NO176304B - Process for the preparation of pharmaceutical implants based on polylactide - Google Patents

Abstract

The system consists of a carrier material based on poly-D,L-lactide and of a drug incorporated therein and, where appropriate pharmaceutical auxiliaries. The carrier material contains defined contents of additives in the form of pore formers, up to about 10% by weight of a physiologically acceptable solvent or plasticiser and/or low molecular weight polymers.

Description

This invention relates to a method for manufacturing

of pharmaceutical implants based on polylactide.

Numerous active substance release systems are known today

which are implantable or injectable. Such systems are preferably used when an active substance is to be given over a longer period of time and oral administration is not possible, reliable or appropriate. Next to the human application, parenteral forms of application in breeding animals or in therapy for diseases in animals are of particular interest. The traditional

conventional dosing of drugs by mixing in the feed has the serious disadvantage that the amount of drug used is not sufficiently accurate.

Implantable active substance f-f release systems should meet the following criteria:

The active substance should be released at a constant rate over a

longer period of time. The implant should break down within a reasonable period of time so that operative removal of the implant after delivery of the active substance is omitted. Furthermore, it is an advantage if the release of active substance f from the carrier can be set so that it can be varied, whereby the degree of release can be adapted to both the active substance and the therapy.

It has been the task of the present invention to provide a method for the production of pharmaceutical implants based on polylactide, which provides a biodegradable active substance release system that releases the active substance at an approximately constant rate over a longer period of time and which degrades over an acceptable period of time.

The task is solved through a procedure for developing

position of an implantable, biodegradable active substance release system consisting of a carrier material of

basis of poly-D,L-lactide and an active substance incorporated in this,

as well as possibly pharmaceutical excipients, where carrier

the material contains defined pore formers, up to 10% by weight of an acetic acid ester and possibly polylactide with a molecular weight between 500 and 5000 Daltons. The method is characterized by the fact that a solution of the polymer containing

holds the active ingredient and additives, is poured into a film which

then dried, after which the film is cut into suitable strips, or a granule consisting of the polymer, active substance and additives, extruded into tubes, possibly with a sleeve, or into rods which are then cut into the desired lengths.

Poly-D,L-lactides are known in a wide molecular weight range. For the implant produced according to the invention, medium-molecular poly-D,L-lactide types are preferably suitable which have an intrinsic viscosity of between 0.15 and 4.5 (measured in chloroform at 25°C, c = 100 mg/100 ml).

In a preferred embodiment, the carrier material for the implant consists of poly-D,L-lactide.

In another embodiment, the implant manufactured according to the invention consists of a copolymer of poly-D,L-lactide and polyglycolide, where, however, the glycolide proportion of the copolymer should not exceed 50 percent by weight.

It has now been surprisingly discovered that the rate of degradation of the implant can be controlled through a defined content of acetic acid ester or another physiologically acceptable solvent or a plasticizer, or by a solvent mixture, which remains quantitatively in the polymer even after longer storage. This is of crucial importance as, on the one hand, the implant must break down sufficiently quickly, while too fast breaking down of the implant, on the other hand, leads to an uncontrolled release of the active substance. The content of acetic acid ester can be up to 10%, below which an increasing proportion of acetic acid ester accelerates the breakdown of the poly-D, L-lactide. It is beneficial to have an active substance release that corresponds to half-lives of between 3 and 60 days and a subsequent breakdown of the implant within approx. 120 days. Under certain circumstances, shorter release and degradation rates can of course also be advantageous.

It has also been established that the addition of acetic acid ester strangely affects the rate of degradation of the implant, but has no significant influence on the release of the active substance.

Suitable acetic acid esters for use in the method according to the invention are alkyl esters of acetic acid, which e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, sec-pentyl, isopentyl and tert-pentyl esters. Particularly preferred is acetic acid ethyl ester.

According to a further embodiment, the implant produced according to the invention can also contain low molecular weight polymers such as e.g. poly(L-lactic acid), poly(D-lactic acid) , poly (D, L-lactic acid) , poly (glycolic acid) , poly(L-lactic-co-glycolic acid) , poly(D-lactic-co-glycolic acid) , poly(D,L-lactic acid-co-glycolic acid) . Poly(L-lactic acid) and poly(D,L-lactic acid) are preferred. The molecular weights (determined by end group titration) are 500 to 5000, preferably 1500 to 2500.

These additives, alone or in combination with an acetic acid ester, also enable regulation of the implant's rate of degradation.

An influence on the release of the active substance can be made in different ways:

a) Addition of a pore former, such as e.g. lactose,

b) the state of the active substance (dissolved, suspended, particle size), c) the processing form of the carrier (monolith, polydisperse, layer arrangement).

In addition to compounds that affect the rate of degradation of the carrier material, the implant produced according to the invention also contains substances in the form of pore formers which enable regulation of the release of the active substance. Suitable pore formers are, for example, water-soluble pharmaceutically acceptable monosaccharides and disaccharides. Lactose is preferred, but glucose, fructose, xylose, galactose, sucrose, maltose, sucrose and related compounds such as mannitol, xylitol, sorbitol are also suitable. Other suitable excipients are salts such as lactates, glyconates or succinates of sodium, potassium or magnesium.

A rapid initial release of the active substance (after implantation) from the carrier material is achieved when the release rate of the pore former is much greater than the release rate of the active substance. This is, for example, the case when the pore former, e.g. lactose, has good solubility and small particle size.

■ A later onset, accelerated release of the active substance is achieved when the solubility of the pore former is significantly less than the solubility of the active substance, such as e.g. when the pore former is poorly soluble in water. Through the delayed, accelerated release of the active substance, it is achieved that the linear release course of the active substance is also ensured with longer administration.

By utilizing the described parameters, implants can be produced which exhibit an individually adjustable release as well as degradation rate.

The monolithic implant can, according to the invention, be injected or implanted in the form of small rods or snake-shaped bodies. The small rods conveniently have such dimensions that they can be implanted with an injection needle or a trocar. For example, the length of a rod is approx.

3 cm and the diameter approx. 2.8 mm.

The following described forms are preferred:

A) massive spells

B) coiled films

C) recased rods

D) serpentine bodies

E) encapsulated serpentine bodies.

All embodiments of the implant produced according to the invention can be built up in several layers, and for example produced according to the following method.

In the dissolved polymer, with e.g. acetic acid ethyl ester as a solvent, the active substance is suspended and the additives according to the invention are mixed. If desired, additional pharmaceutical excipients can be added to the dissolved polymer in addition to the active substance and additives. The suspension is then poured onto a surface and dried to form a film. Below, the drying conditions are set so that the desired residual amount of solvent, generally between 1 and 7%, remains in the polymer. The dried films have a layer thickness of between 30 and 1000 µl, preferably approx. 100 \ i. Apparatus and method for producing such films are known to the person skilled in the art and need no further description. It goes without saying that the drying process must be carried out with some care

(slow, small temperature and vacuum-humidity variations)

so that the film stays flat.

Films with several layers can be obtained by applying a new polymer solution (with or without active ingredient).

After the film has dried, it is cut into small sticks of the desired length.

The small rods of type B consist of one or more rolled up single or multi-layer polymer films.

According to the invention, the B-type implant is also produced from active substance-containing films, where the film thickness is however significantly smaller, usually between 30 and 500 µm, preferably 70-90 µm. After drying, the films are cut up and rolled into rods of the desired diameter, up to 3 mm, which are then cut to the desired lengths. The rods can be rolled up in such a way that the core contains a cavity. In the case of the type B laminate, several films can also be superimposed or, preferably, molded on top of each other, and then rolled into one rod. By combining several film layers, active substances can be combined and layers of different active substance concentration can be prepared. The individual layers can have different release rates. -

In addition to an alternating layer sequence, it is also possible to first form a rolled-up core and then place additional film layers on the outside.

By using film layers with different release characteristics, it can be achieved with an implant that different active substances are released in a predetermined time sequence. It is not absolutely necessary that all film layers contain an active substance.

When producing implants of type B, the films should have a relatively high content of solvent residues (approx. 10%) when they are rolled together. This prevents the films from becoming brittle. The finished coiled small rods are then again subjected to a drying process to set the desired content of solvent residues.

Implants of type C and D and E can advantageously be produced by extrusion or injection molding of granules of active ingredient and polymer or copolymer, possibly with additives, such as e.g. polylactic acid, a plasticizer such as e.g. triacetin or a pore former, such as lactose.

The active substance f release for the encapsulated forms C and E occurs as a result of their construction in different ways. The suspended active substance in the core of the rod with form C diffuses through pores that are formed in the capsule by the release of e.g. lactose. Decisive release factors are therefore the degree of loading of the capsule and the particle size of the lactose.

In contrast to the encapsulated forms of type C which contain a massive active substance-containing core and are enveloped by a "porous" shell, the form E implants consist of a hollow cylinder (tube) containing the active substance which is enveloped on the outside by a shell that is impermeable to the active substance .

In form E, the active substance suspended in the snake-shaped body - when the sheath is pore-free and impermeable - can only be released in the cavity of the body. With this system, the increasingly longer channels, i.e. the diffusion stretches, are compensated by the amount of active substance in a segment, which is greater the greater the distance from the cylinder axis.

Figure A

Figure A shows a section through embodiment E.

Decisive release factors in addition to polymer degradation and active ingredient content are in this case the dimensions, such as, for example the length and inner diameter of the tube-shaped implant. Of course, the active substance-impermeable sheath for the form E implants consists of a biodegradable polymer, preferably a poly-D,L-lactide. A significant advantage of implants with this shape is that the release of the active substance occurs approximately linearly.

Implants of this type can also be produced on the basis of the previously described films, under which the outer film consists of an active substance-free and active substance-impermeable layer.

Findings so far have shown that implants (types A and B) produced according to the "solvent method" exhibit a different degradation pattern than the extrudates, i.e. the extrudates degrade more slowly with the same polymer composition (cf. Fig.l). The difference is that a defined, higher content of solvent residue cannot be set due to the relatively high temperature during extrusion.

Active substance delivery systems (implants) produced according to the invention, which are produced by extrusion or injection molding techniques, can suitably be produced on the basis of a poly-D, L-lactide with an intrinsic viscosity of between 0.15 and 1.0. Polymers with a lower viscosity (0.15) can already be processed at temperatures lower than 100°C, which has a beneficial effect on the thermal load of the mixed drug.

Implants made from a poly-D,L-lactide with a lower viscosity show both a faster release of the active substance and a faster breakdown of the implant than is the case with higher viscosities (> 0.3), so that an implant may also be broken down already after 10 weeks.

Poly-D,L-lactides with lower viscosity can be produced from poly-D,L-lactides of higher viscosity by partial hydrolysis.

Active substance f-f the rigging of the implants produced in

according to the invention, can be delayed through a further coating of a low-molecular poly-D,L-lactide which does not contain, but is permeable to, active substance. This prevents too rapid release of the active substance in the initial phase immediately after implantation.

Suitable active substances are those that are present in suspension

shape in the polymer. Particularly suitable are e.g. the water-soluble salt forms of bases, such as hydrochlorides or hydrobromides, especially Clenbuterol hydrochloride.

For veterinary medicinal use, the substance groups and compounds mentioned below can also be used in

stick to the invention.

Glucocorticoids for labor induction, e.g.

dexamethasone, betamethasone, flumethasone, as well as their esters and derivatives.

Progestogens for estrus synchronization, estrus and running

time suppression.

/?2-adrenergics for therapeutic and prophylactic use in respiratory diseases, to prevent abortion and childbirth, to promote growth and influence metabolism, such as e.g. Clenbuterol, 4-(2-tert-butylamino-1-hydroxyethyl)-2-cyano-6-fluoro-phenylcarbamic acid ethyl ester hydrochloride,

<*"[[[ 3 - (1-benzimidazolyl)-1,1-dimethylpropyl]-amino]-methyl]-2-fluoro-4-hydroxy-benzyl alcohol methanesulfonate monohydrate, 1-(4-amino-3 -cyanophenyl) -2-isoprbpyl-aminoethanol, ;/3-blockers for "MMA prophylaxis", to reduce transport stress, α2-adrenergics against enteric diseases and for the treatment of hypoglycemic states, as well as for sedation (e.g. clonidine, 2-[2-bromo-6-fluorophenylimino]-imidazolidine, ;benzodiazepines and derivatives such as brotizolam for ;sedation, ;antif logistics for anti-inflammatory therapy eg Meloxicam, somatotropin and other peptide hormones for performance enhancement, endorphins for stimulation of ruminal motility, steroid hormones (natural and synthetic) for growth promotion, e.g. estradiol, progesterone and esters and their synthetic derivatives, such as Trenbolone, antiparasitic agents for combating of endo- and ecto-parasites, e.g. Avermectin, ;cardiac and circulatory active substances, e.g. ethylephrine or Pimobendan. ;On the human medicine In this area, the implants manufactured according to the invention can be advantageously used for the delivery of hormones, especially contraceptives, or cytostatics. ;Active substances can be used with both systemic and local effects. A preferred area of application for the implants produced according to the invention is local cancer therapy. In the following examples, the invention will be explained in more detail. In the examples, the following polymers are used: ;= intrinsic viscosity ;<*> determined by gas chromatography (standard: polystyrene)

Example 1

(Polymer degradation factors: processing method, tacticity, molar mass)

25 g of D,L-polylactide I are dissolved in 75 g of acetic acid ethyl ester and drawn out to form a film on a smooth surface with a spreading knife. After drying for at least 24 hours, this is repeated

two, respectively three times, until a multilayer film of 250 fl thickness has formed. The film is then dried at 23°C and then at 40°C in vacuum to a predetermined residual solvent content, cut into 3 x 2.5 cm pieces and formed into rolls (length 3 cm, 0 2, 8 mm).

Implants produced using the dissolution method show a different relationship with regard to molar mass reduction in a buffer solution than e.g. implants obtained by extrusion, i.e. they have an advantageous faster degradation (Fig. 1) . With regard to the rate of degradation, the tacticity of the polymer plays a greater role than the molar mass, resp. boundary viscosity [ ] (Fig. 2) . That the in vitro degradation rate agrees well with in vivo values shows

Fig. 3.

A significant mass reduction occurs both in vivo and in vitro after approx. 70 days, i.e. after the limiting viscosity has dropped to a value of [ ] 0.3 (100 ml/g) (see Fig. 4).

When applying the implant to sheep, rats and mice, no particular reaction could be determined during the observation period (up to 140 days), i.e. the implant showed good local compatibility (Table 1).

Instead of using the dissolution method, corresponding composite molded bodies can also be produced by extrusion (core with shell) of granules of polymer, active ingredients and additives.

Example 2

(Polymer degradation factors: acetic acid ethyl ester content, polylactic acid addition)

Rolls of multilayer film are produced as described in Example 1, during which, in the case of charge I, 50% of the D,L-polylactide is replaced with D,L-polylactic acid (molar mass 2000). Fig. 5 shows that the molar mass reduction in aqueous medium is accelerated by a content of 4%, resp. 7%, acetic acid ethyl ester, but not with 1%. In this respect, the addition of 50% D,L-polylactic acid has a pronounced effect.

The mass reduction relates to the molar mass reduction as described in Example 1 (Fig. 6).

Example 3

(Active substance release factor: carrier structure)

25 g of D,L-polylactide II ([ ] =2.2 (100 ml/g)) are dissolved in 75 g of acetic acid ethyl ester, in which 5.0 g of Methotrexate (MTX) particle size (30 µm = x = 60 µm) is suspended. , whereupon, analogously to Example 1, three-layer films are produced with a layer thickness of 0.80 mm, of which the top and bottom polymer layers are active substance free. After the residual content of solvent has reached 7%, the multilayer film, in contrast to Example 1, is cut into sticks of 1 x 1 x 10 mm.

From such implants, MTX is released at a constant rate of 63 jLtg/day during 10-60 days both in vivo and in vitro, without the polymer mass decreasing significantly (Fig. 7).

Example 4

(Active substance release factor: lactose addition)

8.8 g of D,L-polylactide II ([ ] =2.2 (100 ml/g)) are dissolved in 45 g of acetic acid ethyl ester and 2.7 g of Clenbuterol are suspended in this. HC1 (20 µl = x = 53 µm), after which a three-layer film corresponding to Example 1 is produced. In the case of charge L, 25 percent by weight of lactose (1-5 ura) is also suspended in the polymer solution for the middle layer.

Fig. 8 shows that the Clenbuterol release in the aqueous medium can be accelerated and thus controlled through the addition of lactose.

Example 5

(Active substance f-freezing factor: polylactic acid addition)

The three-layer film roll L from Example 4 is compared with an analogously prepared preparation where 25% of the D,L-polylactide II is replaced with D,L-polylactic acid (molar mass 2000).

While the Clenbuterol release in an aqueous medium is greatly accelerated by the addition of polylactic acid, the residual content of acetic acid ethyl ester in the range of 1-4% has no effect on the release ratio.

Polylactic acid can therefore, like lactose, be used as an additive that controls the release.

Example 6

(Active substance release factor: carrier structure)

(Embodiment E)

D,L-polylactide III without active substance and a melting granulate of 3 parts by weight D,L-polylactide III and one part by weight Clenbuterol (hydrochloride, 20-53 /Lim) are processed at 90°C (mass temperature) into a double-walled tube (which is possible both with a suitable extruder as well as by injection molding technology).

An implant of embodiment E - manufactured according to Example 6 - with the following dimensions was used for in vitro experiments, i.e. polymer degradation and active substance release: length 10 mm; cavity: diameter - 2 mm; total diameter: 5 mm; outer shell: active substance-free, impermeable; wall thickness 0.5 mm; inner tube containing active substance, wall thickness: 1.0 mm.

Fig. 10 describes the approximately linear polymer mass degradation in vitro, with a half-life of approx. 70 days, Fig. 11 the approximately linear Clenbuterol release.

Fig. 1: Molar mass reduction of polylactide implants [ti] = Boundary viscosity

Experimental conditions in vitro: isotonic phosphate buffer pH 7.4; 37°C

A: coiled rods of D,L-polylactide I (dissolution iaethode) B: extrudate cylinder of D,L-polylactide I

C: D,L-polylactide I powder

Fig. 2: Molecular mass reduction, of polylactide implants Test compounds in vitro: isotonic phosphate buffer pH 7.4; 37°C. Preparation: rolled up rods of polylactide (dissolution method)

A: D,L-polylactide I; 7% acetic acid ethyl ester, Tg = 26°C.

D: D,L-polylactide II; 7% acetic acid ethyl ester, Tg = 30°C.

E: L-polylactide; 7% acetic acid ethyl ester, Fp = 172°C (comparative example)

Fig. 3: Molecular weight reduction of D, L- polylactide implants Preparation: multilayer film rolls, charge D

A. Application: in vivo, sheep, s.c.

B. in vitro, experimental conditions: isotone f osf atbuf f er; pH 7.4; 37°C.

Fig. 4: Mass reduction of polylactide implants Preparation: film rolls of D,L-polylactide

([ti] = 2.19 (100 ml/g));

charge D

A. in vitro experimental conditions: isotonic Phosphate buffer; pH 7.4; 37°C.

B. Application: in vivo, sheep, s.c.

Fig. 5: Molecular mass reduction of polylactide implants

Experimental conditions in vitro: isotonic phosphate buffer; pH 7.4; 37°C Preparation: film rolls (dissolution method)

A: D,L-polylactide I; 7% ethyl acetate; Tg = 26°C

F: D,L-polylactide I; 1% acetic acid ethyl ester; Tg = 48°C

G: D,L-polylactide I; 4% ethyl acetate; Tg = 35°C

H: D,L-polylactide II; 1% acetic acid ethyl ester; Tg = 52°C

I: D,L-polylactide II + 50% polylactic acid (D,L); 1% acetic acid ethyl ester; Tg = 30°C

Fig. 6: Mass reduction of D, L-polylactide implants in vitro experimental conditions: isotone f osf atbuf f er; pH 7.4; 37°C Preparation: film rolls (dissolution method)

A: D,L-polylactide I; 7% ethyl acetate; Tg = 26°C

F: D,L-polylactide I; 1% acetic acid ethyl ester; Tg = 48°C

G: D,L-polylactide I; 4% ethyl acetate; Tg = 35°C

H: D,L-polylactide II; 1% acetic acid ethyl ester; Tg = 52°C

I: D,L-polylactide II + 50% polylactic acid

1% acetic acid ethyl ester; Tg = 30°C

Fig. 7: Methotrexate release (MTX) from polylactide implants Preparation: multilayer rods of D,L-polylactide

([ti] = 2.2 (100 ml/g)),

A. Application: Rat, intracerebral

B. in vitro conditions: isotone f osf atbuf f er; pH 7.4; 37°C

Fig. 8: Clenbuterol release from D, L-polylactide implants in vitro conditions: isotonic phosphate buffer; pH 7.4; 37°C. Preparation: three-layer film rolls ([ti] = 2.2 (100 ml/g)) with 23.5% by weight Clenbuterol HCl and 4% ethyl acetate

Fig. 9: Clenbuterol release from D, L- polylactide implants in vitro conditions: isotone f osph atbuf f er; pH 7.4; 37°C Preparation: three-layer film rolls with 10% by weight lactose and 23.5% by weight Clenbuterol HCl

D,L-polylactide II ([n] = 2.2 (100 ml/g)) Additives: L: 4% ethyl acetate

M: 1% acetic acid ethyl ester

N: 1% acetic acid ethyl ester + 25% D,L-polylactic acid

Fig. 10: Mass reduction of polylactide implants Preparation: double-walled snake-shaped implant of D,L-polylactide III (cf. Example 6) in vitro test conditions: isotonic phosphate buffer pH 7.4; 37°C

Fig. 11: Clenbuterol release from D, L-polylactide implants Preparation: Double-walled snake-shaped implant of D,L-polylactide III (cf. Example 6) Experimental conditions: isotonic phosphate buffer pH 7.4; 37°C

Claims (5)

1. Method for the production of an implantable, biodegradable active substance release system consisting of a carrier material based on poly-D, L-lactide and an active substance incorporated therein, as well as any pharmaceutical excipients, where the carrier material contains defined pore formers, up to 10 percentage by weight of an acetic acid ester and possibly polylactide with a molecular weight between 500 and 5000 Dalton, characterized in that a solution of the polymer containing the active substance and additives is poured into a film which is then dried, after which the film is cut into suitable strips, or, a granule consisting of the polymer, the active substance and the additives, is extruded into tubes, possibly with a casing , or to rods which are then cut into the desired lengths. 2. Method according to claim 1, characterized in that the solution of the polymer containing the active substance and additives is poured into a film, dried until a residual amount of solvent of approx. 10%, possibly several film layers are applied and dried, after which the film is rolled into sticks and the sticks are then dried so that the desired content of solvent remains. 3. Method according to claim 1 or 2, characterized in that at least two films of different composition are rolled together into one rod. 4. Method according to one of claims 1-3, characterized in that a carrier material is used which consists of a copolymer of D, L-lactide and glycolide, where the proportion of glycolide does not exceed 50 percent by weight. 5. Method according to one of claims 1-4, characterized in that a carrier material containing polylactide and/or lactose is used.