DK175848B1 - Formation of implants in situ - by injection of polymer soln. or liq. prepolymer - Google Patents

Abstract

Processes for forming implants in situ in the body comprise: (A) dissolving a non-reactive polymer (I) in a biocompatible solvent (II), introducing the soln. into the body, and alowing (II) to dissipate to form a solid implant; or (B) introducing a liq. biocompatible prepolymer (III) into the body and curing (III) in situ.

Description

DK 175848 B1

The invention relates to a system of biodegradable polymers, and in particular to the use of such polymers to provide injectable, biodegradable implants formed in situ.

5 Prior Art

Heat-cured biodegradable polymers have previously been described for use in medical applications. These polymers are formed by crosslinking reactions which lead to high molecular weight materials that do not melt or form liquid liquids at high temperatures. Typical examples of these materials are the crosslinked polyurethanes described in U.S. Patent No. 2,933,477 and U.S. Patent No. 3,186,971. Copolymers based on e-caprolactone and L-lactide or DL-lactide crosslinked by peroxide initiators are described in U.S. Pat. U.S. Patent Nos. 4,045,418 and 15,057,537. Cross-linked caprolactone copolymers have been prepared by incorporating a bislactone in a monomer release as described in U.S. Patent No. 4,379,138. Trihydroxy-functional copolymers of ε-caprolactone and ε rolactone has been cross-linked with diisocyanates to obtain biodegradable polymers as described in Ritt et al., J. Polym. Sci .: Part A: 20 Polym. Chem., 25: 955-966, 1987. These polymers are also solids when crosslinked or cured.

Although these two classes of biodegradable polymers have many useful biomedical applications, there are several important limitations to their use in the body, where body is defined as the body of humans, animals, birds, fish and reptiles. Because these polymers are solids, in all cases where they have been used, it has been necessary to first form the polymeric structures outside the body, followed by insertion of the solid structure into the body. For example, sutures, clamps and clips are all formed from thermoplastic biodegradable polymers before use. Upon insertion into the body, they retain their original form rather than flow

I DK 175848 B1 I

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In addition to filling in spaces or voids where there is most need

In for them. IN

Similarly, systems for administering drugs using I

In 5 these biodegradable polymers, are formed outside the body. In such I

In case, the drug is incorporated into the polymer and the mixture is formed into an I

In a particular shape, such as a cylinder, disc or fiber, for implantation. With so- I

In solid implants, the drug delivery system must be inserted into the I

In the body by a surgical incision. These surgical incisions are often larger than you are

I 10 desirable in the medical sciences, and leads to a reluctance of patients

In the entities to accept such an implant or drug delivery system

I agree. IN

In The only way to avoid surgical incision with these polymers is to inject I

15 as small particles, microspheres or microcapsules. These may optionally

contain a drug that can be released into the body. Although these small pairs- I

Ticks can be injected into the body with a cannula, they do not always meet the needs

know for a biodegradable implant. Because they are particulate, they form I

Not a continuous film or solid implant with the structural integrity that you

In 20 are required for certain inserted dentures. When inserted into certain body cavities- I

In rooms, such as the mouth, a periodontal pocket, the eye or the vagina, where there is space

In clear fluid flow, these small particles, microspheres or I are retained

In microcapsules poor because of their small size and discontinuous nature. IN

In addition, microspheres or microcapsules are made of these polymers and I

25 containing drugs for release in the body sometimes difficult to · I

You manufacture in large scale and their storage and injection properties

You create problems. Further, another important limitation of I

the system of microcapsules or small particles the lack of reversibility I

without extensive surgical intervention. That is, if there are complications

In 30 tions, after being injected, it is much more difficult to remove them

from the body than is the case for solid implants. IN

3 DK 175848 B1 WO-A-85/00969 discloses a non-toxic physiologically acceptable polymer composition which can be injected and cured when placed in contact with living tissue.

5

Therefore, there is a need for a system for providing a biodegradable polymeric structure useful for overcoming the limitations described above.

Furthermore, there is a need for a system providing injectable solid biodegradable implants formed in situ that can be used as inserted prosthetic devices and / or controlled delivery systems.

Further, there is a need for such a system that can provide implants with a variety of properties ranging from soft to hard, so that they can be used with both soft and hard tissue.

Description of the Invention The present invention relates to a biodegradable, thermosettable polymer system comprising a liquid biodegradable, thermosettable prepolymer for in-situ formation of a solid implant structure in the body by placing the system in the body and curing it. The thermosetting system does not contain solvents and is usually cured with a curing agent.

25

The invention further relates to the use of a biodegradable, thermosettable polymer system to form a biodegradable, thermosettable system for in situ formation of an implant in the body pen by placing systems in the body and curing it. The thermosettable polymer is usually cured with a curing agent.

I DK 175848 B1 I

I I

The invention thus relates to biodegradable, thermosettable polymer systems

In more for in situ formation of prosthetic implants and systems for administration I

I of controlled release drugs which can be administered as a liquid

In many substances, for example, through a cannula, but which coagulates or cures

In 5 it ("solidifies") shortly after dosing to form a solid. The implants I

You are biodegradable because they are made of biodegradable,

In thermosettable polymers. IN

The solution can be placed anywhere within the body, including

In soft tissue, such as muscle or adipose tissue, hard tissue such as bone, I

Or a cavity such as the periodontal, oral, vaginal, rectal, nasal cavity

room, or a pocket, such as a periodontal pocket or the eye's cul-de-sac. Do you know

When applied to drug delivery systems, it is biologically active

In solid substance to the polymer solution, where it is either dissolved to form an I

Or homogeneous solution to form a drug suspension

sion or dispersion within the polymer solution. In the body, the system I forms

In an implant which thereby retains or encloses the drug within it

In polymeric matrix, the implant assuming solid form. The release of the drug I

then follows the general rules for the diffusion or dissolution of a drug;

In 20 contained within a polymer matrix. IN

In the thermoset system, the synthesis of crosslinkable polymers, I

In which are biodegradable and which can be formed and hardened in situ. The ten

thermosetting system comprises reactive liquid oligomeric poly-I

In 25 more which do not contain solvent and which harden on site to I

In the formation of solids, usually by the addition of a curing catalyst

In the sator. IN

The multifunctional polymers useful in the thermosetting system, I

30 is first synthesized by copolymerization of either DL-lactide or L-lactide with I

ε-caprolactone using a multifunctional polyolin initiator and an I

5 DK 175848 B1 catalyst to form polyol terminated prepolymers. The polyol terminated prepolymers are then converted into acrylic ester terminated prepolymers, preferably by acylating the alcohol terminus with acryloyl chloride by a Schotten-Baumann-like technique, i.e. reaction of acyl halides with 5 alcohols. The acrylic terminated prepolymers can also be synthesized in several other ways including, but not limited to, reaction of carboxylic acids (i.e., acrylic and methacrylic acid) with alcohols, reaction of carboxylic acid esters (i.e., methyl acrylate or methyl methacrylate) with alcohols by transesterification, and reaction of isocyanate alkyl acrylates (i.e., isocyanate methyl methacrylate) with alcohols.

The liquid acrylic terminated prepolymer is cured, preferably by the addition of benzoyl peroxide or azobisisobutymitrile, to a more solid structure.

Thus, for an implant using these crosslinkable polymers, the catalyst is added to the liquid acrylic terminated prepolymer immediately prior to injection into the body. Once inside the body, the crosslinking reaction will continue until sufficient molecular weight is obtained to solidify the polymer. When the liquid prepolymer is injected, it will flow into the cavity or gap in which it is disposed and assume its shape when solidified. For drug administration by this system, biologically active agents are added to the liquid polymer systems in the uncatalyzed state.

With the thermosetting system, the benefits of liquid application are achieved.

For example, the polymer can be injected via a cannula into a body while it is liquid, and then left in situ to form a solid biodegradable implant structure. The need for a surgical incision is eliminated and the implant assumes the shape of the cavity. Furthermore, a system for administering drugs can be provided by adding a biologically active substance to the liquid prior to injection. Once the implant is formed, it releases the substance to the body and is then biodegraded. The term "biologically active substance" means Η Η

I DK 175848 B1 I

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There is a drug or other substance capable of producing an ingredient

In effect on a body. IN

It is therefore an object of the invention to provide a thermoset system for I

In the preparation of biodegradable polymers. IN

It is also an object of the invention to provide such a polymer as may be disclosed

You may be useful in the preparation of injectable solid biodegradable implants

In tater formed in situ. IN

I 10 I

It is further an object of the invention to provide such an implant which I

You can be used in a controlled substance delivery system for biological substances

In release. IN

It is further an object of the invention to provide implants which I

You possess a range of properties ranging from soft and elastomeric

I for hard and inelastic so that they can be used with both soft and hard

In tissue. IN

I 20 Brief description of figures and tables I

Figure 1 shows the synthesis of acrylic-terminated prepolymers and subsequently I

In crosslinking by free radical initiators, I

Figure 2 shows structures for the random copolymer of ε-caprolactone and L-lac-I

In time initiated with a diol, I

In Table 1 is a summary of the synthesized bifunctional PLC preparations

You suffer, I

I 30 I

fl 7 DK 175848 B1

Table 2 is a summary of the synthesized acrylic terminated prepolymers, and

Table 3 is a summary of curing studies.

5

Best Methods for Carrying Out the Invention

The invention relates to biodegradable, thermosettable systems for in situ implant formation. Furthermore, the invention relates to a liquid biodegradable polymeric system which can be injected into a body where it forms a solid and releases a biologically active agent at a controlled rate. The biodegradable thermosettable systems comprise thermosetting polymers which are liquid without the use of solvents.

In one possible application of the thermoplastic system, the polymer system is placed in a cannula and injected through a needle into the body. Once in place, the polymer assumes solid form and a solid structure is formed. The implant adheres to the surrounding tissue or bone by mechanical forces and can assume the shape of its surrounding cavity. Thus, the biodegradable polymer system can be injected subdermally just like collagen to build tissue or fill defects. It can also be injected into wounds, including burns, to prevent deep scar formation. Unlike collagen, the degradation time of the implant can be varied from a few weeks to years depending on the polymer selected and its molecular mass. The injectable polymer system can also be used to correct bone defects or provide a continuous matrix when other solid biodegradable implants, such as hydroxypathite plugs, are inserted into bone gaps. The injectable system can also be used for adhering tissue to tissue or other implants to tissue by virtue of its mechanical bonding or containment of tissue and inserted prosthetic devices.

I DK 175848 B1 I

I i

Another possible use of the thermoset system is provision I

I of a drug delivery system. In this application, a bioac- H is added

In tive to the polymer system before injection, and then the mixture of I

In polymer / bioactive substance in the body. In some cases, the drug is also soluble

I 5 in the system so that a homogeneous solution of polymer and I will exist

In drug for injection. In other cases, the drug is not soluble in the system

In the sample so that a suspension or dispersion of the drug is obtained in the powder

In the liner system. This suspension or dispersion may also be injected into the body

In the pen. In either case, the polymer will assume solid form and retain or I

I; 10 enclosed the drug in the solid matrix. The release of drug from these M

In solid implants, the same general rules for the release of a drug follow

Part of a monolithic polymeric device. The release of drug can

I is affected by the size and shape of the implant, the amount of drug in the im- I

In the plant, the permeability factors of the drug and the particular polymer

In 15 as well as the breakdown of the polymer. Depending on the bioactive substance you are

In selected for administration, the above parameters can be adjusted by one skilled in the art

In the field of drug administration to provide the desired release I

In speed and duration. IN

For the purposes of this specification, the term "drug or I

bioactive (biologically active) substance 'without exception physiological or pharmacological I

active substances that act locally or systemically in the body. Typical eczema I

I pierce on drugs and biologically active substances for use with the injected I

In just solid implant systems formed in situ, without limitation, I

In 25 peptide drugs, protein drugs, desensitizers, antigens, I

H vaccines, anti-infectious agents, antibiotic agents, antimicrobial agents, I

In anti-allergens, steroidal anti-inflammatory agents, anti-congestion agents, I

miotics, anticholinergics, sympathomimetics, sedatives, hypnotics, psychi- I

stimulants, tranquilizers, androgenic steroids, estrogens, I

30 substances with progesterone action, humoral agents, prostaglandins, analgesics

In tika, antispasmodics, antimalarials, antihistamines, cardioactive agents, I

9 DK 175848 B1 nonsteroidal anti-inflammatory agents, antiparkinson agents, antihypertensive agents, adrenergic β-blockers, nutritional preparations and benzophenanthrine alkaloids. For those skilled in the art, other drugs or biologically active substances which can be released in an aqueous environment can be used in the injectable administration system described. Various forms of the drugs or biologically active substances can also be used. These include, without limitation, forms such as uncharged molecules, molecular complexes, salts, ethers, esters, amides, etc., which are biologically activated by injection into the body.

The amount of drug or biologically active substance incorporated into the in situ injectable solid implant depends on the desired release profile, the drug concentration required to achieve a biological effect and the time period for the drug to be released for treatment. There is no critical upper limit on the amount of drug incorporated into the polymer solution except the limit for obtaining an acceptable solution or dispersion viscosity for injection through a needle. The lower limit of drug incorporated into the administration system simply depends on the activity of the drug and the time required for treatment.

In all cases, the solid implant formed in the injectable polymer system will undergo a slow biodegradation within the body and allow natural tissue to grow and replace the pressure as it disappears. When injected into a soft tissue defect, it will fill the defective area and provide a scaffold for natural collagen to grow on. This collagen tissue will eventually replace the biodegradable polymer. In hard tissues, such as bone, the biodegradable polymer will support the growth of new bone cells, which will also eventually replace the degraded polymer. In drug delivery systems, the solid implant formed by the injectable system will release the drug contained in its matrix at a controlled rate until the drug is depleted. With some drugs, the polymer will degrade after the drug is bleached.

I DK 175848 B1 I

I 10 I

You know, completely exhausted. For other drugs, such as peptides or protein I

In the drug, the drug will be completely depleted only after the polymer is degraded

To a point where the non-diffusing drug has been exposed to

In the body fluids. IN

I 5 I

In the injectable biodegradable implants formed in situ can also I

I is prepared by cross-linking of biodegradable polymers which fit I

In sending way is made functional. The thermosetting system comprises I

reactive, liquid, oligomeric polymers which cure at the site to form I

In solids, usually by the addition of a curing catalyst. Although I

In any of the biological downgrades described above for the thermoplastic system

In fragile polymers can be used, the limiting criteria are that the oligomer

Low molecular weight tubes of these polymers or copolymers must be I

liquid and must have functional groups at the ends of the pre-I

In 15 polymers which can be reacted with acryloyl chloride to form acrylic ester-I

In terminated prepolymers. IN

In the preferred biodegradable system, it is from poly (DL-lactide-co-I)

In caprolactone), "DL-PLC" formed. Low molecular weight polymers or oligomers

In 20 coolant formed from these materials, liquid liquids are at room I

In temperature. Hydroxy terminated PLC prepolymers can be synthesized by I

In copolymerization of DL-lactide or L-lactide and ε-caprolactone with a multi-I

In functional polyoline initiator and a catalyst. Applicable catalysts for production

Preferably, in the position of these prepolymers are basic or neutral transesterification

In cation catalysts. Metallic esters of carboxylic acids containing up to 1

In 18 carbon atoms such as formic acid, acetic acid, lauric acid, stearic acid and I

In benzoic acid, usually used as such catalysts. The preferred I

In catalysts, tin (II) octoate and tin (II) are chloride, both due to FDA compliance.

In mood and performance. IN

I 30 I

DK 175848 B1 11

If a bifunctional ester is desired, a bifunctional chain initiator such as ethylene glycol is used. A trifunctional initiator such as trimethylol propane forms a trifunctional polymer, etc. The amount of chain initiator used determines the resulting molecular mass of the polymer or copolymer.

At high concentrations of chain initiator, it is assumed that one bifunctional initiator molecule initiates only one polymer chain. On the other hand, when the concentration of bifunctional initiator is very low, each initiator molecule can initiate two polymer chains. In any case, the polymer chains are terminated by hydroxyl groups, as will be seen in Figure 1.1. In this example, it is assumed that only one polymer chain is initiated per bifunctional initiator molecule. This assumption allows the calculation of a theoretical milk cooling mass for the prepolymers.

; A list of the synthesized bifunctional PLC prepolymers is shown in Table 1.

Appropriate amounts of DL-lactide, ε-caprolactone and ethylene glycol were combined in a flask under nitrogen atmosphere and then heated in an oil bath at 155 ° C to melt and mix the monomers. The copolymerizations were then catalyzed by the addition of 0.03 - 0.05 wt% SnCl 2. The reaction was allowed to continue overnight. The hydroxyl number of the prepolymers was determined by standard titration procedure. The Gardner-Holdt viscosities of the liquid 20 prepolymers were also determined by the procedures set forth in ASTM D 1545. The highest molecular weight prepolymer (MW = 5000) was a solid at room temperature, so its Gardner-Holdt viscosity could not be determined.

The diol prepolymers were converted to acrylic terminated prepolymers by reaction with acryloyl chloride under Schotten-Baumann-like conditions as seen in Figure 2 and summarized in Table 2. Other methods of converting the diol prepolymers to acrylic terminated prepolymers can also be used.

30

I DK 175848 B1 I

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I 12 I

Both THF and dichloromethane were evaluated as solvents in acylation I

In the reactions. Several problems were encountered when using THF as I

In solvent. The triethylamine hydrochloride formed as a by-product of RE-I

The action was so finely divided that it could not be effectively removed from the reaction

In the mixture by filtration. It is reported that triethylamine hydrochloride (Et3N.HCI) I

You cause polymerization of acrylic molds (U.S. Patent No. 4,405,798). I I

In several instances where attempts to remove all Et3N.HCI failed, they formed I

In acrylic ester terminated prepolymers gel premature. To effectively remove everything

Thus, in Et3N.HCI it was necessary to extract the prepolymers with I

In 10 water. In reactions performed in THF, it is first preferred to evaporate I

In THF under vacuum, redissolve the oil in CH2 Cl2, filter out Et3N.HCI and then I

In extract the CH2Cl2 layer with water. During the extraction, I sometimes met

I on stable emulsions. Acylations were later performed in CH 2 Cl 2 instead of I

I! THF. The filtration of Et3N / HCl from the reaction mixture was found to be very I

For 15 easier using this solvent and the organic fraction

The ion could be extracted directly with water after filtration. IN

Both the diol and acrylic prepolymers were investigated by IR and 1 HNMR specimens.

In faith copy. The conspicuous feature of the IR spectra of diol prepolymers is an I

In 20 prominent O-H areas centered at ca. 3510 cm -1. After acylation, I-

The intensity of the O-H region is markedly increased and new absorptions occur

In bans at approx. 1640 cm -1. These new absorbances are attributed to the C-C region I

In associated with acrylic groups. Similarly, the presence of I

In acrylic ester groups obvious in the 1HNMR spectra, the characteristic reso- I

In 25 shades for the vinyl protons, the range falls from 5.9 to 6.6 ppm. IN

The acrylic prepolymers and diol prepolymers were then cured as is I

summarized in Table 3. The general procedure for the curing of prepolymer- I

The purees are hereinafter described: to 5.0 g of acrylic prepolymer contained in an I

30 small beaker was added a solution of benzoyl peroxide (BP) for approx. 1 ml CH 2 Cl 2. IN

In some cases, fillers or additional acrylic monomers were added to prepolymer

13 DK 175848 B1 before adding the BP solution. The mixtures were thoroughly stirred and then poured into small petri dishes. These bowls were placed in a preheated vacuum oven for curing. Some of the samples were cured in air and not under vacuum and thus these samples are indicated in Table 3.

: 5

This thermosetting system can be used wherever a biodegradable implant is desired. For example, because the prepolymer remains liquid for a short time after the curing agent is added, the liquid prepolymer / curing agent mixture can be placed in a cannula 10 and injected into a body. The mixture then assumes solid form in situ, thereby obtaining an implant without surgical incision. Furthermore, a system for administering drugs is obtained by adding a biologically active substance to the prepolymer prior to injection. Once the system is in situ, it cures to a solid; over time, it degrades biologically and the biologically active substance is released gradually.

15

DETAILED DESCRIPTION OF EXAMPLES

The invention is further explained by the following examples.

EXAMPLE 1

An illustrative method is described for the synthesis of an acrylic-terminated prepolymer. To an oven-dried, 500 ml three-necked round bottom flask equipped with a drip funnel, gas supply adapter, mechanical stirring equipment and 25 rubber partition was added under nitrogen atmosphere 100.0 g of difunctional hydroxy terminated prepolymer and 200 ml of freshly distilled THF (from CaH 2). The flask was cooled in an ice bath and 24 ml of dry triethylamine (0.95 eq / eq OH) was added via a cannula. The drip funnel was charged with 15.4 g of acryloyl chloride (0.95 eq / eq) in 15 ml of THF and the solution was added dropwise to the stirred reaction mixture over an hour. The mixture was stirred overnight and allowed to reach room temperature. The precipitated triethylene

I DK 175848 B1 I

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In min hydrochloride was removed by filtration and the filtrate was evaporated under vacuum

In vacuo to give a pale yellow oil which was the acrylic terminated prepoly-H

In more. The acylations with CH 2 Cl 2 as solvent were carried out on a lig-H

In nende way. However, the reaction times at 0 ° C were shortened to 1 hour, 1

At 5, the reaction mixtures were allowed one hour to reach room temperature

In turn. Et 3 N 1 HCl was filtered off, additional CH 2 Cl 2 (about 800 ml) added to the filtrate, and I

The filtrate was extracted several times with 250 ml portions of water. The organic I

In layers, dried over MgSO 4 / Na 2 SO 4, filtered and reduced in vacuo

In to an oil. The flasks with acrylic prepolymers were wrapped in foil and stored

In 10 right in refrigerator as a precaution against premature crosslinking. IN

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Claims (14)

29 DK 175848 B1 A biodegradable, thermosettable polymer system comprising a liquid, biodegradable, thermosettable prepolymer, a curing agent and optionally a bioactive agent for in situ formation of a biodegradable solid implant structure characterized in that the liquid acrylic ester terminating oligomeric polymer which can be cross-linked in situ. System according to claim 1, characterized in that the prepolymer is synthesized by copolymerization of DL-lactide with ε-caprolactone. System according to claim 1, characterized in that the prepolymer is synthesized by copolymerization of L-lactide with ε-caprolactone. 15 System according to claim 2 or 3, characterized in that the prepolymer is formed by the polymerization of a polyol initiator. System according to any one of claims 2 to 4, characterized in that a catalyst is added to the copolymerization step. System according to claim 5, characterized in that the catalyst is tin (II) octoate and tin (II) chloride. A system according to any one of claims 1 to 6, for forming a solid implant in situ in a body by mixing the prepolymer and the curing agent and by positioning the system in the body and curing thereof. System according to any one of claims 1 to 7, characterized in that the curing agent is azobisisobutyronitrile or benzoyl peroxide. in DK 175848 B1 I The system of claim 7 or 8, characterized in that it contains a biologically active agent which is released by diffusion or erosion when the implant I I is biodegraded. H System according to any one of claims 1 to 9, characterized in that the system is injectable. H H A system according to any one of claims 1 to 10 suitable for forming an implant I in a periodontal pocket or in tooth extraction sites. A system according to any one of claims 1 to 10, suitable for forming an implant H in a bone defect or wound. H The system of any one of claims 1 to 10, suitable for forming an implant H 15 for bonding tissue to tissue or another implant to tissue. H A system according to any one of claims 1 to 10, suitable for forming an implant I for tissue formation or for filling into a defect. I DK 175848 B1 o o o r il in r in H — OCHCOCHC 4-4 — OCH2CH2CH2CH2CH2c- | —O — R — OH ch3 ch3 n m o ^ Cl R '= H.CH3etc THF. Et3N. 0 ° C - RT R 'OOOO OR' i ii r ii nr ii 1 ni CH2 = C — C-4-OCHCOCHC4-4-OCH2CH2CM2CH2CH2c4— o — r— o — cc = ch2 ch3 ch3 o / -o- o V ° - oo '- ^ y F1G.I DK 175848 B1 I FIG.2 I ϊ SI Co ΤΙΝ (II) OCTOflT I \ + | ♦ HO-R-OH + or 7 2 "SnC'2 IO INITIATOR CATALYST ^ OO _ OI Γ i! Ii 1 ii 1 HJ- OCHCOCHC -J - OCH2CH2CH2CH2CH2C — J —- O — R — OH CH3 CH3 J2n 2m I or H ro OOI Γ 11 II II Hj-OCH2CH2CH2CH2CH2C --- OCHCOCHC - O — R— OH 2m CH3 CH3 zn H or H r ° O-, r O o OOI II 111 Γ II I II II I Γ II 1 HJ -OCHCOCHC-j-J-OCH2CH2CH2CH2CH2c4-0— R— O-- CCHOCCHO -j - f- CCH2CH2CH2CH2CH2o4-H CH3 CH3 π ^ CH3 CH3 * · I