CA1242705A - Esters, their preparation and use - Google Patents

Abstract

NOVEL ESTERS, THEIR PREPARATION AND USE

Abstract This invention provides a polyester of a polyol, said polyol containing at least 3 hydroxyl groups and having a molecular weight of up to 20,000 at least 1 hydroxyl group in said polyol being in the form of an ester, with a poly- or co-poly-lactic acid residue, each having a molecular weight of at least from 5,000.

These are useful for parenteral depot formulations.

Description

~L~ 100~6114 , Novel esters, their preparation and use The invention relates to novel esters,especially polyol esters~
with polymeric hydroxycarboxylic ester residues, their preparation and use e.g. in ~he production of depot forms of pharmacologically active agents.

A broad class of polyol esters having polymeric hydroxycarboxylic ester residues are disclosed from the German Patent No. 1.020.034 in which glycerol esters having polylactide ester residue of 30 lactic acid residues or pentaerythritol ester with poly-lactic acid residue of 16 lactic acid residues are speci-fically described. The patent does not specifically disclose any longer chain polymer esters of polyols having at least three hydroxyl groups.

These products are used as solvents, e.g. for pharmaceutical ]5 purposesl as emulgators or as additives for synthetic materials and plastics, There ls no disclosure of their use for pharma-ceut1cal depot matrix compositions.
Esters from sugar alcohols, e.g. from erythritol, xylitol, ribitol and sorbitol with poly- ~-hydroxycapronic acid are described in Journal of Polymer Science, Polymer Chemistry Edition, Vol. 20, 319-3~6, especially at 323 326 (1982).

The molecular weight of these esters depends on the extent of esterification of the hydroxyl groups of the polyol esters and on the length of the poly- ~-hydroxycapronic acid residues.
Its order of magnitude is from about 26000 ~o 65000.

" 1 ~j '~

76~5 The esters exhibit a star polymer structure, their single polyol residue as the central part being surrounded by acid residue chains. No use of the polyol esters is men-tioned in the publication.

The diffusion velocity of pharmacologically active agents from the ester and the degradation velocity of the ester as a matrix material for active agents are too small for practical use as an implant or microcapsule. Due to the hydrophobic properties of the poly-~-hydroxycapronic acid residues the esters are not suitable as matrix materials for depot forms of pharmacologically active agents.

Several depot forms of pharmacologically active agents have been proposed in the literature. In the ~Juropean application No. 92918, published November 2, 1983, are disclosed polypeptides in a matrix of an ester of e.g.
polyvinyl alcohol (M.W. 14,000) or polyethylene glycol (M.W. 6,000 or 20,~00) containing polymer hydroxycarboxy-lic ester residues, e.y. from lactic acicl (~.W. 26,000 to Ll~,000) and sometimes additionally glycolic acid (M.W.
~0 10, 000) .

However, matrix materials having high molecular pro-portions of such polyol radicals have too hydrophil;c properties and become degraded under use conditions too ~uickly.

25 Aclditionally, the strong hydrophilic properties and soft-ness of the matrix materials hinder their production, the further processing and the use of depot forms, especially microcapsules.

"l . !~,i .L ,"~, 7~

As esters are addltionally mentioned, e.g. dextrane as a polyol, but due to the high molecular weights of the dextranes such ester formation is practically impossible.

Depot forms of pharmacologically active agents in a mat-rix of a polymer of polyols and hydroxy carboxylic acids are proposed as part of a very broad class of products in the International applica~ion WO 78/00011 (PCT) pub-lished December 21, 1978. However, polymers of polyol and hydroxy monocarboxylic acids are not exempli~ied.
Exemplified are depot forms from a polyol ester containing polymeric dicarboxylic acid residues, e.g. of tartaric acid.

The polyol esters have a structure different from the products described above. They have a linear chain and contain alternatively polyol residues and dicarboxylic acid residues.

The formed esters have such a Iow solubility, and solub].e precondensates must be Eormed in order to incorporate the pharmacologically active agents. Only then can the pre~
condensated active agent containing matrix materials be condensed further.

If saturated dicarboxylic acids, such as tartaric acid are usedp it is stated that the final total condensation must be carried out at an elevated temperature (about 170 200C) which is not suitable for heat-sensitive active agents.
Using pentaerythritol as a polyol, strongly cross-linked products are ormed, which are not suitable for incorpo-rating pharmacologically active agents and which do not degrade in vivo su~iciently fast.

~ lQ~-611~

The mass degradation rate for depot formulations made from these materials is too slow.
The manufacturlng process disclosed to produce the microcapsules or other depot forms is also tedio~s.

The known matrix polymers of the art generally have a disadvan-tageous short or long degradation period under conditions of use, e.g. in the body, compared with the required releaseperiod of the pharmacologically active agent~ causing the active agents either to disappear prematurely with the matrix material or to be dis-appeared completely from the still present polymer matri~. Accor-dingly an additional dosage of the depot form cannot be ad-ministered subsequently, since an undesired accumulation of the polymeric matrix material may occur.

The present invention sets out to overcome the above disadvantages and ~o provide a useful pharmaceutical depot form for clinical use.

Furthermore the depot forms made from the polyol esters according to the invention may have the advantage of a drug release t;me which is satisFactorily long, e.9. 1 month, and a short degradation ~ perlod o~ the mass thereafter. They are suitable for the in-corporation of a large v~riety of e.g. water soluble or hydro-phobic active agents.

Additionally9 the polyol esters of the invention may be easy handled and be easily worked up to incorporate ~he active agents and to produce pharmaceutical composition forms, e.g. m;crocapsules and implants. lhese microcapsules are not soft: consequently, they are easy to administer ~hrough an injectlon needle.

5_ 100~611~

The present invention provides anester of a polyol, said polyol con-taining at least 3 hydroxyl grou~ and having a molecular weight of up to 20,000 at least 1 hydroxyl group in said polyol being in the form of an ester, with a poly- or co-poly-lactic acid residue each having a molecular weight of from 5,000 e.g. to 35,000. In another aspect the present invention provides a reaction product of a polyol containing at least 3 hydroxyl groups and having a molecular weight of up to 20~000 or a reactive derivative thereof and lactic acid or a reactive derivative thereof and if desired at least a second hydroxycarboxylic acid or a functional derivative thereof~ the product having a polymer chain of molecular weight of at least 5,000. These products are indi-cated as polyol esters of the invention.

The polyol residues are particularly of a polyol containing a chain of car~on atoms.
A special polyol form is such havinq a linear structure and containing 3 to 6, particularly 6 hydroxyl groups. Suitable polyols having a linear structure include e.g. mannitol1 penta-erythritol, sorbito, ribitol and xylitol. Another preferred polyol form is one having a cyclic structure and containiny 4 to 30 hydroxyl groups.

The polyols of a cyclic structure contain particularly one or more saccharide units and with at least 3 hydroxyl groups per unit.
cxamples of such polyols are those with a fructose structure, e.g.
fructose itself.
Particular polyols with cyclic structure are those having glucose struçture, e.g. glucose i~self, or having 2 to 8 glucose units.
These units are preferably connected in 1,4 andlor 1,6-position, especially in 1,4-position. A polyol con~aining more glucose unitsJ connected in 1,4-positton, is e.g. ~-cyçlodex~rine.

The preferred polyol is glucose.

The polyol esters may have e.g. a polyol residue with at leas~ 2 or 3 hydroxyl groups in the form of esters, which contain poly-lactide or co-poly-lactide chains. Their structures may be thus branched,i.e star shaped. Preferably each such chain has the same hydroxycarboxylic acid residue.
The chains may contain lactide residues alone. Alternatively they may contain additionally e.g. one, two,three or more specific hydroxycarbo-xylic acid residues9 e.g. up to 70 Mol%, e.g. 30-70%.

Preferred extra residues are glycolic acid residues. Preferably up to 70 Mol%, e.g. 30-70%, especially S0 Mol% glycolic acid units are pre-sent. Instead of or in addition to the glycolic acid units other different units may be present, e.g.~ - hydroxycapronic acid units, preferably up to 20 Mol%.
The lactic acid units may be present in optical pure form (D- or L-lackide form) or as their mixtures, e.g. their racemic form (D~L-lactide form).
The present invention also provides a process for the production of a product of ~he invention characterised in that a polyol of a molecular weight of up to 20,000 and having at least 3 hydroxyl groups or a reac-tive derivative khereof is esterified with lactic acid or a reactive derivative thereof or additionally with at least a second hydroxycarbo-xylic acid or a functional derivative thereof.
Preferably the process is characterised in that a polyol of a molecular weight of up ~o 209000 and having at least 3 hydroxyl groups, is reacted with lac~ic acid or additionally with at least a second hydroxycarboxy-lic acid in lactone- or dimeric cyclic ester form, in the presence of a catalys~, which makes a ring opening polymerisation feasible.
The catalyst is preferably Sn-octoate.

~'2~

The reaction c~mponents are e.g. mixed together with the catalyst and reacted at an elevated temperature.

If a solvent is present, e.g. toluene, the components may be reacted at the reflux temperature of the solvent. Without a solvent the reaction temperature can be higher, e.g. if gluc3se is used as a polyol, up to a~out 170 and if ~-cyclodextrine is used, up to 180.
Preferably the reaction is effected in the absence of water.

The ~ormed pDly~l ester of the invention may ke purified and isolated in a conventional manner.

The determination of the lecular weight of the purified product may be effected using oonventional methods, preferably by gelpermeation-chro~atography (GPC1 using polyst~rene as standard ~w~ (Dupont Ultrastyragelo~ R 500 angstrom and 10,000 angstrom as the ool~mn) and tetrahydrofuran as a solvent, at room temperature.

The lecular weights Mw of the polyol esters according to the inven-tion are preferably between 20,000 and 200,000, e.g~ between 20,000 and 80,000.

The ~lecular weight.~ o~ the pol~ol esters of the invention are depen-den~ on the weight ratio of the components ln the reaction and on the reactlon oonditions, e.g. the reaction temperature ~see Example 8). A
lower reaction temperature may lead to shorter polymer chains an~ thus to lower molecular weight poly~l esters.

The isolation and purification may influence the molecular weight of the purified poly~l ester. Changing the isolation and purification conditions leads to a change of the molecular weight (see Exanple 2).
Since the polyol ester may exist generally in fact as a mixture of molecules with chains of a different length and c~mposition of this mixture may be influenced by isolation and purification methods, such as extraction, filtration and the isolation and purification liquids and their amounts and the isolation and purification temperature.

~ 100-6114 The molecular weight of the purified polymer may be increased by removing low molecular weight compounds, e.g. by a suitable pr~ci-pitation of the polymer, e.g. in methanol, or by a membrane fil-tra~ion.

The amountoP components having lower molecular weights may be reduced by membrane filtration to such an extent, that in the molecular weight speckrum, determined by GPC, their peaks al-together have a height of up to 10%, preferably up to 7% of the height of the peak Mw of the polymer.

The invention thus also proYides a product, wherein in the GPC any separate low moiecular weight peaks comprise altogether up to 10% of the height of the peak Mw of the polyester.

The polyol esters of the invention are particularly suitable to in-corporate active agents and produce sustained release effects of the active agents in the body.

The balance of hydrophobic and hydrophilic factors - the polyol re-sidue represents the hydrophllic and the poly lactide or co-poly lactide residue the hydrophob;c factor - can be regu1ated by chancJ;ng the polyols, the extent of esteriPication oP the hydroxyl groups, the chain length of the polymeric chains and the identity and the relative amounts of the specific hydroxycarboxylic acid units in the chain.

fh'7~5 ~ 9 ~ 100-6114 The polyol es~ers according to the invention are therefore particularly suita~le for the preparation of pharmaceutical depot formulations containing pharmacolog;cally active agents. Such depot forrnulations may exist as a polyol ester matrix containing the active agent. Preferred depot forms are implants (e.g. for su~cutaneous administration) and microcapsules (e.g. for oral or particularly for parenteral, e.g. intramuscular administration).

The present invention therefore also provides a pharmaceutically depot form, having a matrlx of the ester of the invention, containing a pharmacologically active agent.

The depot forms are novel and form part of the invention.

The depot forms may be made in conventional manner, the polyol esters according to the invention being easy to handle and often incorporatirg a h;gh concentration of active agent.
In order to produce microcapsules, the active agent may be dis~olved in ~ volatile solvent, such as methylene dichlo-ride. A solution of the polyol ester, e~g. in the same solvent, may then be added and ~:he resulting mixture may be ~prayed into air while carefully regulating the temperature and then dried to form microcapsules.
~lternatively the active agent may be dissolved or suspended9 e.g. in methylene dichloride, and the polyol ester may be dissolved in a volatile, water immiscible solvent, e.g.
methylene dichloride, after which the organic phase may then be mixed vigorously wtth a sttrred aqueous solution, e.g, buffered to pH 7, optionally conta;ning e.g. gelatine as an emulsifier. The organtc solvent rnay then be removed from the resultant emulsion and the resultant microcapsules be filtered off or separated by centrifuging, washed, e.g. in a buffer3 and dried.

7~
- 10 - 1~0-611~

In order to pr~duce implants the acti~e agent may be mixed with the polyol ester and dissolYed in a volakile solvent.
The solven~ may ~e evaporated and ~he residue ground up. An extrusion may be formed in corventional manner, which is then pressed e.g. as implant ~ablets o~ 5 to 159 especially 7 mm, and of 20-89 mg9 e.g. 20-25 mg matrix material a~ 75C and 80 bar during 10 to 20 min.

Depending on the active ag~nt~ the microcapsules may take up an average of up to 60 % ~y weight of the active agent.
The implants are preferably prepared in such a manner that they contain up to 60,e.g. 1 to 20 %,by weight of the active agent.

For the active agent br~rnocriEJt~ne, microcapsules may be preparcd containing at most 25 %, especially up to 18 ~ and implanks containing up to 18 % by weight of the actiYe agent.

The ~icrocapsules may have a diameter from a few subm;cron to a few millimeters. For pharmaceutical microcapsules diameters of at most about Z50 microns, e.g. 10 to 60 microns/are str1ved ~or, in order to ~acilitate passage through an ;njection needle.
The denot formul~tion accordlna to the inventlon may be used to administer a wide variety of classes of active agents, e.g.
pharmacologically active agents such as contraceptives,sedatives, stero;ds, sulphonamides~vaccines 9 Vi tami nes ,anti -mi grai ne drugs, enzymes 9 bronchodilators,cardiovasGular drugs, analgesics,anti=
biotics, antigens, an~i-convu1sive drugs~ anti-inflammatory drugs~
anti-parkinson drugs,prolackin secretiQn inhibitors,anti-asthmatic drugs, geria~ics and anti malarial drugs.

~ 100-6114 The depot formulations may be used for the known indications of the particular active agent incorporated therein.

The exact amounts of active agent and of the depot formulation to 6e administered depends on a number of factors, e.g. the condition tD be treated, the desired duration of treatment, the rate of release of active agent and the degradability of the polymer matrix.
;

The desired formulations may be produced in known manner. The amount of the pharmacologically active agent required and the release rate thereof may be determined on the basis of known in vitro or in vivo techniques, described e.g. in Examples 26-29, e.g. how long a particular active agent concentration in the blood plasma remains at an acceptable 1evel. The degradability of the matrix may also be obtained by in vitro or especially in vivo t'echniques, for example wherein the amount of matrix materials in the muscle is weighed after particular time periods.

The depot formu'lations of the invention may be administered in the form of e~g. microcapsules, e.~. orally preferab'ly subcutane-ously or intramuscularly, preferably in the form of cr in a sus~ension in a suitable liquid carrier or in the form of implants, e.g.
sub-cutaneously.

Repeated administration of the depot formulations of the invention may be effected when the polyol ester matrix has sufficiently degraded, e.g. after 1 month.

~%~25 Examples of doses for the preferred compounds are;
For prolactin secretion inhi~itton with ~romscryptlne, ~or example an l.m. depot formulation may be produced which daily provldes 2.5 to 7.5 mg bromocryptine over a~out 30 days and contains for example 70 to 230 mg bromocryptine mesylate.

For the treatment of bronchial asthma with ketotifen, for example an i.m. depot formulation may be produced which daily provides 0.5 to 0.8 mg ketotifen over about 30 days and contains for example 15 to 25 mg ketotifen.

For the reactivation of cerebral metabolism with codergocrine, for example an i.m. depot formulation may be produced which daily provides 0.1 to 0.4 mg co-dergocrine in about 30 days and contains about 3 to 12 mg.

Depot formulations for other active agents may be formulated in analogous manner1 e.g. to provide the known appropriate, e.g. therapeutlc, concerltration of active agent for parenteral use over an exkended period of ~ime, e.g. 30 days.

As indicated above the polymer degradatlon may be followed in in vivo and in vitro experiments,described in Examples 24 and 25.
It may be seen tha~ the polyol esters of the invention degrade faster than corresponding known polylactide and poly-lactide/gly-colide acids and especially a faster degradation may be seen in the early stage, e.g. up to 30 days~ especially in the case of poly-lactide/slycolide polymer chains.

'7~
-13- 100~

Membrane filtration results in residual polymer products having in general in the early sta~e, especially up to 30 days, a smaller mass degradation rate as that of the corresponding non-fil'cered product. In the case of residual polyol esters of the invention, the degradation may be over 50% up to 30 days, and in the case of the Example 6 as described hereinafter about 70%. After 40 to 50 days it may be practically complete.

In in vitro and in vivo release rate tests the polyol esters of the invention may release the active agent at the same rate order as for corresponding known polymeric poly- or co-poly-lactides, e.g. in 30 days.

The active agents may be released mainly by diffusion from the matrix and only to a small extent by degradation of the matrix material.

This results in a more regular rate of release of active agent.
An advantage of the polyester matrices of the invention in that after a practically complete release of active agent they may be quickly degraded to an accpetable size, which may be transported by the body f'luids from the site of administration.

Accordingly the present invention provides a parenteral pharma-ceutical depot formulation for use as an implant or microcapsules containing a pharmacologically active agent embedded or encap-sulated in a polymer matrix, said formulation being adapted to re-lease al'l or substantially all the active material over an extended period of time and the polymer being adapted to degrade sufficiently to be transported from the site of administration within 20 days af'cer release of all or substantially all the active agent.

- 14 - lOO 6l1 ( In the following examples all temperatures are in degrees Centiyrade and uncorrecked.

HYFL ~is a known filtering aid.

~2~

Polyol ester from D(+)-~lucose, DL-dilactide and diglycolide Example 1:
7~.4 9 (0.684 Mol) of diglycolide, 120.6 9 (0.838 Mol) of DL-dilactide and 0.4 9 (2.2 mMol) of D(+)-glucose (0~2 %) were placed in a 1.5 1 flask and heated, while stirring to 135 in an argon atmosphere after which 1 ml of Sn-octoate was added.

The reaction is exothermic. The temperature i:ncreases to 172.
After 5 minutes stirring is discontinued and ~he brown viscous mixture is reacted further at 130-140 for 17 hours. After cooling 500 ml of methylene dichloride was added. The mixture was dissolved as much as possi~le by 6Oiling and the solvent was separated. This procedure was repeated after which the residue was extracted additionally with 500 methylene dichloride. The combined dark-brown solutions (in total 1500 ml) were puri~ied with 50 9 Hyflolconcentrated to 500 ml and treated with 500 ml of a 10~ aqueous HCl-solution to remove the catalyst. The solution was washed five times with 500 ml of water -to pH 4.5 and diluted to 1 1 with methylene dichloride.

The solution was treated with M9504 and with Hyflo, concentrated to 500 ml and added dropwise within half an hour to 3 1 of methanol at -&0C. ~t this temperature the mixture was stirred for 3 hours. Then the product was filtered off and dried at 40QC in vacuo.

The molecular weight was determined by yel permeation chromato-graphy (GPC):

Mw. = 34 800 Mn = lq 600 M~Mn = 1.77 Acid number; 6.8 Non-reacted lactide: 1.7 %
Non.reacted glycolide:~ 0.4 %
Molar ratio glycolidellactide in the polymer~c chains: 45l55 NMR: 360 MHz; (CDC13) 5.20 (m, 0.55 H, -CH-lactic acid) 4.82 (m, 0.9 Hg -CH2-glycoltc acid) 1.58 (m, 3 H, -CH3-lactic acid) _: (CH2C12) cm 1 2950 (w,CH3); 1760 (s,-COOR); 1390 and 1420 (w,CH3); 1160 (s,-O-); 1090 (s,-O-). , ~l2~70~
- 17 - 100~611 ~c~ ~
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- 18 10~-6114 Comments on Ex~mple 2:
Prepared to show by analysis that the glucose was incorporat~d into the polymer and that indeed a polyolester was formed Measures were taken to intensify the NMR-signal of the glucose.
The glucose was a C13-uniform marked glucose with 98.3 atom percent C13 (LOT No.2358-4 MSD ISOTOPES, Merck, Canada) The NMR-signal of the C13-glucose starting material was compared with the signal of the C13-glucose ester:

C13-Glucose NMR C13 ppm 97.13 (d,C-l~); 93.32 (d,C-la); 77.63 (t,C-5~); 76.92 (t,~-3~); 75.57 (t~C-2~);73 .84 (t,C~3a); 72.92 (t,C-2a);
72.24 (t,C-5a); 71.07 (t,C-4a); 70.63 (t,C-4~);
61.g5 (dxd, C-6o~).

C13-Glucose ester of Exame~ 2:
NMR Cl3 ppm 91.80 (m, C-l~); 89.8~ (m, C-la); 72.51 ~ 66.73 (m, C-2,3,4,5a~); 62.90 (m, C-6).
Since the glucose signals all are broad multiplets, it is assumed~
that the glucose was practically completely incorporated.
Mol ratio lactidelglycolldelglucose = 32.3/66.7/0.2.

7~5 Comments on Example 3:

GPC-determination with simultaneous UV and radtoacttvity determinat~on was used for the analysis of these products.
It is observed that t~e radioactiv-lty of the test sample is propurtionally distributed over the whole range of molecular weights and that both the retention times in the W and the radio-activity determinations are equal.
The radioactlvity of the test sample is about 30 % of the predicted value, indicated that about 0.06 % of the glucose was incorporated (It was started wit~ 0.2 %).

Example 6:
The product of Example 4 was dissolved in methylene dichloride and purified by a membrane filtration under a pressure of

2 atm.

Amicon apparatus - Membrane: DDS 6000 MWCO
Type FS 81 PP
Flow velocity: 2,2 ml/min The end volume was 2000 ml.

Residue: From NMR:
MW 3 42 200 Mw 1.35 lactide = ~ ~Mol ratiO) Mn = 31 300 Mn glycolide 47 ~cid number 3.4 non reacted lactide ~0.2 %
non reacted glycolide<0.4 %
. ~

~ 20 - 100-6114 Filtrate From NMR;
Mw - 21 600 Mw 1,58 lactide 53 (mol ratto) Mn = 13 600 Mn glycolide 46 Acid number 10.1 non reacted lactide 1.2 %
non reacted glycolide<0.4 %
Example 7.
3q.7 9 tO,342 Mol) of diglycolide, 60.3 9 ~0.41g Mol) dilactide and 0.2 9 (1.1 mMol) D(+)-glucose (0.2 ~) and 40 ml of toluene lo are heated in a 750 ml flask, while stlrring to ~oiling temperature (108) after which 0.5 ml Sn-octoate are added. The reaction is slightly exothermic. The temperature was raised to 112. After

3 hours stirring was discontinued and the brown viscous mixture was reacted further three days at 110. After cooling 500 ml of methylene dichloride were added and the mixture was dilute~l al:
boiling temperature, purified with Hyflo and filtered.

The solution was evaporated to dryness, the residue dissolved in methylene dichloride and shaked with 400 ml of a 5 % aqueous HCl solution. The solution was washed four times with 400 ml of water to pH 5 and dilutPd to 1 1 with methylene dichloride.

The solution was dried with MgS0~ and evaporated to dryness in vacuo at 40C, The residue was dried in vacuo at 40.

Molecular weight: Mw = 32 200; Mn ~ 18 400; MwlMn = 1.75c NMR and IR: As tn Example 1.

~2~

100-~114 , ~
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Example ~;
~n an analogous manner as descr1~ed tn Example 6 the following product was prepared ~y membrane filtration from the product of Example 8:

Flo~ velocity; 1 ml/min The end volume was 2200 ml Residue From NMR:
Mw = 26 200 Mw = 1.45 lactide = 62 (mol ratio) Mn _ 18 000 Mn glycolide 37 Acid number 4.0 non reacted lactide < 0.2 %
non reacted glycolide < 0.4 %

Filtrate; From NMR:
Mw = 12 ~oo Mw 3,75 lactide = 60 (mol ratio) :I.5 Mn - 3 300 Mn glycolide 40 Acid number 9.7 non re~ct~d lactide <0.2 %
non reac~ed glycolide ~0.4 %

~2~:~t~
- 23 - 1~0-611~

Polyol ester from ~-cyclodextrtne, DL-dilactide and diglycolide _ _ . .. .
Example_ 0;
26.1 g o~ diglycolide, 3~.6 g of DL-dilactide and 0.635 9 ~-cyclodextrine were heated in a 5~0 ml flask, while stlrring to 140,in a nitrogene atmosphere after which 0.125 ml of Sn-octoate was added. The reaction is distinctly exothermic. The temperature was raised to 180. After 10 mlnutes stirring was discontinued and the brown vtscous mixture was reacted further at 140 for 17 hours.

The purification and isolat~on were carried out in an analogous manner as described in Example 1.

Molecular weight (GPC): Mw = 75 700, Mn = 72 300; MwlMn - 1,05.
Non reacted lactide: 2 %
Non reacted glycolide: <0.4 %
Mol ratio glycol;dellactide in the polymeric chains: 47l53 NMR and IR: ~s in Example 1.

7~
- 2~ - 100 611~

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7~3~;

Example 13:
The product of Example 10 was treated în an analogous manner as descrlbed in Example 6. The filtration pressure was however ralsed to 3 atm.

Flow velocity 0.2 mllmin.

Residue~ From NMR:
Mw = 72 200 Mw = 1.20 lactide 53 (mol ratio) Mn = 59 800 Mn glycolide 47 Acid number 1.0 .
lo Filtrate; From NMR:
Mw = 27 100 Mw _ 1,75 lactide = 52 (mol ratio) Mn = 15 500 Mn glycolide 48 Acid number 21,Z

Example 14;
Th~ product of Example 10 was treated in an analogous ~anner as described in Example 6. The filtration pressure was however raised to 2 atm.
Flow velocity 0.3 mllmin .
Restdue:
Mw ~ 76 700 MW _ 1.06 Mn - 72 300 Mn Filtrate:
Mw a 67 ~00 ~ = 1.43 Mn ~ ~7 600 Mn Example 15;
Equal amounts of the residues of the Examples 13 and 14 lead~
after Intermediate dissolution in methylene dichloride,to a mixture of the following formation:

Mw = 70 000 Mw = 1.36 Mn = 51 600 Mn ., ,~.

- 27 ~ l~)a~

a~ ~ ~ ~e ~e ~e a~e .
aJ ~ ,_ _ ~ N et S~ 00 ~V
a~
r ~ C~J d~
~r-- r c; ~0 r~

r-- ~ ~ d ~a~r-- ~ u L5 ~:1 r~ s r--~ O 3~ co ~

r~ r-- 5- O O O O
~ O ~ ~ ~r) ~
O 4- . c~ O
~ s ~ u~ Ln O ra, e r~, r~ v~
E r 0 r~ _ v C~ ~v~ ~ O _ S_

4--~1~ r~ r~ Ul r~
u7_~n r~ 00 = Q~
a~~~IJ . u~
OC ~ I _ _ O

E~ r~

r~ O _ C~ ~ _~ C~ r~
u~ ~ o , ~e . ~ s::
~;:: O ~ ~ t_. S_ X~ ~ O ~, ~ ~_ o L~ ~ ~S ~ r~.

~ ~3 ~ 100-511 a~ ~ ~e ~ ~e ~e ~ ~
~ o o oo oo a~ ~:n V~/ \~V
Q t t'~
.- ~ .a c- Ln o r ~ O ~ ~ Ln I d' el ~.
'~7 r~ 0_ a~ ~ 31'- ~ c~ ~ co o 1~
~ o - - ~l C~ -~ - o o o o o o o o o Q O o o o ~ Ln o o CO o ~ o o o ~r~ 3 00 0 1~ ~ n ~ O Otl ~) O a) I~
O S ~ ~ O t~ l L 1 0 O O r c~J
~J) ~ L.) Q Ln Ln ~ I~ ~O O S_ ,-.-- a E C~l et a~- a~ ~9 Ln a~
O tl~ a) ~ ~ ~ Ln Ln r~ .
x s v E ,_ ,_ ,_ ,_ _ a~~ I .~ f~ ~ 3 ~ = ~ f 'O~ ~r~ 1~0 O O
'~'a L

r '~ r- _ = ~ = =
tn al o - ~1 -~) LO Q
O E ~ fa O = : = = = 1_ ~J V~ fll .1 ~ O i t~
l o ~ O I 0 ~ ~ .t .- ~ fa C10 O f-- V ,~ S '~ C~J ~ ~ o a a r f8 ;0~ Ln ~ CTI ~ V ~ v~e v~ê ~ _ E 7 .c~ o v _ Ln a~ ~ O ~ ~~ 4~ ~~ *
~ ~ ~ ~ ~ æ ~ ~ ~

.

'7~;

f, Comments on Example 17:

NM~ (in CDC13) ~ (ppm) 5.23 (m, -CH of lactic acid, 1H); 4.83 (m, -CH~ of glyco1ic acid, 1.73 H); 4.46 - 4.17 (m, -CH- and -CH2- of mannitol and of the terminal lactic- or glycolic acid units.

Mol ratio: lactidelglycolide/mannitol = 1:0.86 : 0.08.
This corresponds to a Mw of 1530 (however in the signal 4.46-4.17 are also included the termina1 lactic- or glycolic acid units).

Used amount mannitol 672XlO 4 Mol%; incorporated amount 526~10 4 Mol%.

Comments_on Example l~.
NMR (in CDC13) (ppm) 5.23 (m, -CH~ of lactic acid, lH); 4.9-4.65 (m, -C~!2 of glycolic acid~ l,SH); 4.45-4.10 (m, -CH2~ of pentaerythritol and -CH- and -CH2- o~ the termlnal lac~ic acid or glycolic acid units, lH); 1.58 (m, CH3 of lactic acid, 3H).

Mol ratio lactide/glycolide/pentaerythritol: 1:0.75:0.15 (however in the signal 4.45-4.10 are also included the terminal lactic~ or glycolic acid units).
Used amount pentaerythri~ol 960xlC 4 Mol%, incorporated amount (from NMR) = loooxlo 4 Mol% (the signals at 4.45-4.10 p~n do not exc1usively relate to pentaerythritol).

-3()_ 10~-6114 Determination of _he degradation of polyol ester in vitro Example 24:

30 to 80 ~1m thick films are moulded from 5% solutions of the polyol ester of Example 6 in methylene dichloride. The films are dried for 50 hours at 40 in vacuo, thereafter several days in an desiccator containing P205.

300 mg of the film, divided into little pieces were added to 30 ml of distilled water and shaken at 37 (50 rpm).
The amount of polymer was determined periodically by ~iltration and weighing.

Example 25:

Implants in the fornt of tablets of 7 mm diameter and oF 23 - 25 mg, pressed from a polyol ester granulate of Example 6 at 80 bar and 75 for lO min., were implanted i.p. in rats. After a certain period they were extracted from the tissue with methylene dichloride, and thereby ceparatecl from organic tissue material, evaporated to (:Iryness and weighed 76~5i - 31 - 100-611~

Release of active agents from pol~ol ester matrices in vitro . _ Example 26;
Release tests were carried out with microcapsules, which contained 6romocriptine as active agent. The microcapsules were prepared according to the above described spray drying method with the following parameters:

Bromocriptine mesylate 2.6 9 Matrixpolymer of Example 9 (residue) lOoO g Methylene dichloride 100 ml Spray conditions (NIR0 equipment) T~mperature of the input 50C
Temperature of the ouput 40C
Air pressure 2 atm Influx 32 ml/min After their preparation the microcapsules were dried for 48 hours.
at 30 in a low vacuunl, sieved (<180 um) and washed with citrate buffer at pH 3. The microcapsules contained 17.9 ~ of the active agent.

A~ter repeated drying in low vacuum (48 hours, 35, 0.1 bar) and sievlng (< 180 um) the microcapsules were gamm~sterilized at 2.5 Mrad.

s The release was measured photometrically at 301 nm at 25C
in citrate buffer pH 4 as an extraction medium, poured freshly through the microcapsules with a flow velocity o~ 235 mllmtn.

Over a period of 24 hours about 62 % of the act~ve agent was regularly released.

N.B. The release in vitro was measured at pH 4 because of better solubility of bromocryptine at this pH.

Example 27 Release tests were carried out with microcapsules, which contained codergocrine as a active agen~s.

The microcapsules were prepared according to the above described emulsion process with the following parameters:

Codergocrine base 7 g Matrix polymer of example 5 13 y Methylene dichloride~0 ml Ethanol ~4% 30 ml Emulsifying condit;ons:
Volume ratio organic phase/aqueous phase: 1:65 Rotation speed of the turbine p = 3100 rpm The release was measured as described in Example 26.

- 33 ~ 100-611 Exame~ 28:
The process of Example 27 was carried out with the following parameters:

Keto~i~en base 5 9 Matrix polymer of example 5 15 3 Methylene dichloride 80 ml Emulsifying conditions:
Yolume rat;o organ;c phase/aqueous phase: 3:13 P - 2000 rpm Stirring time: 2 hours The microcapsules contained 16.5 % Ke~oti~en.

Example Z9: Release of active _ ents from polyol ester matr;ces_in vivo Release tests were carried out with microcapsules, which contained bromocriptine as active agent .

The microcapsules were prepared according to the above described spray dryi-ng process in the NIR0-spray drying apparatus, equipped with a centrifugal spray gun. The matrix polymer conststed of the product of Example 4 and contained 17.8 ~ bromacrlptine.

:

7~9~

~ 3~ ~ 100-6114 An amount of these microcapsules9 corres~onding to 5.0 mg bromocriptine-mesyla~e, in a vehicle of 0.2 ml of sodium carboxymethylcellulose, was injected in the right thigh muscle of a rabbit. Period;cally blood was taken from the rabbit during 21 days.

The blood levels of ~he medicine were measured by a specific radioimmunoassay and had a mean value of 1.6 nglml (A.U.C. =
33.0). The blood levels were practically all between 1.20 and 1.80 nglml.

Claims (26)

Claims:

1. An ester of a polyol, said polyol containing at least 3 hydroxyl groups and having a molecular weight of up to 20,000 at least 1 hydroxyl group in said polyol being in the form of an ester, with a poly- or co-poly-lactic acid residue each having a molecular weight of at least 5,000.

2. A reaction product of a polyol containing at least 3 hydroxyl groups and having a molecular weight of up to 20,000 or a reactive derivative thereof and lactic acid or a reactive derivative thereof and, when required, at least a second hydroxycarboxylic acid or a functional derivative thereof, the product having a polymer chain of molecular weight of at least 5,000.

3. A product according to claim 1 or 2, in which the polyol is the linear polyol mannitol, pentaerythritol, sorbitol, ribitol or xylitol.

4. A product according to claim 1 or 2, in which the polyol is a polyol with 6 hydroxyl groups.

5. A product according to claim 1, in which the poly-ol is a polyol with a cyclic structure and with 4 to 30 hydroxyl groups.

6. A product according to claim 5, in which the polyol is a polyol with one or more monosaccharide units with at least 3 hydroxyl groups per unit.

7. A product according to claim 6, in which the polyol is a polyol with fructose structure.

8. A product according to claim 7, in which the polyol is a polyol, which comprises one fructose unit.

9. A product according to claim 1, in which the polyol is a polyol with glucose structure.

10. A product according to claim 9, in which the polyol is a polyol, which comprises one glucose unit.

11. A product according to claim 9, in which the polyol is a polyol, which comprises 2 to 8 glucose units.

12. A product according to claim 11, in which the polyol is a polyol, in which the glucose units are connected in 1, 4 and/or 1,6-position.

13. A product according to claim 12, in which the polyol is a polyol, in which the glucose units are connected in the 1,4-position.

14. A product according to claim 13, in which the polyol is a polyol, which comprises one .beta.-cyclodextrine unit.

15. A product according to claim 1 or 2, with acid resi-dues comprising 30 to 70 Mol% of glycolic acid units.

16. A product according to claim 1 or 2, with acid resi-dues comprising up to 20 Mol% of .epsilon.-hydroxycapronic acid units.

17. A product according to claim 1 or 2, wherein, having at least 2 ester chains, each of the chains comprise the same hydroxycarboxylic acid residues.

18. A product according to claim 1 or 2, wherein in the GPC any separate low molecular weight peak comprises al-together up to 10% of the height of the peak Mw of the polyester.

19. A process for the production of the product of claim 1, characterized in that a polyol of a molecular weight of up to 20,000 and having at least 3 hydroxyl groups or a reactive derivative thereof is esterified with lactic acid or a reactive derivative thereof and if desired with at least a second hydroxycarboxylic acid, or a functional derivative thereof.

20. A process for the production of the product of claim 1, characterized in that a polyol of a molecular weight of up to 20,000 and having at least 3 hydroxyl groups, is reacted with lactic acid or additionally with at least a second hydroxycarboxylic acid in lactone- or dimeric cyclic ester form, in the presence of a catalyst, for facilitating a ring opening polymerization.

21. A process according to claim 19, characterized in that at least some of the low molecular weight parts are removed from the product.

22. A process according to claim 21, characterized in that the product is subjected to membrane filtration.

23. A depot matrix material of a product according to claim 1, containing a pharmacologically active compound.

24. A depot matrix material of a product according to claim 23, containing bromocriptine, ketotifen, or co-dergocrine as a pharmaceutically active agent.

25. A parenteral pharmaceutical depot formulation for use as an implant or microcapsules containing a pharmacologi-cally active agent embedded or encapsulated in a polymer matrix according to claim 1 or 2, said formulation being adapted to release all or substantially all the active material over an extended period of time and the polymer being adapted to degrade sufficiently to be transported from the site of administration within 20 days after release of all or substantially all of the active agents.

26. A parenteral pharmaceutical depot formulation for use as an implant or microcapsules containing bromocriptine, ketotifen or co-dergocine as a pharmacologically active agent embedded or encapsulated in a polymer matrix accord-ing to claim 1 or 2, said formulation being adapted to release all or substantially all the active material over an extended period of time and the polymer being adapted to degrade sufficiently to be transported from the site of administration within 20 days after release of all or substantially all of the active agents.