl gallate.
The following specific examples will serve further to illustrate the practice of the invention. Table I immediately following identifies the ketene acetals of the Examples (Compounds I through XII) and it also identifies ketene acetals of a sub-group of Type I which may be used.
Figure imgf000022_0001
Figure imgf000023_0001
Figure imgf000023_0002
Figure imgf000023_0003
Figure imgf000023_0004
Figure imgf000023_0005
Compounds XI and XII and methods of preparation are as follows:
Figure imgf000024_0001
Figure imgf000025_0001
Example 1
10.00 grams (0.0543 moles) of Compound I and 6.40 grams (0.0543 moles) of 1,6-hexanediol were weighed into a 200 ml 3-necked, paddle stirred flask under rigorously anhydrous conditions. The anhydrous conditions were maintained while 50 ml of dried tetrahydrofuran was added to the flask and the stirrer activated. After a very brief induction period, the reaction mixture spontaneously warmed up to 43°C and then gradually returned to room temperature. After stirring at room temperature for about one hour the high molecular weight poly (ortho ester) was isolated by either precipitation into n-hexane which contained a small amount of triethylamine followed by filtration of the white solid, or by evaporation of the tetrahydrofuran in a Teflon coated pan placed in a vacuum chamber.
The polymer had the following structure
Figure imgf000026_0001
The infrared spectrum is shown in Figure 1 and the C13 NMR spectrum in Figure 2. The weight average molecular weight obtained by light scattering was 166,000 and the poly dispersity obtained from gel permeation chromatography 1.52. The degree of polymerization, n, was 335. Example 2-5
Following the procedure of Example 1, but replacing 1,6-hexanediol with: trans-1,4-cyclohexane dicarbinol; 1,2-propanediol; ethylene glycol; 2-methyl - 1,3-propanediol, the following polymers are formed:
Figure imgf000027_0001
Example 6
Using the same conditions as in Example 1, 15.00 grams (0.0781 moles) of compound II and 9.22 grams (0.0781 moles) of 1.6-hexanediol are dissolved in 90 ml of tetrahydrofuran and 3 ml of a solution containing 1 x 10-6 moles of iodine per ml of pyridine are added. There is an immediate temperature rise to 52°C after which it gradually returns to room temperature. After stirring at room temperature for about one hour, the polymer is isolated as described in Example 1, and has the following structure where n is 10 to 1000.
Figure imgf000028_0001
Example 7
Using the same conditions as in Example 1, 42.00 grams (0.1567 moles) of Compound V and 14.10 grams (0.1567 moles) of 1,4-butanediol are dissolved in 200 ml of 1,2-dimethoxyethane and 1 ml of solution containing 1 x 10-4 mole of p-toluenesulfunic acid monohydrate per ml of tetrahydrofuran is added. After the slight temperature rise subsides, the mixture is stirred at room temperature for about one hour and the polymer is isolated as described in Example 1. The polymer has the following structure where is 196,000 and the is 1.48.
Figure imgf000029_0003
The polymer has the following structure:
Figure imgf000029_0001
Example 8
Repeating the procedure of Example 7, but replacing Compound V and 1,4-butanediol with 40.00 grams (0.1667 mole) of Compound VI and 19.67 grams (0.1667 mole) of 1,6-hexanediol, the following polymer is obtained:
Figure imgf000029_0002
Example 9
Repeating the procedure of Example 6 , but replacing Compound II and 1, 6-hexanediol with 12.00 grams (0.0652 moles) of Compound I and 7.43 grams (0.0652 moles) of trans-1,4-cyclohexanediol, the following polymer is obtained:
Figure imgf000030_0001
Example 10
Repeating the procedure of Example 6 , but replacing Compound II and 1, 6-hexanediol with 35.00 grams (0.1768 moles) of Compound III and 25.11 grams (0.1768 moles) of trans-1, 4-cyclohexanedicarbinol, the following polymer is obtained:
Figure imgf000030_0002
Example 11
Repeating the procedure of Example 6 , but replacing Compound II and 1, 6-hexanediol with 25.00 grams (0.1437 moles) of Compound VII and 20.41 grams (0.1437 moles) of trans-1,4-cyclohexanedicarbinol, the following polymer is obtained:
Figure imgf000031_0001
Example 12
Repeating the procedure of Example 6, but replacing Compound II and 1, 6-hexanediol with 30.00 grams (0.0673 moles) of Compound VIII and 6.06 grams (0.0673 moles) of 1,4-butanediol, the following polymer is obtained:
Figure imgf000031_0002
Example 13
Repeating the procedure of Example 6, but replacing Compound II with 28.00 grams (0.1228 moles) of Compound IX and using 14.40 grams (0.1228 moles) of 1, 6-hexanediol, the following polymer is obtained:
Figure imgf000032_0001
Example 14
Repeating the procedure of Example 7, but replacing Compound V and 1, 4-butanediol with 30.00 grams (0.1220 moles) of Compound X and 9.27 grams (0.1220 moles) of 1,2-propanediol, the following polymer is obtained:
Figure imgf000032_0002
Example 15
Repeating the procedure of Example 1 but employing a mixture (0.02715 moles each) of 1 , 6-hexanediol and trans-1, 4-cyclohexane dicarbinol, the following polymer is obtained:
Figure imgf000033_0001
The two diol residues are randomly located in the chain and are shown as alternating merely for convenience.
Example 16
Repeating the procedure of Example 6, but replacing Compound II and 1,6-hexanediol with a mixture of 7.00 grams (0.0380 moles) of Compound I and 7.30 grams (0.0380 moles) of Compound II and 4.71 grams (0.0760 moles) of ethylene glycol, the following polymer is obtained:
Figure imgf000033_0002
Similarly the groups derived, from the two diketene acetals are randomly located.
Example 17
Repeating the procedure of Example 6, but replacing Compound II and 1,6-hexanediol with 25.00 grams (0.1359 moles) of Compound I and 30.98 grams (0.1359 moles) of bisphenol-A, the following polymer is obtained.
Figure imgf000034_0001
Example 18
The procedure of Example 7 is repeated except that no solvent is used and instead the reaction mixture is heated to 70°C in order to achieve a homogeneous solution. Compound V and 1,4-butanediol used in Example 7 are replaced with 33.06 grams (0.1333 moles) of Compound IV and a mixture of 9.60 grams (0.1000 moles) grams 1,4-butanediol and 5.39 grams (0.0333 moles) of 1,2,6-hexanetriol. The following crosslinked polymer is obtained:
Figure imgf000035_0001
Figure imgf000035_0002
As in the case of Examples 15 and 16, the residues of the diol and the triol are randomly located. The joint use of a diol and a triol enables one to control the density of crosslinking.
Example 19
The procedure of Example 6 is repeated except that no solvent is used and instead the reaction mixture is heated to 65°C in order to achieve a homogeneous solution. Compound II are 1,6-hexanediol used in Example 6 are replaced with 25.00 grams (0.1263 moles) of Compound III and 16.92 grams (0.1263 moles) of trimethylolpropane. The following crosslinked polymer is obtained:
Figure imgf000036_0001
In Examples 18 and 19 the pendant valence bonds indicate crosslinking to similar chains.
Example 20
The procedure of Example 6 is repeated except that no solvent is used and instead the mixture is heated to 60°C in order to achieve a homogeneous solution. Compound II and 1, 6-hexanediol are replaced with 10.00 grams (0.0794 moles) of Compound XI and 7.38 grams (0.1191 moles) of ethylene glycol. The following polymer is obtained:
Figure imgf000037_0001
Example 21
The procedure of Example 6 is repeated except that no solvent is used and instead the mixture is heated to 85ºC in order to achieve homogeneous solution. Compound II and 1,6-hexanediol are replaced with 15.00 grams (0.0490 moles) of Compound XII and 6.62 grams (0.0731 moles) of 1,4- butanediol. The following polymer is obtained:
Figure imgf000038_0001
The following example is illustrative of the use of the polymers of this invention as carriers or matrices for a drug.
Example 22
Delivery devices were prepared by putting 7.2 grams of the polymer of Example 1 on a Teflon coated pan heated to a surface temperature of about 150°C to provide a melt consistency permitting mixing to produce a thorough dispersion of 0.8 grams of micronized Na2CO3 and 2.0 grams of micronized norethindrone into the polymer melt. Sheets of the polymer mixture 20 mil and 40 mil in thickness 3" x 3" square were pressed at 135°C (275°F), and 10,000 psi between sheets of Teflon covered foil using the appropriate thickness mold spacers. 1/4" discs were punched from these sheets. These discs are suitable as implants.
Alternatively, the drug may be incorporated in the mixture of monomers before polymerization. In the case of crosslinked polymers such as those of Examples 18 to 21 this will be done because the polymers are infusible and insoluble in solvents.
The same procedure may be employed with any of the polymers of the present invention such as those of Example 2 to 21.
Other drugs may be similarly incorporated in the polymers of the invention. Among others these drugs or beneifical agents may include any of those mentioned in Choi and Heller U.S. Patent 4,093,209 column 29, line 45 to column 30, line 37; also insecticides and other biologically active agents.
Examples 18 and 19 illustrate the use of polyols having a functionality greater than two and Examples 20 and 21 illustrate the use of ketene acetals having a functionality greater than two. As stated above, where crosslinking is desired , it is preferred to use tri- and higher functionality polyols because of their greater availability. Mixtures of polyols of different functionality, e.g. 2 and 3 and/or mixtures of ketene acetals of different functionality, e.g. 2 and 3 may be used. By using, for example, a mixture of diol and triol the density of crosslinking can be controlled by the ratio of diol to triol.
As noted above, a sub-group of Type I polymers are derived from ketene acetals of the formula:
Figure imgf000040_0001
That is, the group ® may contain no single radical as in Compound I to which all four of the interior acetal oxygen atoms are attached. Examples of such Type I ketene acetals and resulting polymers are as follows:
Figure imgf000041_0001
Figure imgf000042_0002
Figure imgf000042_0001
The corresponding polymers are as follows, in which R represents the polyol residue:
Figure imgf000042_0003
Figure imgf000042_0004
Figure imgf000043_0001
Figure imgf000043_0002
Figure imgf000043_0003
Figure imgf000043_0004
It will be understood that crosslinked polymers of Compounds XIII through XVII may be produced by using tri- and higher functionality polyols, and/or by using ketene acetals of tri- or higher functionality.
Among the advantages of my novel polymers are the following: Being prepared by a reaction between a ketene acetal and polyol, they do not require removal by heat and distillation of small molecules. Also, the reaction proceeds to a high degree of polymerization at low temperatures. Therefore, a drug, even one that is sensitive to elevated temperatures, can be incorporated in the mixture of monomers and will appear in the polymer without degradation. This is especially advantageous in the case of crosslinked polymers. These are infusible and insoluble, and therefore are not susceptible to incorporation of a drug after the polymerization process is complete, but this disadvantage is overcome by adding the drug to the mixture of monomers and carrying out the reaction, if need be, in a mold which molds the polymer with the drug incorporated to the desired shape and size as it is formed. Also, the polymer structure is pure and the finished product does not contain unreacted monomer.
It will be apparent from the specific examples that the reactions of ketene acetals with polyols are facile. They proceed at room temperature and being exothermic, they are allowed to rise in temperature as the reaction proceeds to completion. Suitable solvents are polar aprotic solvents, e.g. glyme, diglyme, dimethylacetamide, dimethyl, sulfoxide, dimethyl-formamide, acetonitrile, pyrrolidone, and methylbutyl ether. When crosslinking occurs, solvents are not used. Catalysts are not required but when used, suitable catalysts are iodine in pyridine, p-toluensulfonic acid; also Lewis acids such as boron trichloride, boron trifluoride, boron trichloride etherate, boron trifluoride etherate, stannic oxychloride, phosphorous oxychloride, zinc chloride, phosphorous pentachloride, antimony pentafluoride, stannous octoate, stannic chloride, diethylzinc, and mixtures thereof; also, Bronsted catalysts in addition to p-toluene sulfonic acid such as poly-phosphoric acid, crosslinked polystyrene sulfonic acid, acidic silica gel, and mixtures thereof. The amount of catalyst used may be about one part catalyst to about 500 parts of the ketene acetal monomer. Smaller or larger amounts can also be used, such as 0.005% to about 2.0% based on the weight of the starting monomer.
Referring to the Type I and Type II polymers, there are various organic groups such as those in the R-O- groups, those forming parts of pendant groups such as
Figure imgf000045_0001
those forming linking groups or parts of linking groups such as ® and
Figure imgf000045_0002
and the polyol residue R. Referring to these groups collectively as "R groups", the following observations are in order: In some instances, the "R groups" may be hydrogen. Where they are not hydrogen, they are essentially hydrocarbon groups as defined above; i.e., they do not exclude groups containing hetero atoms provided the presence of the hetero atom or atoms is not incompatible with the intended use and with bioerodibility, and do not give rise to toxic or non-metabolizable degradation products. An instance of such permissible groups containing hetero atoms is the case where R (the polyol residue) is derived from a polymer of an alkylene oxide (e.g. ethylene oxide, propylene oxide, butylene oxide, tetrahydrofuran and the like) in which case R has the formula
Figure imgf000046_0001
in which X is 1, 2 or 3, R is hydrogen or alkyl, and n is an integer equal to one or more. Another case is that of hydroxy terminated polyesters represented by the general formula
Figure imgf000046_0002
in which case R is represented by the formula
Figure imgf000046_0003
wherein a and b are positive integers. Examples of such polyesters are the glycolides and lactides. The "R groups" as defined above may be of low molecular weight, e.g. methyl, ethyl, -CH2-CH2- , etc., or they may be of high or intermediate molecular weight. Practical considerations will influence the choice of molecular weight. For example, "R groups" of high molecular weight which are pendant groups, or which form linking groups or parts of linking groups, or are parts of R-O- groups, or which are derived from high molecular weight polyols, may be available only from expensive starting materials, or may impart less desirable characteristics to the polymer.

Claims

CLAIMS WE CLAIM:
1. Polymers of polyols and ketene acetals having a functionality of two or more.
2. Polymers according to Claim 1 wherein the polyol and/or the ketene acetal has a functionality greater than two and the resulting polymer is crosslinked.
3. Polymers according to Claim 2 wherein at least some of the polyol reactant has a functionality greater than two.
4. Polymers according to Claim 3 wherein the polyol reactant is a mixture of a diol and a polyol having a functionality greater than two.
5. Polymers according to Claim 2 wherein the ketene acetal has a functionality greater than two.
6. Linear polymers according to Claim 1 wherein both the polyol and the ketene acetal have a functionality of two.
7. Polymers having the repeating mer unit :
Figure imgf000049_0001
wherein n is an integer substantially greater than 10; wherein R1 and R2 are hydrogen or the same or different essentially hydrocarbon groups and may be separate groups or may form parts of a cyclic group; ® is a quadrivalent organic grouping; R3 and R4 are hydrogen or the same or different essentially hydrocarbon groups and may be separate groups or may form parts of a cyclic group; R5 is an essentially hydrocarbon group which is the residue of a polyol R5(OH)a wherein a is an integer equal to two or more, such polyol being a single molecular species or a mixture of molecular species; and wherein such linear chain may be crosslinked with other similar chains.
8. Polymers according to Claim 7 wherein ® is a single quadrivalent radical attached to all of the interior acetal forming oxygen atoms.
9. Polymers according to Claim 8 wherein ® is a spiro structure.
10. Polymers according to Claim 8 wherein ® is an open chain aliphatic group.
11. Polymers according to Claim 8 wherein ® contains a carbocyclic group.
12. Polymers according to Claim 7 wherein R5 in at least some of the mer units is alkylene or contains a carbocyclic group.
13. Polymers according to Claim 7 wherein R5 in at least some of the mer units is derived from a polyol of greater functionality than three and the polymers are crosslinked.
14. Polymers according to Claim 13 wherein some of the R5's are derived from diols and others are derived from polyols of greater functionality.
15. Polymers having the repeating mer unit
Figure imgf000050_0001
wherein n is an integer substantially greater than 10; wherein R1, R2, R3 and R4 are the same or different essentially hydrocarbon groups, R1 and R2 being separate groups or parts of a cyclic group and R3 and R4 being separate groups or parts of a cyclic group; R5 is an essentially hydrocarbon group which is the residue of a polyol R5(OH)a wherein a is an integer equal to two or more, such polyol being a single molecular species or a mixture of molecular species; R6 is a valence bond or an essentially hydrocarbon group; R7 and R8 are hydrogen or essentially hydrocarbon groups which may be separate groups or may form parts of a cyclic group; and wherein such linear chains may be crosslinked to similar chains.
16. Polymers according to Claim 15 wherein the group
Figure imgf000051_0001
is selected from the class consisting of alkylene and groups containing a carbocyclic ring.
17. Polymers according to Claim 15 wherein R5 in at least some of the mer units is alkylene or contains a carbocyclic group.
18. Polymers according to Claim 15 wherein R5 in at least some of the mer units is derived from a polyol having a greater functionality than three and the polymers are crosslinked.
19. Polymers according to Claim 18 wherein some of the R5's are derived from diols and others are derived from polyols of greater functionality.
10. A method of producing poly (orther esters) which comprises polymerizing a mixture of a polyol and a ketene acetal having a functionality greater than one.
21. The method of Claim 20 wherein the polymerization is carried out at a temperature not greatly in excess of the temperature to which the reaction mixture rises by reason of the heat of reaction.
22. The method of Claim 20 wherein the reaction is carried out in the substantial absence of a solvent.
23. The method of Claim 20 wherein a beneficial agent is incorporated in the mixture of monomers before they are polymerized.
24. The method of Claim 23 wherein at least one of the monomers has a functionality greater than two and the resulting polymer is crosslinked.
25. Polymers of Claim 1 in admixture with beneficial agents.
26. Polymers of Claim 7 in admixture with beneficial agents.
27. Polymers of Claim 15 in admixture with beneficial agents.
28. Polymers of Claim 25 in shaped form fitted for end use.
29. Polymers of Claim 26 in shaped form fitted for end use.
30. Polymers of Claim 27 in shaped form fitted for end use.
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0524831A1 (en) * 1991-07-24 1993-01-27 Merck & Co. Inc. Process for the manufacture of bioerodible poly(ortho esters) and polyacetals
EP0537000A2 (en) * 1991-10-11 1993-04-14 Merck & Co. Inc. Poly(orthocarbonate acetal) bioerodible polymers

Families Citing this family (160)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4489056A (en) * 1982-06-30 1984-12-18 Merck & Co., Inc. Acid anhydrides as rate controlling agent for the erosion of polymers which latter polymers have beneficial substances dispersed throughout their matrix or where the polymer matrix surrounds the beneficial substance
US4513143A (en) * 1982-12-01 1985-04-23 Sri International Preparation of ketene acetals
US4532335A (en) * 1983-03-07 1985-07-30 Sri International Preparation of ketene acetals by rearrangement of allyl and substituted allyl acetals
US4639366A (en) * 1984-06-06 1987-01-27 Merck & Co., Inc. Polymers containing pendant acid functionalities and labile backbone bonds
US4549010A (en) * 1984-06-27 1985-10-22 Merck & Co., Inc. Bioerodible poly(ortho ester) thermoplastic elastomer from diketene diacetal
US4697575A (en) * 1984-11-21 1987-10-06 Henry Ford Hospital Delivery system for interstitial radiation therapy including substantially non-deflecting elongated member
US4754745A (en) * 1984-11-21 1988-07-05 Horowitz Bruce S Conformable sheet material for use in brachytherapy
US4780319A (en) * 1985-07-08 1988-10-25 Merck & Co., Inc. Organic acids as catalysts for the erosion of polymers
US4764364A (en) * 1986-02-25 1988-08-16 S R I International Method of preparing bioerodible polymers having pH sensitivity in the acid range and resulting product
US4855132A (en) * 1986-02-25 1989-08-08 S R I International Method of preparing bioerodible polymers having pH sensitivity in the acid range and resulting product
US4763642A (en) * 1986-04-07 1988-08-16 Horowitz Bruce S Intracavitational brachytherapy
DE3788301D1 (en) * 1986-05-15 1994-01-13 Hoechst Ag Biodegradable polymers for depot preparations with controlled release of active ingredients.
US4713441A (en) * 1986-08-01 1987-12-15 Sandoz Pharmaceuticals Corp. Polyacetal hydrogels formed from divinyl ethers and polyols
US4842868A (en) * 1986-09-26 1989-06-27 Helwing Robert F Covalently bonded active agents with carbonium ion base groups
DE3700128A1 (en) * 1987-01-03 1988-07-14 Hoechst Ag BIODEGRADABLE POLY- (HYDROXYALKYL) - AMINODICARBONIC ACID DERIVATIVES, METHOD FOR THE PRODUCTION AND USE THEREOF FOR DEPOT PREPARATIONS WITH CONTROLLED ACTIVE SUBSTANCE DELIVERY
US4913903A (en) * 1987-02-04 1990-04-03 Alza Corporation Post-surgical applications for bioerodible polymers
US4906714A (en) * 1988-08-02 1990-03-06 E. I. Du Pont De Nemours And Company Partially fluorinated polyesters from ketene acetals and fluorinated vinyl monomers
US4957986A (en) * 1988-08-02 1990-09-18 E. I. Du Pont De Nemours And Company Partially fluorinated polyesters from ketene acetals and fluorine monomers
US4957998A (en) * 1988-08-22 1990-09-18 Pharmaceutical Delivery Systems, Inc. Polymers containing acetal, carboxy-acetal, ortho ester and carboxyortho ester linkages
US5108755A (en) * 1989-04-27 1992-04-28 Sri International Biodegradable composites for internal medical use
US4946931A (en) * 1989-06-14 1990-08-07 Pharmaceutical Delivery Systems, Inc. Polymers containing carboxy-ortho ester and ortho ester linkages
US5013821A (en) * 1989-06-15 1991-05-07 Pharmaceutical Delivery Systems, Inc. Ortho and thio-ortho ester polymer
US5030457A (en) * 1989-08-28 1991-07-09 Pharmaceutical Delivery Systems, Inc. Bioerodible polymers useful for the controlled release of therapeutic agents
KR920702383A (en) * 1989-08-28 1992-09-03 원본미기재 Biocorrosive polymers useful for controlling the release of therapeutic agents
US5047464A (en) * 1989-09-20 1991-09-10 Merck & Co., Inc. Bioerodible thermoset elastomers
US5217712A (en) * 1989-09-20 1993-06-08 Merck & Co., Inc. Bioerodible thermoset elastomers
DE4002736A1 (en) * 1990-01-31 1991-08-01 Hoechst Ag Poly-amino-di:carboxylic acid co-anhydro-amino-di:carboxylic derivs. - bio:degradable polymeric peptide(s) for controlled release of pharmaceuticals
NZ239370A (en) * 1990-08-22 1994-04-27 Merck & Co Inc Bioerodible implantable controlled release dosage form comprising a poly(ortho ester) or a polyacetal with an active agent incorporated into the chain backbone
JPH04120376U (en) * 1991-04-16 1992-10-28 横河電機株式会社 Relay inspection circuit
US5461140A (en) * 1992-04-30 1995-10-24 Pharmaceutical Delivery Systems Bioerodible polymers for solid controlled release pharmaceutical compositions
ES2118408T3 (en) * 1993-05-03 1998-09-16 Loctite Corp LIQUID CRYSTALS SCATTERED IN POLYMERS OF TIOL AND ALKENE RICH IN ELECTRONS.
US5401885A (en) * 1993-06-01 1995-03-28 Huls America, Inc. Method of preparing ortho esters and 1.1-dialkoxycycloalkanes
US5442033A (en) * 1993-07-20 1995-08-15 Ethicon, Inc. Liquid copolymers of epsilon-caprolactone and lactide
ES2109136B1 (en) * 1994-04-22 1998-07-01 Vita Invest Sa BIODEGRADABLE CARBONED SKELETON POLYMERS OF RYE ACETALS AND ALCOHOLS, PROCEDURE FOR THEIR OBTAINING AND THE CORRESPONDING COMPOSITION AND USE.
US5811510A (en) * 1995-04-14 1998-09-22 General Hospital Corporation Biodegradable polyacetal polymers and methods for their formation and use
FI98136C (en) * 1995-09-27 1997-04-25 Biocon Oy A tissue-soluble material and process for its manufacture
US5968543A (en) * 1996-01-05 1999-10-19 Advanced Polymer Systems, Inc. Polymers with controlled physical state and bioerodibility
US5939453A (en) * 1998-06-04 1999-08-17 Advanced Polymer Systems, Inc. PEG-POE, PEG-POE-PEG, and POE-PEG-POE block copolymers
NZ509797A (en) * 1998-07-10 2003-11-28 Univ Sydney Prophylactic treatments of neovascularisation in macular degeneration using a steroid
AUPQ496500A0 (en) * 2000-01-06 2000-02-03 University Of Sydney, The Kit
US6613355B2 (en) 2000-05-11 2003-09-02 A.P. Pharma, Inc. Semi-solid delivery vehicle and pharmaceutical compositions
US20050042194A1 (en) 2000-05-11 2005-02-24 A.P. Pharma, Inc. Semi-solid delivery vehicle and pharmaceutical compositions
AU2001288829A1 (en) 2000-09-06 2002-03-22 Ap Pharma, Inc. Degradable polyacetal polymers
US6590059B2 (en) 2001-05-11 2003-07-08 Ap Pharma, Inc. Bioerodible polyorthoesters from dioxolane-based diketene acetals
EP1395626A1 (en) * 2001-05-11 2004-03-10 AP Pharma, Inc. Peg-poe, peg-poe-peg, and poe-peg-poe block copolymers
US6524606B1 (en) 2001-11-16 2003-02-25 Ap Pharma, Inc. Bioerodible polyorthoesters containing amine groups
US20040001889A1 (en) 2002-06-25 2004-01-01 Guohua Chen Short duration depot formulations
US20040062778A1 (en) * 2002-09-26 2004-04-01 Adi Shefer Surface dissolution and/or bulk erosion controlled release compositions and devices
US7354574B2 (en) * 2002-11-07 2008-04-08 Advanced Ocular Systems Limited Treatment of ocular disease
US6863782B2 (en) * 2002-11-15 2005-03-08 A.P. Pharma, Inc. Method of preparing di(ketene acetals)
US7045589B2 (en) * 2002-11-15 2006-05-16 A.P. Pharma, Inc. Bioerodible poly(ortho esters) from dioxane-based di(ketene acetals), and block copolymers containing them
KR20060002922A (en) * 2003-03-31 2006-01-09 알자 코포레이션 Non-aqueous single phase vehicles and formulations utilizing such vehicles
US7056591B1 (en) * 2003-07-30 2006-06-06 Advanced Cardiovascular Systems, Inc. Hydrophobic biologically absorbable coatings for drug delivery devices and methods for fabricating the same
US7083802B2 (en) * 2003-07-31 2006-08-01 Advanced Ocular Systems Limited Treatment of ocular disease
US20050181018A1 (en) * 2003-09-19 2005-08-18 Peyman Gholam A. Ocular drug delivery
US7083803B2 (en) * 2003-09-19 2006-08-01 Advanced Ocular Systems Limited Ocular solutions
US7087237B2 (en) * 2003-09-19 2006-08-08 Advanced Ocular Systems Limited Ocular solutions
US7329413B1 (en) 2003-11-06 2008-02-12 Advanced Cardiovascular Systems, Inc. Coatings for drug delivery devices having gradient of hydration and methods for fabricating thereof
US9114198B2 (en) 2003-11-19 2015-08-25 Advanced Cardiovascular Systems, Inc. Biologically beneficial coatings for implantable devices containing fluorinated polymers and methods for fabricating the same
US7220816B2 (en) 2003-12-16 2007-05-22 Advanced Cardiovascular Systems, Inc. Biologically absorbable coatings for implantable devices based on poly(ester amides) and methods for fabricating the same
US7435788B2 (en) 2003-12-19 2008-10-14 Advanced Cardiovascular Systems, Inc. Biobeneficial polyamide/polyethylene glycol polymers for use with drug eluting stents
WO2005074942A1 (en) * 2004-02-04 2005-08-18 Retmed Pty Ltd Slow release steroid composition
US20050192257A1 (en) * 2004-02-26 2005-09-01 Peyman Gholam A. Predictors for patients at risk for glaucoma from steroid therapy
CA2557216A1 (en) * 2004-02-26 2005-09-09 Advanced Ocular Systems Limited Heparin for the treatment of ocular pathologies
US8685431B2 (en) 2004-03-16 2014-04-01 Advanced Cardiovascular Systems, Inc. Biologically absorbable coatings for implantable devices based on copolymers having ester bonds and methods for fabricating the same
US8778014B1 (en) 2004-03-31 2014-07-15 Advanced Cardiovascular Systems, Inc. Coatings for preventing balloon damage to polymer coated stents
CA2562356A1 (en) * 2004-04-08 2005-10-27 Retmed Pty Ltd Treatment of ophthalmic conditions with mineralcorticoids
WO2005102303A2 (en) * 2004-04-21 2005-11-03 Advanced Ocular Systems Limited Antiprostaglandins for the treatment of ocular pathologies
US7820732B2 (en) 2004-04-30 2010-10-26 Advanced Cardiovascular Systems, Inc. Methods for modulating thermal and mechanical properties of coatings on implantable devices
US20050288481A1 (en) * 2004-04-30 2005-12-29 Desnoyer Jessica R Design of poly(ester amides) for the control of agent-release from polymeric compositions
US20050271700A1 (en) * 2004-06-03 2005-12-08 Desnoyer Jessica R Poly(ester amide) coating composition for implantable devices
US20050287184A1 (en) 2004-06-29 2005-12-29 Hossainy Syed F A Drug-delivery stent formulations for restenosis and vulnerable plaque
US7350479B2 (en) * 2004-09-10 2008-04-01 United States Of America As Represented By The Secretary Of The Army System and method for controlling growth of aquatic plants utilizing bio-eroding means implanted in triploid grass carp
US7166680B2 (en) 2004-10-06 2007-01-23 Advanced Cardiovascular Systems, Inc. Blends of poly(ester amide) polymers
US7390497B2 (en) 2004-10-29 2008-06-24 Advanced Cardiovascular Systems, Inc. Poly(ester amide) filler blends for modulation of coating properties
US8609123B2 (en) 2004-11-29 2013-12-17 Advanced Cardiovascular Systems, Inc. Derivatized poly(ester amide) as a biobeneficial coating
US20060122152A1 (en) * 2004-12-03 2006-06-08 Peyman Gholam A Heparin for the treatment of ocular pathologies
US7419504B2 (en) 2004-12-27 2008-09-02 Advanced Cardiovascular Systems, Inc. Poly(ester amide) block copolymers
US8007775B2 (en) 2004-12-30 2011-08-30 Advanced Cardiovascular Systems, Inc. Polymers containing poly(hydroxyalkanoates) and agents for use with medical articles and methods of fabricating the same
US7202325B2 (en) * 2005-01-14 2007-04-10 Advanced Cardiovascular Systems, Inc. Poly(hydroxyalkanoate-co-ester amides) and agents for use with medical articles
US20060235084A1 (en) * 2005-03-31 2006-10-19 Jorge Heller PEG-polyacetal diblock and triblock copolymers and pharmaceutical compositions
US7456213B2 (en) * 2005-03-31 2008-11-25 A.P. Pharma, Inc. PEG-poly(ortho ester) graft copolymers and pharmaceutical compositions
US20070014760A1 (en) 2005-07-18 2007-01-18 Peyman Gholam A Enhanced recovery following ocular surgery
WO2007011880A2 (en) 2005-07-18 2007-01-25 Minu, L.L.C. Enhanced ocular neuroprotection/neurostimulation
US20070020312A1 (en) * 2005-07-20 2007-01-25 Desnoyer Jessica R Method of fabricating a bioactive agent-releasing implantable medical device
US20070027105A1 (en) 2005-07-26 2007-02-01 Alza Corporation Peroxide removal from drug delivery vehicle
US8377462B2 (en) * 2005-07-29 2013-02-19 Advanced Cardiovascular Systems, Inc. PEA-TEMPO/PEA-BZ coatings for controlled delivery of drug from implantable medical devices
US20070066493A1 (en) * 2005-09-22 2007-03-22 Halliburton Energy Services, Inc. Orthoester-based surfactants and associated methods
US7713916B2 (en) 2005-09-22 2010-05-11 Halliburton Energy Services, Inc. Orthoester-based surfactants and associated methods
US7919637B2 (en) * 2005-10-11 2011-04-05 Fujifilm Corporation Fluorine-containing spiroacetal compound and method of producing the same
CA2629300C (en) 2005-11-17 2014-07-08 Zogenix, Inc. Delivery of viscous formulations by needle-free injection
US7910152B2 (en) 2006-02-28 2011-03-22 Advanced Cardiovascular Systems, Inc. Poly(ester amide)-based drug delivery systems with controlled release rate and morphology
EP2374472B9 (en) 2006-03-16 2019-06-12 Dyax Corp. Compositions and methods for treating ophthalmic disorders
US20070264338A1 (en) * 2006-05-12 2007-11-15 Shah Devang T Base-stabilized polyorthoester formulations
US20070264339A1 (en) * 2006-05-12 2007-11-15 Ap Pharma, Inc. Base-stabilized polyorthoester formulations
US20070265329A1 (en) * 2006-05-12 2007-11-15 Devang Shah T Methods for the prevention of acute and delayed chemotherapy-induced nausea and vomiting (CINV)
US20070281870A1 (en) * 2006-06-02 2007-12-06 Halliburton Energy Services, Inc. Stimuli-degradable gels
US7306040B1 (en) * 2006-06-02 2007-12-11 Halliburton Energy Services, Inc. Stimuli-degradable gels
US8323676B2 (en) * 2008-06-30 2012-12-04 Abbott Cardiovascular Systems Inc. Poly(ester-amide) and poly(amide) coatings for implantable medical devices for controlled release of a protein or peptide and a hydrophobic drug
US20090258028A1 (en) * 2006-06-05 2009-10-15 Abbott Cardiovascular Systems Inc. Methods Of Forming Coatings For Implantable Medical Devices For Controlled Release Of A Peptide And A Hydrophobic Drug
US7458953B2 (en) * 2006-06-20 2008-12-02 Gholam A. Peyman Ocular drainage device
EP2044142A2 (en) * 2006-06-29 2009-04-08 Medtronic, Inc. Poly(orthoester) polymers, and methods of making and using same
US7771739B2 (en) * 2006-06-30 2010-08-10 Abbott Cardiovascular Systems Inc. Implantable medical devices comprising semi-crystalline poly(ester-amide)
US9028859B2 (en) 2006-07-07 2015-05-12 Advanced Cardiovascular Systems, Inc. Phase-separated block copolymer coatings for implantable medical devices
SI2046382T1 (en) * 2006-07-10 2016-12-30 ESBATech an Alcon Biomedical Research Unit LLC scFv ANTIBODIES WHICH PASS EPITHELIAL AND/OR ENDOTHELIAL LAYERS
US8030436B2 (en) * 2006-07-13 2011-10-04 Advanced Cardiovascular Systems, Inc. Poly(ester-amide) elastomers and their use with implantable medical devices
US7731987B2 (en) * 2006-07-13 2010-06-08 Advanced Cardiovascular Systems, Inc. Implantable medical device comprising a pro-healing poly(ester-amide)
US20090181063A1 (en) * 2006-07-13 2009-07-16 Michael Huy Ngo Implantable medical device comprising a pro-healing poly(ester-amide)
US20080014245A1 (en) * 2006-07-14 2008-01-17 Stephen Pacetti Drug-eluting implantable medical device with free radical scavenger for protecting drugs during sterilization and related method
US8268347B1 (en) 2006-10-24 2012-09-18 Aradigm Corporation Dual action, inhaled formulations providing both an immediate and sustained release profile
KR20090082447A (en) 2006-11-09 2009-07-30 알콘 리서치, 리미티드 Water insoluble polymer matrix for drug delivery
US20080114076A1 (en) * 2006-11-09 2008-05-15 Alcon Manufacturing Ltd. Punctal plug comprising a water-insoluble polymeric matrix
US20080175882A1 (en) * 2007-01-23 2008-07-24 Trollsas Mikael O Polymers of aliphatic thioester
US20080306584A1 (en) * 2007-06-05 2008-12-11 Pamela Kramer-Brown Implantable medical devices for local and regional treatment
US8252361B2 (en) * 2007-06-05 2012-08-28 Abbott Cardiovascular Systems Inc. Implantable medical devices for local and regional treatment
US9737638B2 (en) * 2007-06-20 2017-08-22 Abbott Cardiovascular Systems, Inc. Polyester amide copolymers having free carboxylic acid pendant groups
US7927621B2 (en) * 2007-06-25 2011-04-19 Abbott Cardiovascular Systems Inc. Thioester-ester-amide copolymers
US8956642B2 (en) 2008-04-18 2015-02-17 Medtronic, Inc. Bupivacaine formulation in a polyorthoester carrier
US8475823B2 (en) 2008-04-18 2013-07-02 Medtronic, Inc. Baclofen formulation in a polyorthoester carrier
ES2563061T3 (en) 2008-04-28 2016-03-10 Zogenix, Inc. New formulations for the treatment of migraine
US8889172B1 (en) 2008-04-30 2014-11-18 Abbott Cardiovascular Systems Inc. Amorphous or semi-crystalline poly(ester amide) polymer with a high glass transition temperature
EP2303393A4 (en) * 2008-05-07 2011-10-19 Obj Ltd Method and apparatus for enhanced transdermal diffusion
US8765162B2 (en) 2008-06-30 2014-07-01 Abbott Cardiovascular Systems Inc. Poly(amide) and poly(ester-amide) polymers and drug delivery particles and coatings containing same
EP2326304A2 (en) 2008-07-17 2011-06-01 Merial Limited Methods for enhancing the stability of polyorthoesters and their formulations
US20100047319A1 (en) * 2008-08-21 2010-02-25 Michael Huy Ngo Biodegradable Poly(Ester-Amide) And Poly(Amide) Coatings For Implantable Medical Devices With Enhanced Bioabsorption Times
EP2370064A4 (en) * 2008-12-11 2012-09-19 A P Pharma Inc Methods for enhancing stability of polyorthoesters and their formulations
US20120207770A1 (en) 2009-10-14 2012-08-16 Nanyang Technological University Antiproliferative agent
EP2343046A1 (en) 2010-01-08 2011-07-13 Nirvana's Tree House B.V. Functionalised triblock copolymers and compositions containing such polymers
US9452037B2 (en) 2010-05-25 2016-09-27 International Scientific Pty Ltd Delivery of oral care products
US9463330B2 (en) 2010-06-17 2016-10-11 International Scientific Pty Ltd Delivery of skin care products
AU2012220537A1 (en) 2011-02-23 2013-08-29 Ams Research Corporation Pelvic implant and therapeutic agent system and method
AU2012220564A1 (en) 2011-02-23 2013-08-29 Ams Research Corporation Drug releasing pelvic treatment system and method
JP6267649B2 (en) 2011-11-18 2018-01-24 リジェネロン・ファーマシューティカルズ・インコーポレイテッド Polymer protein fine particles
US10220093B2 (en) 2013-02-28 2019-03-05 Mira Pharma Corporation Long-acting semi-solid lipid formulations
US9849180B2 (en) 2014-09-15 2017-12-26 Hui Rong Shen Long-acting semi-solid lipid formulations
MX352907B (en) 2013-03-15 2017-12-13 Heron Therapeutics Inc Compositions of a polyorthoester and an aprotic solvent.
EP3509601A1 (en) 2014-04-21 2019-07-17 Heron Therapeutics, Inc. A pharmaceutical composition comprising a delivery system, an amide-type local anesthetic, and meloxicam
RS61202B1 (en) 2014-04-21 2021-01-29 Heron Therapeutics Inc Compositions of a polyorthoester and an organic acid excipient
US9801945B2 (en) 2014-04-21 2017-10-31 Heron Therapeutics, Inc. Long-acting polymeric delivery systems
EP3134068B1 (en) 2014-04-21 2021-07-21 Heron Therapeutics, Inc. Long-acting polymeric delivery systems
EP3154552B1 (en) 2014-06-11 2021-03-24 International Scientific Pty Ltd Device and method to treat or prevent joint degeneration
CA3002916A1 (en) 2015-10-23 2017-04-27 Lyndra, Inc. Gastric residence systems for sustained release of therapeutic agents and methods of use thereof
SG11201804384UA (en) 2015-12-08 2018-06-28 Lyndra Inc Geometric configurations for gastric residence systems
SG11201803197UA (en) 2015-12-16 2018-05-30 Regeneron Pharma Compositions and methods of manufacturing protein microparticles
JP2019532947A (en) 2016-09-30 2019-11-14 リンドラ，インコーポレイティド Gastric retention system for sustained delivery of adamantane drugs
CA3059449A1 (en) 2017-04-24 2018-11-01 Cocrystal Pharma, Inc. Pyrrolopyrimidine derivatives useful as inhibitors of influenza virus replication
US11890395B2 (en) 2017-06-16 2024-02-06 Avery Therapeutics, Inc. Three dimensional tissue compositions and methods of use
EP3684321A4 (en) 2017-09-20 2021-10-06 Lyndra Therapeutics, Inc. Encapsulation of gastric residence systems
US10561606B2 (en) 2017-12-06 2020-02-18 Mira Pharma Corporation Injectable long-acting local anesthetic semi-solid gel formulations
US11426418B2 (en) 2017-12-06 2022-08-30 Mira Pharma Corporation Injectable long-acting semi-solid gel formulations
EP3829719A1 (en) 2018-07-27 2021-06-09 Cocrystal Pharma, Inc. Pyrrolo[2,3-b]pyridin derivatives as inhibitors of influenza virus replication
EP3849978B1 (en) 2018-09-10 2022-11-02 Cocrystal Pharma, Inc. Pyridopyrazine and pyridotriazine inhibitors of influenza virus replication
AU2019361038A1 (en) 2018-10-17 2021-05-13 Cocrystal Pharma, Inc. Combinations of inhibitors of influenza virus replication
US20220048897A1 (en) 2018-11-26 2022-02-17 Cocrystal Pharma, Inc. Inhibitors of influenza virus replication
MX2022006236A (en) 2019-11-25 2022-06-22 Regeneron Pharma Sustained release formulations using non-aqueous emulsions.
CA3167217A1 (en) 2020-01-13 2021-07-22 Durect Corporation Sustained release drug delivery systems with reduced impurities and related methods
US20230151034A1 (en) 2020-03-17 2023-05-18 Cocrystal Pharma, Inc. Peptidomimetic n5-methyl-n2-(nonanoyl-l-leucyl)-l-glutaminate derivatives, triazaspiro[4.14]nonadecane derivatives and similar compounds as inhibitors of norovirus and coronavirus replication
IL297069A (en) 2020-04-10 2022-12-01 Cocrystal Pharma Inc Inhibitors of norovirus and coronavirus replication
EP4251128A1 (en) 2020-11-25 2023-10-04 Regeneron Pharmaceuticals, Inc. Sustained release formulations using non-aqueous membrane emulsification
WO2023014758A1 (en) 2021-08-03 2023-02-09 Cocrystal Pharma, Inc. Inhibitors for coronaviruses

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2687407A (en) * 1951-07-18 1954-08-24 Dynamit Nobel Ag Production of resins from diallylidene pentaerythritol and a polyhydroxy alcohol
US2909506A (en) * 1956-07-10 1959-10-20 Union Carbide Corp Modified acrolein-pentaerythritol resins
US2957856A (en) * 1958-08-29 1960-10-25 Union Carbide Corp Phosphorus-containing spirobi(metadioxane) resins
US3087918A (en) * 1957-08-01 1963-04-30 Union Carbide Corp Modified acrolein-pentaerythritol resins
US4136252A (en) * 1976-04-08 1979-01-23 Alza Corporation Polymeric orthoesters having arylene arrangement
US4180646A (en) * 1975-01-28 1979-12-25 Alza Corporation Novel orthoester polymers and orthocarbonate polymers

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4069307A (en) * 1970-10-01 1978-01-17 Alza Corporation Drug-delivery device comprising certain polymeric materials for controlled release of drug
US4093709A (en) * 1975-01-28 1978-06-06 Alza Corporation Drug delivery devices manufactured from poly(orthoesters) and poly(orthocarbonates)

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2687407A (en) * 1951-07-18 1954-08-24 Dynamit Nobel Ag Production of resins from diallylidene pentaerythritol and a polyhydroxy alcohol
US2909506A (en) * 1956-07-10 1959-10-20 Union Carbide Corp Modified acrolein-pentaerythritol resins
US3087918A (en) * 1957-08-01 1963-04-30 Union Carbide Corp Modified acrolein-pentaerythritol resins
US2957856A (en) * 1958-08-29 1960-10-25 Union Carbide Corp Phosphorus-containing spirobi(metadioxane) resins
US4180646A (en) * 1975-01-28 1979-12-25 Alza Corporation Novel orthoester polymers and orthocarbonate polymers
US4136252A (en) * 1976-04-08 1979-01-23 Alza Corporation Polymeric orthoesters having arylene arrangement

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0524831A1 (en) * 1991-07-24 1993-01-27 Merck & Co. Inc. Process for the manufacture of bioerodible poly(ortho esters) and polyacetals
WO1993001799A1 (en) * 1991-07-24 1993-02-04 Merck & Co., Inc. Process for the manufacture of bioerodible poly(orthoester)s and polyacetals
EP0537000A2 (en) * 1991-10-11 1993-04-14 Merck & Co. Inc. Poly(orthocarbonate acetal) bioerodible polymers
EP0537000A3 (en) * 1991-10-11 1993-08-04 Merck & Co. Inc. Poly(orthocarbonate acetal) bioerodible polymers

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