CS196258B2 - Process for preparing asymmetric substituted 1,4-dioxan-2,5-diones - Google Patents

Abstract

The 1,4-dioxane-2,5-diones conform to the formula <IMAGE> in which R1, R2, R3 and R4 are as defined in Claim 1. They are prepared by a1) reacting an alpha -halo-, alpha -(lower alkanoyl)oxy- or alpha -(lower alkyl)sulphonyloxyacetic acid which is appropriately substituted by R1 and R2 with an alpha -hydroxyacetic acid which is appropriately substituted by R3 and R4 in the presence of a strongly acidic catalyst, or a2) reacting monochloroacetic acid with L-lactide or poly-(D,L-lactic acid) in the presence of antimony trioxide, titanium dioxide or tetraisopropyl titanate, b) rendering the resultant product alkaline, and c) cyclising the product. The homopolymers and copolymers of the 1,4-dioxane-2,5-diones of the formula I are compatible with living human and mammal tissue, can be used surgically and are biodegradable to give tissue-compatible components which are absorbed by living tissues. At least 2% by weight of the 1,4-dioxane-2,5-diones are copolymerised with compounds of the formula <IMAGE> in which R5, R6, R7 and R8 are as defined in Claim 6, by heating in the presence of a catalyst, giving polymers which contain at least 2% by weight of copolymerised compounds of the formula I. The polymers can be used for the production of shaped surgical aids which can be absorbed by living tissue.

Description

(54) Method. the preparation of unsymmetrically substituted 1,4-dioxane-2,5-diones

The present invention relates to a process for the preparation of unsymmetrically substituted 1,4-dioxane-2,5-dione.

The compounds of the present invention are useful for the preparation of polymers, either homopolymers of unsymmetrically substituted 1,4-dioxane-2,5-diones or copolymers, which polymers are compatible with living mammalian tissues, especially human tissues, and these materials may be used for surgical purposes and are biodegradable to components compatible with tissues that are absorbable by living tissues. It will be noted below that the primary degradation of the polymer is hydrolytic cleavage into products that can be removed by living tissues and these products are degradable to excretionable components or are excretable as such.

Because of the surgical requirements of seams, absorbable fabrics, gauze, bone clamps and the like whose absorption and strength characteristics are different, it is desirable that the strength and absorbability spectrum meet the surgical requirements for different procedures. .

Hydroxyootic acid has the trivial name of glycolic acid.

acid or .alpha.-hydroxypropanoic acid has a trivial name. · 2 lactic acid. Lactic acid has the formula CH 3 CHOHCOOH and has an asymmetric carbon atom and therefore exists in two different optically active forms, commonly known D- (-) -lactic acid, and L- (+) -lactic acid. If not j ^! otherwise noted or not contemplated, the term lactic acid as used herein refers to an equimolar or racemic mixture.

Lactide is defined as the product of internal cyclic esterification of two -? - hydroxyalkanoic acid molecules. If the α-hydroxyalkanoic acid is lactic acid, it is the product. alone / lactide,. which gives the name to a whole series of compounds. Generally, the reaction can be illustrated.

wherein R 1 and R 2 are each independently hydrogen or alkyl. .

From the type of reaction, these laphides are symmetrical, tor is, they have two identical R 1 groups and two identical R 2 groups on a six-member

6 25 8 circle. Compounds where R 2 is hydrogen are more common.

These compounds, which can be named by a systematic nomenclature, for example as lactic acid lactide, with R 1 methyl and R 2 hydrogen atom, are correctly named and numbered as 3,6-dimethyl-1,4-dioxane-2,5- dion.

In the present invention, the substitution is not symmetrical and therefore the products are not correctly classified as lactides but named as ^; 3-, or 3,6-substituted 1,4-dioxane-2,5-diones. . .

The simplest and possible basis of the group is 3-methyl-1,4-dioxane-2,5-dione, which is given the trivial name monomethylglycolide. Another name is 3-methyl-2,5-diketo-1,4-dioxane. This compound has a portion of the property of a glycolide and a portion of a lactide, but gives controlled and controlled polymers that are empirically similar to a glycolide-lactide copolymer but have a controlled structure with unique and desirable properties.

When the glycolide is homopolymerized, the product is called homopolymaric poly (hydroxyacetic acid) or poly (glycolic acid) or polyglycolide. The individual units of the polymer chain are oxyacetyl residues

O

II. .

Which may be called glycolic acid residues or glycolic acid units or glycolic acid bonds, although water is eliminated during polymerization and polyester is formed. Preferably, the term glycolic acid unit is commonly used herein. '' '

Similarly, if the lactide is homopolymerized, the product is called homopolymeric poly (lactic acid) or poly (α-hydroxypropionic acid) or polylactide. The individual units in the polymer chain are

2-hydroxypropionol residues

CH 3 O II —O — CH — C—.

These may be called lactic acid residues, lactic acid units or lactic acid bonds.

Preferably, the term lactic acid unit is used herein. The steric configuration, if any, is indicated and does not follow. The steric configuration of the product is typically the same as the starting material. If additional regularity from one antipode is desired, the appropriate starting material is selected.

In chain polymerization, three consecutive glycolic acid units have the abbreviation G-G-G and the three consecutive lactic acid units have the abbreviation L-L. · Regularly alternating polymer of glycolic acid units and lactic acid units · abbreviated as —G — L — G— —L — G — L. The other order is similarly represented in capital letters. Hexaflucracetone sesquihydrate has the abbreviation HFAS; hexailuorisopropanol has the abbreviation HIPA; polyglycolic acid) is truncated by PGA and 3-methyl-1,4-dioxane-2,5-dione truncated by MDD.

For comparison, the name O-choracetyl-L-lactic acid is used with the designation DL- or L or <D, where appropriate for the formula:

ClCH 2 C-O-CH-C-OH

II I II

O CH5 o

Other common names include L-2- (chloroacetoxy) -propionic acid and L-a- (chloroacetoxy) -propionic acid.

When copolymerizing two monomers, the relative reactivity ratio varies depending on the catalyst used and the reaction conditions, and one of the monomers tends to polymerize much faster than the other.

For example, an equimolar mixture of glycolide and lactide polymerizes so that the glycolide tends to bind to the growing chain much more easily and provides so-long long sequences of glycolic acid units with occasional lactic acid sequences and how they change concentration of unreacted components, the ratio of lactide to glycolide increases, and the resulting polymer may then contain almost the same number of glycolic acid units and lactic acid units. If the polymerization is stopped before completion, a disproportionately larger amount of unreacted lactide remains in the reaction vessel. The occurrence of pairs of glycolic acid units and pairs of lactic acid units is basically irregular and the predominance of the glycolic acid units predominates in the first part of the chains formed, and the increasing ratio of lactic acid units is in those parts of the chain that are formed last. ^r

If the 'polymerization' proceeds to the end, the last part of the resulting chains is predominantly a pair of lactic acid units due to the minimum amount of glycolide remaining to bind to the chain.

Under normal polymerization conditions, the irregular arrangement prevails and, since the product tends to be of an amorphous nature rather than a crystalline nature. For the formation of the crystalline polymer, it is necessary that the longer part of the chain be spherically regular. For example, a regular brick wall is easily constructed from regular brick having a size of 5.08 X 10.16 'X 20.32 cm including mortar. On the other hand, irregular stones or multiple sizes do not create a regular structure so easily. Analogously, if polymer molecules grow with irregular sequences, the crystallinity of the product decreases compared to polymers with exactly regular group sizes.

The unsymmetrically substituted 1,4-dloxane-2,5-diones prepared according to the present invention provide two different units of α-hydroxyalkanoic acid precursors during polymerization, but which are very regular.

The unsymmetrically substituted dioxanedione, 3-methyl-1,4-dioxane-2,5-dione, the lactic acid unit and the glycolic acid unit are in fact cyclic and in polymerization this ring is opened and attached to the polymer chain and thus the unit lactic acid and glycolic acid are attached to the polymer chain. .

Although the ring opening and attachment is strictly uniform, the end product has regularly alternating lactic acid units and glycolic acid units. If the polymerization is irregular because of the unity. The glycolic acid is attached to each lactic acid unit, no more than two glycolic acid units or two lactic acid units are linked in the resulting chain.

Since the hydrolytic cleavage of the polymer chain is more likely on the adjacent glycolic acid unit and also more likely between the two glycolic acid units, the minimum groups of lactic acid units allow faster hydrolytic cleavage and the polymers with adjacent glycolic acid units are tissue absorbable much faster than strictly alternating units. glycolic acid and lactic acid units.

Copolymerization of a certain amount of glycolide with 3-methyl-1,4-dioxane-2,5-dione increases the ease of hydrolytic cleavage.

When the polymerization of a mixture of glycolic acid and lactic acid is used to form a copolymer with the elimination of water, the sequence of units in the final copolymer is somewhat irregular, with the first resulting parts tending to contain multiple units of glycolic acid. Since the polymerization of these chains is not always identical, and due to difficulties in analysis, it is not easy to ascertain the exact sequence in the chain, but the general properties of the polymer are those of interest and found that the additional regularity it brings The use of unsymmetrically substituted 1,4-dioxan-2,5-dione leads to polymers that are both chemically and spherically uniform.

The unsymmetrically substituted 1,4-dioxane-2,5-diones of the present invention are of medical significance since their polymers, including homopolymers and copolymers with various lactides, including glycolide and lactide, are useful as surgical elements as will be described Furthermore, but additionally unsymmetrically substituted 1,4-dioxane-2,5-dlones are excellent weakly acidic agents. They can be used as such agents as baking powders or for controlling the pH in the boiler water. They can also be used in non-aqueous alkali neutralization systems. Since the chains described can range from methyl to long chain alkyl, including a branched chain, unsaturated chain, aryl or arylalkyl, which may further contain halogen, alkoxy, aryloxy, arylalkoxy, ether, ester and amido substituents in the side chain, the relative distribution between the aqueous and solvent components in the system can vary as well as the solubility in water or oil and solvent, and thus 1,4-dioxane-2,5-dlonone distributes to the desired positions. Due to the size and position of the side chain, the rate of hydrolysis is influenced, the acidity of the system and thus the usability of the acid can vary over a wide range according to the requirements of the system and the wishes of the operator. Non-substituted materials are often desirable for medical use. The wide range of substituents allows for greater compliance in pH control and biodegradable polymers for use in packaging and the like. The use of side chains with unsaturated bonds allows crosslinked polymers to form. This uniformity leads to greater strength, greater crystallinity and easy reproducibility and controllable characteristics that are desirable when used by surgeons.

By copolymerizing the 1,4-dioxane-2,5-dione of the present invention with either glycolide or lactide, the physical properties vary either towards polyglycolic acid or polylactic acid and the absorption characteristics vary. The length of the polymer chain as seen from the intrinsic viscosity of the polymer is also important in determining the rate of hydrolytic degradation in tissues, and thus by adjusting both the intrinsic viscosity and the component ratio, a wide range of tissue-absorbable surgical preparations can be prepared. the requirements of surgeons for a particular application. .

For many purposes, it is desirable that the tissue-absorbable synthetic polymer retain its strength for 2 to 60 days and then degrade and absorb. Since the loss of strength is gradual, it must begin 'in living tissue very early, but the corresponding' strength 'must be maintained for the period of surgery required and the' ultimate absorption 'of the polymer must occur only after that time. While polymers with glycolic acid and lactic acid units are often preferred, dioxanediones are also useful in which the substituents are ethyl, propyl, isopropyl, butyl, isobutyl, cyclohexyl and phenyl.

The present invention provides a process for the preparation of unsymmetrically substituted 1,4-dioxane-2,5-diones of the general formula I wherein:

R1 and R2 are not the same as ·. R 3 and R 1, R 1 has at least 1 carbon atom;

R 1, R 2, R 5, and R 6 are separately selected from hydrogen. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, cyclohexyl and phenyl, which comprises reacting a compound of formula R1 and R2; have above. this meaning · a

X is halogen or R is —CO— —O— or ·. R —SOž-O— wherein R jes,, methyl, ethyl or propyl, with a compound of the general formula. of formula III

R3. I.

, HO — C — O — OH ··. Μ II. ·. · · Ri · C. ·.

· ·. . (III) where

ce II Rl I where X — C — C — OH  I II. Rž 0 (ii)

X-C-C-OH + II

Λ ⁰ (i) xc ~ what у

R 3 and R 1 are as defined above, in the presence of a strongly acidic catalyst, such as concentrated sulfuric acid, p-toluenesulfonic acid, a strong, acidic ion-exchange resin or other substance which acts as strong · acid, to form · acyloxy acid, · which by alkalinization and cyclization forms a compound of formula I. ·

The reaction of the present invention proceeds according to the following scheme:

HO-CC-OH ¹ J A ° (II)

-C-C-OH I II v

ÍIIU

X-e-C-O-C ^ C- OH.NR, I · II Jo

«0 (A)

The catalyst A used for the first stage is a strongly acidic catalyst such as concentrated sulfuric acid, p-toluenesulfonic acid, strongly acidic ion exchange resins and other materials which act as strong acids. Trialkylamine, such as triethylamine, is preferably used as reagent B 'for the second step, but sodium methylate in methanol, pyridine or a strongly basic ion exchanger may also be used. In the above scheme, trialkylamine was used as reagent B. In cyclization step 3, the reaction is conveniently carried out in the presence or absence of a solvent or diluent. .

Due to the well-known tendency of α-hydroxyalkanoic acids to cyclize or polymerize and then depolymerize or open the ring, unsymmetrical 1,4-dioxane-2,5-diones would be expected to polymerize, depolymerize, and cleavage to form symmetric components that could allow the formation of long groups of the same units in the final polymer. Fortunately, it has been found that this irregularity does not occur and that the regularity of the units of acids in

196288

As the polymer is retained, the characteristics of the polymers can be modified for specific applications and their reproducibility retained.

Due to the optical activity that can occur when R 1 and R 2 are different or if R 5 and R 1 are different, different stereoisomeric components can be obtained. It is particularly preferred to use L- or D- or DL-lactic acid as the starting material. Optically active forms have different melting points and differences in physical characteristics. It is often convenient to use L-lactic acid as the starting material and the polymer then contains units in the L-configuration. For example, chloroacetic acid and L-lactic acid can be used as starting materials to give the L-form of 3-methyl-1,4-dioxane-2,5-dlone.

In general, the surgical use of the polymers prepared by the process of the present invention is the same as described above for the use of polyglycolic acid. These uses are quite variable

For clarity, certain terms are defined and exemplary uses of new polymers are given.

“Fiber” has a simple, long, thin, flexible structure of non-absorbable or absorbable material. It may be a continuous or staple fiber.

“Stapl” is used to denote a group of shorter fibers that are usually woven on longer continuous threads.

An absorbable fiber is a fiber that is absorbed, that is, digested or dissolved in living mammalian tissue.

A "yarn" is a plurality of fibers, either continuous or staple, braided together.

'Yarn' means a plurality of fibers or threads twisted, braided, braided or laid in parallel to form a unit for the further production of woven fabric or for its own use or as a monofilament of this size, either woven or used independently.

"Fabric" means three-dimensionally processed fibers, namely, woven, knitted, made to felt or otherwise treated to a flexible layer of two dimensions and a third dimension which is thin in thickness. Fabrics can be cut to the required dimensions before or during use,

Except where stated or implied above, the term fabric includes absorbable and non-absorbable fabrics or fabrics or fabrics or fabrics with a partially absorbable polymer.

A 'bandage' is a knitted, woven, felted or braided fabric of at least one layer, designed to protect and heal wounds. As used herein, the term &quot; dressing &quot; also encompasses the dressing when it comes into contact with the wound. The dressing may also be internal.

“Bandage” is a band of gauze or other material that holds the bandage in place to squeeze a wound, immobilize a certain

Part, enclosed cavities in tissue or suppressed bleeding. If the bandage does not come in contact with the wound or wound exudate, it is not necessary for the bandage to be of an absorbable polymer. If the bandage may be at least partially desirable in living tissue absorbency, at least a portion thereof may be made of an absorbable material.

A "response" is comprised of a medicament and a carrier where the medicament is deposited at the desired location and the carrier allows slow release so as to prolong the therapeutic effect of the medicament.

Slowly digestible preparations include pills and tablets that can be administered orally or subcutaneously or into the body cavity where the drug is slowly released. Digestion may be in the intestinal tract or in the tissue depending on the site of administration. The absorbable polymer is selected to ensure drug release at the appropriate dose.

The dressing may partially regulate growth, such as in nerve tissue ¹ , which grows slowly and its regeneration is exacerbated by the rapid growth of scar tissue that can block the growth of nerve tissue. With a wrapped sheath of absorbable polymer fabric or a graft or tube used to support, position, maintain and protect, the regeneration of nerve tissue and its function is greatly improved.

_v For different purposes and in different tissue types, the rate of absorption varies. The laterally absorbable seams or rigid load-bearing prostheses should have an initial strength of at least three days, sometimes up to thirty days or more, and preferably be completely absorbable by muscle tissue within forty to ninety days or more depending on the cross-section. The rate of absorption in other tissues may vary much more.

Minimum dressing is often required for dressings. Some dressings, for example used for abrasions of the skin, may have a strength of only a few hours until the scab is formed, and a rapid decrease in strength and rapid absorption is an advantage that the dressing does not delay when the scab falls off. For burns and major injuries, strength is required to be longer.

As is common in many biological systems, the requirements are not absolute and the rate of absorption, as well as strength for a short period of time depends on the patient and varies for each individual, the location in the body as well as the cross-sectional thickness of the polymer.

The absorbable polymer may be shaped as a tube or as a surgical table and may also be spun into thin fibers and fabrics or felted onto absorbable tampons or absorbable gauze or may be used in conjunction with other compressible structures such as prostheses in the human or animal body, where the structure needs strength for a short period of time and then absorbable.

No.

Tubes, including branched tubules or T-shaped connections for blood vessels, Й1у or for intestinal procedures, nerve connections, tendon connections, tables for attaching and supporting damaged kidneys, liver and other internal organs, protection of damaged areas, such as abrasions, especially large abrasions, or where the skin and tissue underneath are damaged or surgically removed.

⁷ In internal organ surgery, bleeding can be a major problem. Some organs have characteristics such that stapling or ligation is difficult to prevent bleeding. For example, the human liver may suffer traumatic damage, have a tumor, or otherwise require surgery. In the past, it was very difficult to remove a portion of the liver or to staple the liver without the associated problem of seam removal. and bleeding on the surface causing major complications, which would either prevent surgery or cause adverse prognosis.

It has now been found that the absorbable polymer swabs or pads or velor of the present invention can protect the surface and allow new areas of surgery. For example, the fibers may be made into woven gauze or felted into a tampon or velor, preferably the structure is associated with textile standards and these tampons may be placed on the surface of a bleeding organ such as the liver or lungs and in conjunction with either mild stitching or With ligation, the element is held in position when a certain amount of body fluid flows into the swab and is absorbed there, leading to hemostasis and preventing further loss of body fluid. If the liver or lungs are treated in this way, the organ can be placed in the body cavity and the wound can be closed.

Where surgically suitable, tampons or fabrics can be used as cushions to prevent the stitching from tearing off. For example, if the liver is sutured, the absorbable polymer may be placed on the surface to thicken the tissue and prevent suture from tearing. These gauze or felt inserts protect the tissue from cutting.

Absorbable pads, bandages or tampons are excellent for use in surgery where it is necessary to remove most or all of these tampons, felt or pads, but where inadvertence or accidentally the portion may remain. For example, in surgical operations, one problem is the cotton swab lint that remains in the wound. If an absorbable polymer is used, any small fragment that accidentally remains in the wound is absorbed ^; the swab is absorbed without any consequences, which is accidentally left in the wound.

The use of a synthetic absorbable polymer, such as tampons or pads, is particularly preferred for use in surface abrasions. In the past, it was necessary to apply a dressing and it was necessary at no cost to prevent the dressing from overgrowing the nonabsorbated material into the tissue. If an absorbable polymer gauze is used and part of such gauze comes under regenerating tissue, then the polymer is absorbed.

The dressing that comes in contact with the tissue should be sterile. To maintain sterility, sterile packages are preferably used which tear just prior to use.

Even in cosmetic or skin surgery where the use of silk stitches has been common in the past which, after regeneration of the tissue to a self-retaining state without leaving scars, it is now possible to implant the stitches through the skin using synthetic absorbable polymers, a portion below the skin surface is absorbed and a portion above the skin surface falls off. The resulting minimum degree of scarring of the skin surface is highly preferred.

Surgery requires that different tissues remain in a certain position during healing. Defects and wounds in the abdominal and thoracic walls and other such tissues must be reconstructed, with a hernia often requiring a pernament connection or support. For some surgical procedures, temporary solid support is required before the body tissue is healed, whereupon the foreign component is no longer desirable once the tissue can be loaded. Tissue retention is readily accomplished by using either an absorbable synthetic polymeric monofilament or polyfibrous fabric or a mesh or using a non-absorbable material such as a polyethylene or polypropylene or polyester fabric or a two-component mesh with an absorbable synthetic polymer. The use of bicomponent fabrics has the advantage of providing additional reinforcement to maintain the tissue in position during the initial regeneration with the absorbable portion, thereby allowing the body tissue to affect and strengthen the permanent mesh.

Commonly with other surgical procedures, it is often desirable that a two-component structure be used to locate non-absorbable elements with an absorbable synthetic polymeric element that maintains the structure in the desired geometric configuration at the beginning of healing. As the absorbable element is absorbed, the regenerating tissue disrupts and replaces the dissolved synthetic polymer such that the non-absorbable element is left in the desired configuration and interwoven with living tissue to transfer pressure to each other.

The choice of non-absorbable gain, partially absorbable gain, or fully absorbable gain depends on the surgeon's choice and is dependent on the condition of the patient, body composition and other medical factors.

For example, a synthetic absorbable polymeric swab may be used in the cavity after tooth extraction to stop blood flow.

The swab is either absorbed regenerating

196238 tissues, or decomposes dp mouth and allow better recovery after plucking.

The bakery use of the polymers of the present invention includes, but is not limited to:

A. Extractable polymer itself

1. Solid products shaped or machined

(a) orthopedic breastfeeders, clips, screws, plates;

(b) staples (eg for use in stopping blood),

(c) sprays;

d) hooks, buttons, latches,

(e) bone substitutes (eg jaw prostheses),

f) needles,

g) non-permeable intrauterine devices (sperm cells).

(h) temporary drainage or test tubes or capillaries;

(i) surgical instruments;

j) vascular implants or stiffeners,

(k) vertebral discs;

l) extracorporeal tubes for artificial kidneys, heart and lungs,

2. Fibrous products, knitted or woven, including velor.

a) bandages for burns,

b) hernia patches,

(c) absorbent paper or coatings;

(d) bandages with medication;

(e) facial substitutes;

(f) gauze, fabric, leaves, felt or swabs for stopping blood in the liver;

(g) gauze;

(h) dental seals;

(i) surgical threads;

3. Růzpé

(a) flakes or powder for burns or abrasions;

b) foam as absorbable prosthesis,

. (c) substitutes for fixation wires;. .

(d) fog spraying for prostheses.

B. Absorbable polymer у combined with other products.

1, Solid products, shaped or machined

(a) slowly digestible ion-exchange resins

(b) slowly absorbing other pills or tablets releasing the active substance, orally implanted or intramuscular,

c) reinforced bone pins, needles and the like ,,

Z, Fiber products _;

(a) vascular couplings or substitutes;

b) bandages for Mze surface, ·

c) burn dressings (in combination with other films),

d) coated surgical threads (coating on threads of this polymer),

-e) coating the polymer on a yarn of other material,

f) a bicomponent yarn, one component of which is a polymer of the present invention and the components are either stapled or braided;

(g) multi-component woven fabrics or gauze where the other constituents are either nonadsorbable or more rapidly absorbable.

The synthetic nature and hence the predictable formability and consistency in the characteristics obtained from the controlled process is highly desirable.

One preferred method for sterilizing synthetic absorbable prostheses is to heat under conditions such that all microorganisms and malignant materials are inactivated. A preferred conventional method is to employ a sterile gas such as ethylene oxide. Other sterilization methods include radiation by x-rays, gamma radiation, neutrons, electrons, and the like, or by intense ultrasonic vibration energy or a combination of these methods. The present synthetic absorbable polymer can be sterilized by any of these methods 1 when there are noticeable but acceptable changes in the physical nature.

A controlled release rate is highly desirable. Some drugs are injected with the requirement that the drugs be absorbed as quickly as possible. In others, they need to be positioned so that the maximum concentration of release is within the required limit of 6,258. The drug was available over a longer period of time. So is it advantageous that one implant can last? any time required for a particular medical intervention. For example, in pills to prevent pregnancy, certain steroids need to be kept low for a long period of time. The steroids may be dissolved in chloroform, the polymer of the present invention may be added, the mixture dried and tableted. The polymer, its molecular weight, and the hydrolytic rate affect the relative rate of release, drug, and absorption of the carrier. ,

For contraceptive purposes, the active substance should be released for a long time. A composition containing? The absorbable polymer can be shaped and used as an intrauterine contraceptive device, with the advantage that both the shape and the release of the active ingredient act and, in addition, the device has a limited duration of action. When using steroids for the treatment of pathological conditions, the dose may be adjusted so that it is uniformly released over -1 to 30 days or the like. For other drugs the release time may be even more variable. For some antibiotics, an effective concentration of 1 to 2 days is preferred to control some pathogens.

Where it is desired to further delay the release rate, the polymer may be coated with other materials, such as silicones. For example, there are pathological conditions in which release of the drug or hormone is required for the rest of the subject's life.

Sterility is required for subcutaneous implants and is also suitable for oral preparations. If the drug tolerates heating, irradiation or sterilization with ethylene oxide, this type of sterilization may be used. For more labile medicaments, for example, absorbable depot preparations are prepared in a sterile manner from sterile ingredients, or the sterilization is selected to be. the medicine tolerated her.

In addition, other substances such as colorants, antibiotics, antiseptics, anesthetics and antioxidants may be added. Surfaces. may be coated with silicones, beeswax and the like to modify the release rate. .

The absorbable polymer can be spun into fibers and used in the form of strips. Fibers · diameter about; 0.05 cm are particularly suitable for processing. The sheets or tubes of this absorbable polymer are wrapped around the nerves that have been traumatically disrupted and protect the nerves during its regeneration from scar tissue growth. .

The ends or edges of the mono-component or multicomponent fibers containing the absorbable polymer may be rendered rigid by fitting these edges together with or without additional solid absorbable polymer to the desired shape. However, it is often easier to insert or maintain a flexible fibrous prosthetic tube if the end of the tube is of a size and shape suitable for use. .

There is a growing interest and importance of implantation of cosmetic products, for example, some women due to partial surgical removal of breast tissue after cancer or traumatic injuries are left with smaller breasts than they think fit. Furthermore, some women are not equipped by nature as required by fashion trends at a certain time. In the past, silicone injections have been used. Silicones increased the appearance of the breasts, however, due to their migration capabilities, they were also transferred to other less strategic areas.

Non-migratory prosthesis implants have been used which consist of a sponge-like plastic or a plastic bag partially filled with a viscosity fluid corrected for natural tissue simulation. The bag is implanted with a slit under the breast and lifts the breast tissue from the lower thoracic wall, which allows for surgical reconstruction and gives a very natural appearance and flexibility.

The difficulty lies in the possibility of changing the position of the implanted bag from the desired location due to weight or pressure.

If the bag used is constructed of a physiologically inert material such as polypropylene or silicone film, the bag may be prepared with an uneven surface in which the fibers of polypropylene or other material are attached by loops or fusing to prepare the bag to which they are attached non-absorbable fibers. If fibers of two-component tissue containing a tissue-absorbable polymer are attached in the form of a fabric or other form, the bag can easily be placed and the portion consisting of the tissue-absorbable polymer is absorbed and replaced with natural tissue. The implant perfectly implants in the body, especially the chest wall, and is thus protected from accidental displacement.

According to one method, a prosthesis is implanted in the form of a bag containing a viscous liquid which may consist of one or more chambers with sites suitable for puncture such that after implantation with a hypodermic needle it can be punctured through skin, tissues and prosthesis sites suitable for puncture. puncture to remove or add liquid and so with · minimal obstacles in a short time and without great cost · can adjust volume according to fashion · or user requirements.

Similarly designed elements using the same coupled two-component systems are useful for filling other areas within the inner tissue. For example, a person may be injured in a car accident or some tissue must be removed as a result of a tumor. By filling a prosthesis of suitable size and shape, the surface shape can be reconstructed, which has a great psychological effect on the person.

Similar but solid compositions may be implanted in the nose, chin or ears and may be modified, rebuilt, or repaired the subject's surface shape. In many cases, it was found that the psychological benefit of the person far outweighed any surgical risk, cost or difficulty associated with the operation.

· Two-component systems · can be used to aid in the placement of implanted devices such as · internal conductors or hearing aids.

In cases with large surface abrasions, dressings, often gauze, pads or wraps are used to absorb blood or lymph, which is associated with major problems as the gauze bandage is stuck into the wound or infiltrated by regenerating tissue. In the past, bandages were often changed to prevent this infiltration. Removing stuck bandages is very painful.

Large surface abrasions such as slip abrasions on a hard surface after falling from a motorcycle may be wrapped with a synthetic absorbable polymer gauze. The wounds tend to bleed into. absorbable polymeric gauze, however, the porosity of the gauze facilitates rapid bleeding.

By using several layers and allowing the blood to at least partially solidify, a minimum amount of absorbable polymer gauze can be used and the main protective bandage is performed with a conventional cotton bandage. Then minimal dressing changes are required. The outer cotton gauze may be removed to check for infection, but the absorbable polymer gauze is retained in place and partially heals into the tissue and partially remains over the tissue. Fewer manipulation steps make it easier to prevent infection with new pathogens. After healing, the gauze under the new skin surface is absorbed by the body and the unabsorbed gauze and scab easily detach. . .

Representative syntheses are given in the following examples, and parts are by weight unless otherwise indicated.

Example!

Synthesis of 3-methyl-1,4-dioxane-2,5-dione mole of chloroacetic acid (94.5 g) 1 mole of D, L-lactic acid (107.0 g 85% solution in water) and 8 g of Dowex ion exchange resin 50. WX (equivalent to 1 ml of concentrated sulfuric acid) and 200 ml of benzene are heated to boiling and the theoretical amount of water is collected in the Dean-Stark trap. The solution was allowed to cool to room temperature and the ion exchanger was filtered off. The benzene is evaporated under vacuum in a rotary evaporator. Unreacted chloroacetic acid is sublimed at 26.6-53.3 Pa. The O-chloroacetyl-D, L-lactic acid is distilled at 108-118 ° C at 26.6-40 Pa. Mp 73-74 ° C. After crystallization from toluene, O-chloroacetyl-D1-lactic acid has mp 72-74 ° C.

3.34 g (0.02 mol) of O-chloroacetyl-D, L-lactic acid and 2.02 g (0.02 mol) of triethylamine are dissolved in 670 ml of dimethylformamide. Solutions of is heated to + 100 · 5 ° C for 6 hours · · and · then allowed to cool to ambient ^temperature: room temperature. The solid was evaporated in vacuo to give a red colored semi-solid residue. The product was extracted with acetone to leave solid triethylamine hydrochloride.

The acetone extract was evaporated to give a red oil which solidified on standing to give a red-yellow solid. Crystallized by dissolution in hot isepropanel and cooling to -25 ° C. D, L-3-methyl-1,4-dioxane-2,5-dione has a melting point of 64-65 ° C. (0.7 g). Further purification by sublimation at 50-60 degrees Celsius 1.33 Pa gives 0.3 g of mp 63.8-64.2 ° C. Analysis found 46.57% C, calculated 46.10% C, found 4.73% H and calculated 4.60 ·% H. Proton nuclear magnetic resonance spectrum · product in CDCl 3 has the following absorption where S (delta) ~ ppm shift from tetramethylsilane standard; doublet, 3 protons (1.66, 1.72 delta, J = 6 Hz); 1 proton quartet (4.97), 5.03, 5, 1d, 5.16 delta, J = 6-7 Hz); quartet, 2 protons (4.78, 4.94, 4.96, 5.12 delta, J = 16 Hz), confirms the structure of 3-methyl-1,4-dioxan-2,5-dione.

The product is as expected racial. and.

PMR spectrum of 3-methyl-14-dioxane-2,5-dione

The proton nuclear magnetic resonance spectrum of the compound shows that a number of protons in the chemical environment are located in different chemical environments and exhibit a series of absorption bands whose areas correspond to the number of protons. Furthermore, the absorptions are cleaved into multiplets by adjacent protons in a characteristic manner that further assists the assignment. strips in chemical structure. Spectrum of S-methyl-1-oxolaxan-4-SiOion of formula

From the 100 MHz Varian Ha-100 spectrometer, the following absorptions are divided in such a way that the splitting of one absorption into multiplets can be seen.

198258

Table I

Delta belt position (2)

Cleavage (Hezz)

Relative area

Assignment

1,661

1.72 J

5.03 ^? ·

2.10.

2.16

4,78 '

4,94 ⁷

4.96

2.12. '

Hz

Hz

Hz

Hz

Ha

H ^b

H ^c

H ^c protons.

protons or H ^d or H ^d

Atom. hydrogen attached to a carbon atom carrying an oxygen atom, such as. Ha should absorb at 1.3 to 2 delta. The absorption should be split into two bands separated by 2 to 13 Hz. The value found is 1.69 (doublet diameter is 6 · H ₂ J.):

An ambient proton such as H ^b should absorb at a higher delta than. ;

or. CH3 — O— as it is influenced by both the —O— group, each causing a downward shift from CH4. H ^b should be cleaved to the bands with a constant of 6 Hz corresponding to the cleavage

Table II observed for CH3 protons. However, ve. in fact, only 3 bands are observed, but the fourth band (2.03 to 2.06) is expected to be randomly coincident with a strong band of other origin. So 3 belts. 2.03, δ, 10 and 2.16 delta are assigned to H ^b .

Protons with surrounding H ^c a. H ^d should be absorbed at approximately the same delta as .H ^b and at the first approximation H ^c and H ^d appear. that they have the same neighborhood and provide one belt. In fact, one must be somewhat closer than the other to. CHs group on the opposite side. circle and thereby. their surroundings are different. The spectrum shows a quartet of bands caused. this pair as expected for. two differently interacting protons. Cleavage of 16 Hz between the first and second bands. and third and fourth bands _: is in accordance with the cleavage observed between protons. on . the same. carbon atom. A quartet of this type was not observed in the spectrum of either the glycolide or the lactide shown in the following table for comparison.

Compound

Belt position

3-mstli il4L, did ^ i ⁱ Xan ^ - ^ ₂₎ didnn

1.66

1.72

2.03

2.10

2.16 lactide

1.66

1.72 glycolide

4.94

2.01

2.07

2.14

4.94

Thus, the PMR of -2,2-dione is a tour and not a spectrum. 3-Methyl-1,4-dioxane in accordance with the present mixture of glycolide and lactide.

sealed under vacuum. The tube is then

Example 2

Homopolymerization of 3-methyl-1,4-dioxane-2,5-dione at 122 ° C.

1.0 g of 3-methyl-N-dioxane-4-dione prepared as described in Example 1 was placed in a glass tube together with 0.80 ml of an ether solution containing 0.1 mg of SnCl. 2HzO per ml. The ether solution was evaporated and the tube was placed in an oil bath heated to 122 ° C for 80 hours. The tube was then cooled, opened and the contents dissolved in 10 mL hexafluoroacetone. sesquihydrate (HFAS). This solution was then added dropwise to 100 ml of methanol. and the precipitated polymer obtained is dried under vacuum for two days at room temperature. The resulting polymer weighs 0.6 g (67% conversion) and has a melting point determined by differential thermal analysis of 100 ° C and an intrinsic viscosity in · HFAS of 0.38 dl / g (0.2 g / 100 mL) at 30 ° C. Deň: 32 ° C. The PMR spectrum measured in hexafluoroacetone sesquideuterate exhibits the following absorption, where (2) del198258 ta = ppm shift from tetramethylsian as standard: 5.402, 5.332, 4.904, 1.676, 1.605 delta.

The intrinsic viscosity as used herein is -η inh = '· ^ln ·, where η rel is the viscosity ratio) of a 0.5% (w / v) polymer solution in tetrafluoroacetone sesquihydrate to the viscosity of the solvent alone ac = 0.5 g per 100 ml.

PMR spectrum of poly (3-methyl-1,4-dioxane-2,5-dione)

Proton nuclear magnetic resonance spectrum of a polymer containing glycolic acid units

O

II (-O-CH2-C-) and lactic acid units -O-CH-C-)

I II

Nizo shows a number of protons that exist in each of the various chemical neighborhoods of the polymermho chain. For the poles (D, L-lactic acid), the methine CH) proton appears as a · quartet whose center is located at 5,286 delta (where delta is the ppm shift to the lower magnetic field from methyl absorption in the tetramethylsilane standard). The quartet absorption area is one third of the methyl absorption area as expected. The structure of the quartet is caused by spin-spin affecting the protons of the attached —СНз group and further justifies the assignment.

In the copolymers of D, L-lactide and glycolide containing 52 units of lactic acid and 48 units of glycolic acid, two overlapping quartets were observed with centrenT positioned as shown in Table III. A quartet with a center at 5.276 is closer to the center at the poles (lactic acid) (5.286) and can be assigned to the methine proton of the lactic acid central unit of the sequence —L — L — L—

СНз О СНз О СНз O

I-II-II-II-o-c-c-o-c-c-o-c-c-

H H H

The second quartet in the copolymers has a center at 5,310, which is very close to the single quartet observed in the copolymers of lactic acid units and glycolic acid units of 8: 92, where isolated lactic acid unit bands should prevail. Quartet 5,310

can be assigned to the central meth- mu proton of the sequence —L — L — G— —G — L — L— or О СНз O СНз O II 1 II 1 II

—О — CH2C — О — С- С — O — C — C—

H H or СНз O СНз O O 1 II ' 1 II II —O — c- 1 • c — 0 -C — C — O — CH2C- 1 ! H 1 H

The (3-methyl-1,4-dioxane-2,5-dione) pole spectrum prepared according to Example 2 shows an absorption quartet centered at 5.367, which is a significantly shifted cd of absorption assigned to the sequences - L-L-L, -G —L ———————————————————————————————————————————————————————————————————————————————————————————————. that this sequence should predominate when the polymerization of this monomer is carried out by a gradual attack of the active end group to the less hindered carbonyl group of -3-methyl-1,4-dioxane-2,5-dione to form the chain - G — L — G- The presence of minor amounts of —G — L — L — and —L — L — G “sequences cannot be excluded from the PMR spectrum, since minor absorption at 5.307-5.310 can be masked by basic methine absorption.

Thus, the methine absorption of the lactic acid unit is influenced by the position between two adjacent units. If two lactic acid units change to one lactic acid unit in the neighborhood and then no lactic acid is present in the neighborhood, the shift to higher delta values for methine absorption occurs.

'24

T a b u 1 k a · .III

Chemical shift (delta) for multiplet center

Polymer. = CH (quartet) ·· = CH 2 .. (singlet) —CH3. (doublet) · .: poles (lactic acid .;) · · ..- 5,288 - 1,633 52/48 mol% copolymer · - .. - lactide and glycolide. ./ 5,310. 5,276 .4,908 1,641 8/92 mol% of the copolymer lactide and glycolide. , 5,307 . 4,920. 1,639 · poles (3-methyl-1,4-dioxane-2,5-dione) 5,367 4,907 1,643 assignment sequence —GLG— —GLL— —L — LL— . . .. and - · - —LLG — z

Ex. k 1 and d 3

Polymerization of D, L-3-methyl-1,4-dioxane-2,5-dione at 220 ° C,

Do glass. 0.5 g of 3-methyl-1,4-dioxane-2,5-dione and 0.1 ml of ether solution are placed in the tube. containing 0.1 mg SnCl2.2H2O per ml and 0.06. ml of an ethereal solution containing 20 mg of lauryl alcohol per ml. The ether was evaporated, the tubes sealed under vacuum and placed in a heated oil bath for two hours. at 220 ° C. After cooling and opening, the contents are dissolved in 5 ml of HFAS. This solution was added dropwise to 59 ml of methanol and the resulting precipitated polymer was dried under vacuum at 50 ° C for 2 days. The formed pollen (D, L-3-methyl-1,4-dioxane-2,5-dione weighs 0.14 grams and has an intrinsic viscosity of 0.65 dl / g in HFAS. (0.5 g / 100 ml) at 30 ° C.

Example 1 d. 4,

Polymerization of D, L-3-methyl-1,4-dioxan-2,5-dlonone at 180 ° C.

2.0 g of D, L-3-methyl-1,4-dioxane-2,5-dione and 0.4 ml of an ether solution containing 0.1 mg of SnCl2 are placed in a glass tube. 2HsO per ml. The ether was evaporated and the tube sealed in vacuo. The tubes are then placed in a heated oil bath. Mp 180 ° C. + 5 ° C and kept at this temperature for 24 hours. The tube is cooled, • opened, and the contents dissolved in 40 ml of hexafluoropropanol (HIPA). This solution was added dropwise to 400 ml of methanol and the resulting precipitated poly (D, L-3-methyl-1,4-dloxane-2,5-dione) was dried under vacuum at 50 degrees Celsius for 16 hours. . The resulting 1.65 grams polymer had an intrinsic viscosity in HFAS of 0.83 dl / g (0.5 g / 100 mL) at 30 ° C.

Example 1 a d 5

Extrusion of poly (D, L-3-methyl-1,4-dioxane-2,5-dione) as monofilament

A 0.5 g sample of the polymer of Example 4 is placed in a cylinder (1 cm in diameter) with a Custum Scientific equipped with a 1 cm high stopper at the bottom having a 0.5 mm vertical opening in the center. The monofilament, which is extruded through the orifice, has a diameter of 0.05 to 0.15 mm and is fairly - weak. · Hand to · Four times the original length on a hot plate with a surface temperature of 50 to 60 ° C. The fibers are then thicker and have a fracture strength of 120 to 147 MPa.

Ex. D. 6 .. · ./ · · · · · '. · ··· '·

Polymerization - D, L-3-methyl-1,4-dioxan-2,5-diene at 180 ° C. _F

6.0 g of D, L-3-methyl-1,4-dioxane-2,5-dione and 1.2 ml of an ether solution containing 0.1 mg of SnCl2 are placed in a glass tube. 2HzO-per ml. The ether evaporates and the tube is then sealed. The sealed tube is placed in an oily pre-heated to 180 ± 2 ° C and left at this temperature for 4 hours. The cooled tube is opened and the contents dissolved in 120 ml of boiling acetone and the solution is added dropwise to 1200 ml of methanol. The resulting poly (D, L-3-methyl-1,4-dioxane-2,5-dioma) precipitate was dried in vacuo. vacuum · two days at 25 ° C. The resulting polymer weighs 1.4 g (23% by conversion) and has an intrinsic viscosity in HFAS of 1.19. dl / g (0.5 g / 100 mL) at 30 ° C.

Example 7 · 9 to 9.

Copolymerization of D, L-3-methyl-1,4-dioxane-2,5-dione with glycolide

The amounts of D, L-3-methyl-1,4-dloxan-2,5-diene and the glycolide listed in Table IV are mixed in a glass tube with 0.80 ml of an ether solution containing 0.1. mg SnCl2. 2HaO per ml and 0.5 ml ether solution 20 mg lauryl alcohol per ml. The ether · was evaporated and the tube sealed in vacuo. The tubes were placed in an oil bath and heated at 220 degrees Celsius for two hours. The contents were then cooled and opened and dissolved in HFAS and precipitated in methanol. The precipitated polymer was dried under vacuum at 50 ° C for two days.

_26:. Table IV, ...... \.

Example 7 Example, 8 Example 9

Mol% D, L-3-methyl-1,4-dioxane-2,5'-dione · ...... ', ·· ... · ...

Weight of glycolide used (g) Weight of D, L-3-methyl-1,4-dloxane-2,5-dione used (g)

Polymer conversion (%) Melting point - (Fisher-Johns apparatus) Intrinsic viscosity in HFAS - (0.5 mg / ml) 30 ° C.

Mol%, D, L-3-methyl-1,4-dioxane-25-dione in polymer - (PMR)

Examples 10 and 11

Implantation of a copolymer of glycolide and D, L-3-methyl-1,4-dioxane-2,5-dione in rabbits

The copolymers of Examples 7 and 8 (and polyglycolic acid (PCA), 0.89 intrinsic viscosity) are formed into strips by compressing with 0.4 g of powdered polymer at room temperature in a press 1.9 X 1.27 X 7.62 cm hydraulic pressure, 7.260- kg per adapted plunger for 30 seconds Carver hydraulic - pressure. This piece is pressed

10 25: , 50 3.58 2.96 1.86 0.44 ’ : 1.10 2.08 80 79 25 Mp 212 ° C 188 ° C- . ·. · 132 ° C

0.45 0.32 0.18 ·

4.8 16.2 31.7 cut into - 4 strips of size, 3.8 X - 0.63 cm and weighing - about -0.1 g. Each strip is placed in a plastic envelope, dried under vacuum, The heat was sealed and sterilized overnight with ethelyl oxide, after which the excess ethylene oxide was stripped off. Individual strips are then subcutaneously implanted in rabbits. At specified intervals, rabbits - are killed and - observed - se - tissue reactions at the site - implantation. The degree of absorption is determined visually. - The tissue response in all cases is not remarkable; The degree of absorption determined is shown in Table V.

Table V

PCA Control Example 7

Example 8 molar ratio of polymer D, L-3-methyl-1,4-dioxane-2,5-dione and glycolide absorption after 15 days absorption - after 30 days - 90 absorption after · 45 days

Example 12 · - ·

Implantation - Poles (D, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R &apos;

Poly (D, L-3-methyl-1,4-dloxane strips) were prepared according to the procedures of Examples 10 and 11 - Table VI

PCA Poles (D, L-3-methyl 1-1,4-dioxane-2,5-dione) absorption after · 15 days 50,49% 0.0% absorption after 30 days 85.85% 50.50.% absorption after 45 days 100,100% 85,100%

Example 13.

Preparation of o-chloroacetyl-L-lactic acid

In a 2 liter two-necked round-bottomed flask equipped with a magnetic stirrer and a Dean-Stark trap was added 750 ml of benzene and 8.0 g of Dcowex 50W-X resin. To this suspension was added 262.2 g (2.78 mol) of monochloroacetic acid - The mixture was heated until water no longer formed.

100 g (1.11 mol) of crystalline are then added

0/100%

- 100%

100%

4.8 / 95.2 16.2 / 83.8

40 - 50% <25% - ..

100% 90—100%

100% - _

-2.5 ₇ dione). prepared according to an example. 6 and - implanted - in rabbits. The tissue response is by no means remarkable. The determined absorption rate of the sample pairs of these strips and polyglycolic acid (PCA) as a control is shown in Table VI.

L-lactic acid in ten successive portions by adding an additional portion until water is eliminated after the previous addition. .

Once . - eliminate - all water, stop heating, filter the resin from the hot solution. The resin was then washed with two 50 ml portions of hot or benzene. The washings were added to the reaction mixture and the solvent was evaporated in vacuo.

The crude oil was then cautiously distilled to remove excess mono-chloro-acetic acid. The residual oil is then distilled at a temperature of 95-105 ° C and a pressure of 6.66 Pa. 143.3. g. (77.3%) of o-chloroacetyl-L-lactic acid, which is then redistilled to give 130 g (70.3%) of the product, m.p. 94-100 ° C.

6.66 Pa.-.

Calculated for

CCHž — C — O — CH — C — OH

II I II '

% C, 36.05%; H, 4.24%. Cl, 21.29 min. h, 166.56.

Found

3 ^ * 5866

4.41: 20.74

173

Wd ²⁵ . = -660 ° ± 0.7 (C 1.34, CHCl 3),

IR belts

IR belts

Example 14

Preparation of L-3-methyl-1,4-dioxane-2,5-dione

Example 15

Preparation of poly-L-3-methyl-1,4-dioxah-2,5-dione n

Copolymerization of L-3-methyl-1,4-dioxane-2,5-dione with glycolide.

PMR (CDCl3, TMS) quartet [5.00, 5.06, 5.14,

5.20 (5), doublet (4.98, 4.94 Å), doublet (1.70, 1.64 3).

PMR (CDCl3, TMS) singlet 9.53 .alpha., Quartet

5.33, 5.26, 5.19, 5.12 <5, singlet 4.16, doublet 164.1.56 5..

3050 cm -1, 2975 cm ^-1 , 1750 cm -1, 1460 cm -1, 1412 cm -1, 1378 cm -1, 1345 cm -1 1315 cm -1, 1183 cm -1, 1135. _cm -1 ·. 1095 cm @ -1, 1043 cm @ ^-1 , 957 cm @ -1, 930 cm @ -1, 833 cm @ -1, 788 cm @ -1.

[.alpha.] D @ 25 -245 DEG (± .alpha.). (C = 0.988, benzene)

3450 cm -1, cm -1,. 1345 1195 cm · -! cm -1, 1036 cm -1, 1378

1225 cmcm -1, 1053

1775 cm-1 1448 cm-1, 1296 cm-1,

1130 cm -1, δ cm -1, 958 cm -1, 849 cm -1,? CH2

-CH.rC ~ O-C ~ (CO · 1 L H.

g (0.170 mol) of o-chloroacetyl-L-lactic acid is dissolved in 4500 ml of free amine-free dimethylformamide. To this solution was added 35.83 mL (26.0 g, 0.256 mol) of dry triethylamine. The solution is then heated to. 10.0 ° C and maintained at this temperature

0.5 g of L-S-methyl-1 H -dloxane-2 H -dione from Example 14 was polymerized in the presence of 0.002 wt% stannous chloride dihydrate for 24 hours at 180 ° C. Gets. thus 0.5 g of polymer IV = 0.33 and the softening point is 56 to 60%.

4 hours. At the end of this time, the heating was discontinued, the solvent was removed in vacuo. and an oily semi-solid residue is obtained.

Evaporate. with 1 liter of dry diethyl ether and the insoluble triethylamine hydrochloride is filtered off. The ether was then removed in vacuo and the oil dissolved in benzene. The benzene is then extracted with 50 ml of cold distilled water, the pH of which is adjusted to 2.5 with hydrochloric acid. The benzene solution is then rapidly dried over anhydrous sodium sulfate and then dried for one hour with molecular sieves. The sieves were filtered off, washed well with 50 ml dry benzene, the combined solvent and washings were evaporated in vacuo to give 16.9 g (51%) of an oil which crystallized from isopropanol at -20 ° C. The semi-solid product is cold filtered and rapidly recrystallized from a minimum amount of boiling isopropanol. Two further recrystallizations from isopropanol gave a white solid L-3-methyl-1,4-diOxane-2,5-dione, mp 38-39 degrees Celsius (8.0 g, 24%).

The polymerization tube 1 is filled with an appropriate amount of monomer listed in Table VII and 0.012% SnCl 3. 2HzO na. the weight of the monomer in the ether solution. The ether was evaporated and the tube sealed in vacuo. The tube was then heated in an oil bath at 190 ° C for 24 hours.

The tubes were removed from the bath, cooled in a dry ice bath in acetone, opened, and dissolved in HFAS. The polymer is then precipitated from the solution with methanol, filtered and dried in a vacuum oven over hoc.

Table VII

Example · 16

Example 17 mol% L-3-methyl-1,4-dioxane-2,5-dione mol% glycolide of L-3-methyl-1,4-dioxane-2,5-dione grams glycolide

Melting point (differential thermal analysis 10 ° C / min) intrinsic viscosity in HFAS (0.5 mg / ml) 30 ° C · mol% ^ 3--06 ^ 71-1,4 ^^ 311-2, 5-dione in copolymer yield in%

15 Dec 25 85 75 ' 0.5 0.5 2.53. . 1 · 34 196 ° C 175 ° C 0.53 / 0,60 7.2 12.4 78 ......... 83

Example 18

Preparation of 3,3-dimethyl-1,4-dioxane-2,5-dione

In a flask containing two liters of chloroform, 1 mol of 2 - hydroxy isobutyric acid (104,1 g) and 2,2 mol of triethylamine (224 g), cooled in an ice bath. 1 mol of chloroacetyl chloride (127 g) was added slowly. Adding takes 1 hour. The chloroform is evaporated to give a semi-solid red product which is triturated several times with acetone and the red acetone extract is decanted. The white solid residue is triethylamine hydrochloride. Acetone extracts were combined. and concentration in vacuo afforded a red oil which was distilled under vacuum. Fractional distillation collects 103-110 ° C / 1 mmHg. This fraction solidifies and the green semi-solid product is recrystallized from isopropyl alcohol and then sublimed at 75 ° C / 13 Pa to give 15 g of a white solid, mp 82-83 ° C. Dissolve the solid in 3000 mL of benzene at 10 ° C and extract successively with three 300 mL portions of a 0.01 N hydrochloric acid solution saturated with sodium chloride, then dry the benzene phase by filtration 1 through a pad of anhydrous sodium sulfate into a flask containing anhydrous sulfate. magnesium. After filtering off the magnesium sulfate, the benzene was evaporated in vacuo to give a solid 3,3-dimethyl-1,4-dioxane-2,5-dione, which was recrystallized from iso propyl alcohol and sublimed at 75 ° C. 13.3 · Pa. 13 g of solid are obtained, m.p. 85-86 ° C, calculated 50.00 O / o and found 50% C, calculated 5.52 and found 5.60% H.

The PMR spectrum of this sample in CDCl 3 shows the following absorption, where δ '= ppm shift from tetramethylsilane absorption: · singlet 6 protons at 1.72 and singlet 2 protons at 5.02 δ.

Examples 19-21

Copolymerization of glycolide and 3,3,3,4-dihydro-1,4-dioxane-2,5-dione.

Amounts of 3,3-dimethyl-1,4-dioxane-2,5-dione listed in Table VIII are added to 3 glass tubes. 1.2 ml of an ethereal solution of SnCl2.2H2O (0.1 mg / ml) and 0.75 ml of an ethereal solution of lauryl alcohol (10 mg / ml) are then added to each tube. The ether was evaporated and the tubes evacuated and sealed, then heated at 220 ° C in an oil bath for two hours. After cooling and opening, the tube content is dissolved in 20 ml of hexa-fluoroacetone sesquihydrate per gram of solid obtained. The polymer solution was added to ten times methanol. The precipitated polymer is then extracted for two days in Soxlet with acetone. The undissolved polymer was dried under vacuum at 50 ° C for 24 hours.

Table VIII

Example 19 Example 20 Example 21

(A) glycolide, g 5.27 4.60 3.95 (B) 3,3-dimethyl-1,4- d, oxane-2,5-dione 0.74 1.45 2.05 molar ratio (A) / (B) in the handpiece 90/10 80/20 70/30 % conversion 82 76 64 intrinsic viscosity (I.V) · 0.54 0.45 0.44 mol% B in the polymer 2.1 4,5 6.0 ·

9 82 5 8 i31

Example 1 ad 2 2 _; ; · ..

Copolymerization of D-Lactide with D, L-3-methyl-1,4-dioxane-2,5-dione in a 90:10 molar ratio.

0.54 g of D, L-3-methyl-4, 4-dioxane-2,5-dione (0.00415 mol) and 5.41 g of .beta.-L-actide (0.0376 moi) were added to the polymerization tube. 20 ml of an ethereal solution of SnCl 2 · 2H 2 O (0.1 mg / ml) and 0.75 ml of an ethereal solution of lauryl alcohol (10 mg / ml). The ether was evaporated, the tube was evacuated, sealed and heated to 180 ° C for 24 hours. The contents of the cooled tube diff. The solution was precipitated with methanol. The solid obtained is dried under vacuum at 50 ° C for 24 hours. The monomer conversion to polymer was 79% and the polymer had an intrinsic viscosity of 1.36. According to PMR, the molar percentages of D., L-3-methyl-1,4-dioxane-2,5-dione units in the polymer were 7.9.

Example 23

Copolymerization of D, IL-actide with D.L-methyl 1-1,4-dioxane-2,5-dione in 80:20 molar ratio

1.21 g of D, L-3-methyl-1,4-diOxane-2,5-doone (0.00931 mol) and 4.86 g of D, L-lactide ( 0.0338 mol). · Pos. The conversion was then identical to that of Example 22. The monomer conversion to polymer was 74% by weight, and the polymer had an intrinsic viscosity of 1.24. According to PMR, the polymer contains 14.7 mole percent of units derived from D, L-3-methyl-1,4-dioxane-2,5-dione. .

Example 2 4

Copolymerization of L-lactide with D, N-S-methyl-1, 4-dioxane-2,5-dione in a 90:10 molar ratio

Example 22 is repeated to replace L - (-) - lactide with DL-lactide Conversion was 78 percent, intrinsic viscosity 0.73 and polymer contains PMR spectrum 7.6 mole% derived units · From N, N-S-methyl-1H-dioxane-2,5-dione.

Example 2 5 ^!

Copolymerization of L-actide with D, L-3-methyl-1,4-dioxane-2,5-dlonone ratio 80:20

Example 23 is repeated, replacing L - (-) - lactide with D, L-lactide. The conversion was 75% intrinsic viscosity 0.61 a. the polymer contains 10.2 mole percent units of P, L-3-methyl-1,4-diocane-2,5-dione according to the PMR spectrum.

Example 26

Preparation of O-chloroacetyl-L-lactic acid.

A mixture of 57.6 g (0.4 mol) of sublimed L32

-lactide, 378 g (4.0 mol) of monochloroacetic acid and 2.8 g of SbaO3 are heated for 8 hours in an oil bath at 180 ° C and then for 24 hours at 130 ° C, then finally for five hours. 185 “C. The excess monochloroacetic acid is then distilled off in vacuo, and the resulting O-chloroacetyl-L-lactic acid is distilled at 90-110 degrees Celsius and 6.66 Pa to give 109.3 g (82%) of product. The product is then slowly redistilled at 94-100 ° C / 6.66 Pa to give 100.5 g (75.4% O-chloroacetyl-L-lactic acid), which is identical to the product prepared from L-lactic acid and monochloroacetic acid.

When 3.1 g of TiO 2 is used in place of SbaO 3, yield 69.2 g of product (51.9%). Tetraisopropyl titanate can also be used as catalyst. · ·

Example · 27 ·. ·. · .. · ··

Preparation of O-chloroacetyl-β, L-lactic acid, from. Poly-P.L-lactic acids.

530.1 g (5.55 mol) of monochloroacetic acid, 100 g, (1.39 eq.) Of oleic-D, L-lactic acid and 1.5 g of Sb2O3 are heated under stirring 24. hours to 160 ° C. The excess monochloroacetic acid is then distilled off in vacuo and distilled at 85-10.0 ° C / 10 Pa to yield 122.5 g (53%) of O-chloroacetyl-β, L-lactic acid. The material obtained is identical to the product prepared from D.L-lactic acid and monochloroacetic acid.

Example 2 8, · ''

Preparation of β, L-3-methyl-1,4-dloxane-2,5-dlone. from glycolic acid and D-lactic acid

To 543 g · 70% aqueous glycolic acid solution · 276 g 85% aqueous solution of D.L-lactic acid are added. This is heated in the distillation apparatus at atmospheric pressure until the water no longer distills. Then 6 g of Sb2O3 are added and heating is continued at a pressure of 1.33 kPa until 350 g of distillate (distillation head temperature 120-180 ° C) are obtained. The distillate is then fractionated using a Vigreaux column at 1 mm Hg to give 40 grams of fraction A (bp 114-140 ° C) and 160 g of fraction B (bp 142-153 ° C). Fraction B partially solidified at 5 ° C and then recrystallized from 320 ml of isopropanol. The recrystallized product was further purified by fractional distillation on Vigreaux. column and the fractions listed in Table IX are obtained. Fractions were analyzed by gas chromatography.

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Table IX

Fraction number Weight g T. v. (1,33 kPa) 1 20 May Mp 142-144 ° C 2 54 Mp 144-146 ° C 3 10 Mp 146-148 ° C Example 2 9

Preparation of D, L-3-methyl-1,4-dioxane-2,5-dione from glycolic acid and D, L-lactic acid

Example 28 was repeated until fraction V was obtained by distillation. This fraction was then fractionated by high-performance distillation apparatus to give D, L-3-methyl-1,4-dioxane-2,5-dione of greater than 99% purity as determined by gas chromatography.

The choice of L-, D-, or D-, L- components in the polymerization batch determines the optical activity of the units in the polymer. When a single optical isomer is used, the polymer has a greater tendency to crystallize.

Product Composition Weight % glycolide lactide n, L-M.D.D.

2270

1377

776

The rate of tissue absorption in a living organism is influenced by the susceptibility of the polymer to hydrolysis prior to implantation, the molecular weight and the size and shape of the implanted polymer, as well as the chemical composition of the polymer. In general, the greater the ratio of glycolic acid units, the faster the absorption. The drier the polymer, the slower the absorption and the higher the molecular weight, the stronger the polymer.

The use of the copolymers and homopolymers of the present invention allows a greater range of absorption characteristics suitable for surgical devices.

Claims (2)

OBJECT OF THE INVENTION A process for the preparation of unsymmetrically substituted 1,4-dioxane-2,5-dione of the general formula I wherein R1 and R2 are not the same as R3 and Ra, R1 has at least 1 carbon atom and R 1, R 2, R 3 and R a are independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, t -propyl, butyl, isobutyl, cyclohexyl and phenyl, characterized in that a compound of formula II is reacted Ri AND X — C — OH — II. R 0 (II), where R 1 and R 2 are as defined above and X is a halogen atom or a group R — CO — O — or a group R — SO2 - O — wherein R is methyl, ethyl or propyl with a compound of formula III R3 HO — C — C — OH R4 O (III), where R 3 and R 4 are as defined above, in the presence of a strongly acidic catalyst such as concentrated sulfuric acid, p-toluenesulfonic acid, a strongly acidic ion exchange resin or other substance that acts as a strong acid to form an acyloxy acid which forms by compounding and cyclization AND. 2. A process according to claim 1, which comprises reacting chloroacetic acid with lactic acid to form O- (chloroacetyl) -lactic acid, and cyclizing to form 3-methyl-1,4-dioxane-2,5- dion.