EA045044B1 - MIXTURES OF BIODEGRADABLE COMPOSITIONS FOR DRUG DELIVERY TO MODULATE THE KINETICS OF RELEASE FROM A DRUG OF AT LEAST ONE ACTIVE INGREDIENT - Google Patents

Description

Field of technology

The present invention relates to biodegradable drug delivery compositions containing a mixture of at least three block copolymers taken from triblock and diblock copolymers consisting of polyester and poly(ethylene oxide) blocks, wherein the triblock copolymer contains one polyethylene oxide block between two polyester blocks and the diblock copolymer includes a polyester block and a single-terminated poly(ethylene glycol) block, as well as at least one pharmaceutically active ingredient. The weight ratio of triblock copolymers to diblock copolymers in this dosage form for modulating the release kinetics of at least one active ingredient is from 1:19 to 5:1. When included in a block copolymer, poly(ethylene oxide) (PEO) or polyoxyethylene is often referred to as poly(ethylene glycol) (PEG), and for the purposes of the present invention these terms are used interchangeably.

State of the art

In the field of sustained drug delivery, systems based on diblock or triblock copolymers are used to deliver a variety of drugs and are typically designed to deliver specific drugs, whether hydrophobic or hydrophilic drugs. Depending on the physicochemical properties of the drug, dosage forms vary in the concentration of polymers, types of polymers used, molecular weight of polymers and solvents used in dosage forms.

The type of environment into which the drug is delivered is also an important factor when developing a drug delivery system. Thus, there are drug delivery compositions that are prepared using temperature-sensitive polymers, phase-sensitive polymers, pH-sensitive polymers, and photosensitive polymers. See, for example, K. AI-Tahami, J. Singh Smart Polymer Based Delivery Systems for Peptide and Proteins, Recent Patents on Drug Delivery & Formulation, 1: pages: 65-71 Bentham Science Publishers, LTD. 2007.

US Patent No. 6,592,899 describes a PLA/PLGA oligomer in combination with a block copolymer to increase the solubility of a hydrophobic drug in a hydrophilic environment.

US Patent No. 6,541,033 describes a sustained release pharmaceutical composition based on thermosensitive, biodegradable hydrogels consisting of a block copolymer of PLA or PLGA and PEG for sustained delivery of biologically active agents.

Hydrogels containing triblock copolymers are described in US Patent No. 6,350,812.

US Patent No. 9,023,897 B2 describes biodegradable drug compositions containing a triblock copolymer and a diblock copolymer, as well as a pharmaceutically active ingredient.

However, there remains a need to provide biodegradable drug delivery compositions containing diblock and triblock copolymers with improved release rate modulation properties of at least one active ingredient. For example, there may be a need for compositions with an increased rate of release of the active ingredient compared to already known drug delivery compositions comprising diblock and triblock copolymers. The composition must be capable of controlling the release of at least one active ingredient over a period of time without adversely affecting the physical properties of the dosage form.

In addition, the biodegradable drug delivery compositions of the present invention can be in the form of long-acting dosage forms with a lower initial burst release of the drug and a time-modulated rate of drug release according to first-order, zero-order, or pseudo-zero-order kinetics. This is illustrated by the flattening of drug release curves.

In addition, the biodegradable drug delivery composition can be modulated without compromising the injectability of the composition.

Thus, one of the objects of the present invention is to modulate the release kinetics of at least one pharmaceutically active ingredient from a biodegradable triblock/diblock depot without compromising or improving the physical properties of the dosage form before and/or after its administration by injection.

By improvement is meant a reduction in one or both of the following: injectability of the dosage form and viscosity of the dosage form.

Brief description of the invention

The present invention provides a biodegradable drug delivery composition containing:

(i) a mixture of at least three different block copolymers, each of these block copolymers being:

(a) a biodegradable triblock copolymer having the formula:

Av- Bw- Αχ, where A is a polyester, B is polyethylene glycol, v and x are the number of repeating units in the range from 4 to 3000, and w is the number of repeating units in the range from 3 to 300, with v = x or v Ф x;

or (b) a biodegradable diblock copolymer having the formula:

Cy-Az, where A is a polyester, C is a polyethylene glycol end group, and y and z are the number of repeating units, with y ranging from 2 to 250, and z ranging from 4 to 3000; and where the mixture contains at least one copolymer (a) and at least one copolymer (b); and the weight ratio of the total amount of at least one copolymer (a) and the total amount of at least one copolymer (b) is from 1:19 to 5:1; and (ii) at least one pharmaceutically active ingredient. In one embodiment of the present invention, said polyester A is selected from the group consisting of polylactide (PLA), polyglycolide, polycaprolactone, polyethylene adipate, polyhydroxyalkanoate, and mixtures thereof, and optionally the polyethylene glycol terminated with methoxy polyethylene glycol.

In one embodiment of the present invention, said at least one biodegradable triblock copolymer (a) A is PLA and/or at least one biodegradable diblock copolymer (b) A is PLA. In one embodiment of the present invention, said biodegradable drug delivery composition further comprises:

(a) a biodegradable triblock copolymer having the formula:

P LAuPEG _vd -P LA _X where v and x are the number of repeating units in the range from 4 to 3000, and w is the number of repeating units in the range from 3 to 300, with v=x or v^x; and/or (b) a biodegradable diblock copolymer having the formula:

M PE Gu-PL Az where y and z are the number of repeating units, with y varying in the range from 2 to 250, and z varying in the range from 4 to 3000.

In one embodiment of the present invention, said biodegradable drug delivery composition comprises:

(a) a biodegradable triblock copolymer having the formula:

P LAu-PEGsch-P LA _X where v and x are the number of repeating units in the range from 4 to 3000, and w is the number of repeating units in the range from 3 to 300, with v = x or v Ф x; and (b) 2, 3 or 4 different biodegradable diblock copolymers, each of which has the formula: MPEGy-PLAG where y and z are the number of repeating units, with y varying from 2 to 250, and z varying from 4 up to 3000;

and wherein the weight ratio of the total amount of biodegradable triblock copolymer (a) to the total amount of 2, 3 or 4 different biodegradable diblock copolymers (b) is from 1:19 to 5:1.

In one embodiment of the present invention, said biodegradable drug delivery composition comprises:

(a) two different biodegradable triblock copolymers, each having the formula:

P LAu-PEGshch-P LA _X where v and x are the number of repeating units in the range from 4 to 3000, and w is the number of repeating units in the range from 3 to 300, with v=x or v^x; and (b) 1, 2, 3 or 4 different biodegradable diblock copolymers, each of which has the formula:

MPEGu-ΠΠΑζ where y and z are the number of repeating units, and y varies from 2 to 250 and z varies from 4 to 3000;

and wherein the weight ratio of the total amount of two different biodegradable triblock copolymers (a) to the total amount of 1, 2, 3 or 4 different biodegradable diblock copolymers (b) is from 1:19 to 5:1.

In one embodiment of the present invention, the composition is an injectable liquid and is suitable for forming a depot when administered to the body by injection, or is in the form of solid particles, or rod-type implants, or bulk dosage forms. In one embodiment of the present invention, the weight of the polyethylene glycol chain is in the range from 180 g/mol to 12 kg/mol, or from 194 g/mol to 12 kg/mol, or from 200 g/mol to 12 kg/mol, or from 100 g/mol to 4 kg/mol, and the molecular weight of the end group polyethylene glycol chain is in the range of 100 g/mol to 2 kg/mol, or 164 g/mol to 10 kg/mol.

In one embodiment of the present invention, the biodegradable drug delivery composition further comprises a pharmaceutically acceptable carrier, wherein the pharmaceutically acceptable carrier is optionally a solvent, optionally an organic solvent.

In one embodiment of the present invention, the pharmaceutically active ingredient is hydrophobic; and/or the pharmaceutically active ingredient is risperidone, bupivacaine, ivermectin, octreotide, meloxicam, or combinations thereof.

In one embodiment of the present invention, the at least one pharmaceutically active ingredient is present in an amount of from 0.05 to 60% (w/w), optionally from 0.05 to 40%, optionally from 0.05 to 30% , optionally from 0.05 to 10%, optionally from 0.05 to 7%, optionally from 0.05 to 2%, based on the total weight of the composition.

In one embodiment of the present invention, when the composition is an injectable liquid, the at least one pharmaceutically active ingredient is present in an amount of from 0.05 to 60% (w/w).

In one embodiment of the present invention, when the composition is a rod-type implant, the at least one pharmaceutically active ingredient is present in an amount of from 50 to 80% (w/w).

In one embodiment of the present invention, said mixture of at least three different block copolymers is present in an amount of from 2 to 60% (wt./wt.%) of the total weight of the composition, optionally from 10 to 50%, optionally from 20 to 40 %, optionally from 20 to 35%, optionally from 30 to 50%.

In one embodiment of the present invention, one or more triblock copolymer is present in an amount of from 1 to 50% (w/w), optionally from 5 to 40% of the total weight of the composition.

In one embodiment of the present invention, one or more diblock copolymer is present in an amount of from 1 to 57% (w/w), optionally from 2.5 to 45% of the total weight of the composition.

In one embodiment of the present invention, the weight ratio of the total amount of biodegradable triblock copolymers (a) to the total amount of biodegradable diblock copolymers (b) in said biodegradable drug delivery composition is from 1:5 to 3:1.

In one embodiment of the present invention, the molar ratio of polyester repeating units to ethylene oxide in the composition is from 0.5 to 22.3, optionally from 0.5 to 10, optionally from 0.5 to 3.5 in the triblock copolymer, and from 0.8 to 15, optionally from 1 to 10 in the diblock copolymer.

In one embodiment of the present invention, the biodegradable drug delivery composition comprises three different block copolymers as defined above, or four different block copolymers as defined above, or five different block copolymers as defined above, or six different block copolymers as defined above. -copolymers as defined above.

In one embodiment of the present invention, the biodegradable drug delivery composition comprises one biodegradable triblock copolymer as defined above, or two different biodegradable triblock copolymers as defined above, or three different biodegradable triblock copolymers as defined above, or four various biodegradable triblock copolymers as defined above.

In one embodiment of the present invention, the biodegradable drug delivery composition comprises one biodegradable diblock copolymer as defined above, or two different biodegradable diblock copolymers as defined above, or three different biodegradable diblock copolymers as defined above, or four different biodegradable diblock copolymers. as defined above.

In one embodiment of the present invention, the biodegradable drug delivery composition comprises a triblock copolymer present in an amount from 1 to 50% (w/w) of the total weight of the composition, a diblock copolymer present in an amount from 1 to 57 % (wt./wt.%) of the total weight of the composition and one or more additional diblock or triblock copolymers, each of which is present in an amount of from 0.2 to 20, optionally from 0.5 to 20 (wt./wt.%) ) from the total mass of the composition.

In one embodiment of the present invention, the biodegradable drug delivery composition is a composition according to Composition No. 16, 28, 29, 290, 45, 46, 49, 64, 115, 119, 124, 126, 163, or 199, defined below in example 3 in table. 1-6 of this description.

In one embodiment of the present invention, the release of at least one active ingredient can be modulated.

In one embodiment of the present invention, the biodegradable drug delivery composition is suitable for delivering an active ingredient to a subject, optionally

- 3 045044 a therapeutically effective amount of the active ingredient, for at least 1 day, optionally for at least 3 days, optionally for at least 7 days, optionally for at least 30 days, optionally for at least 90 days, optionally for at least 1 year.

In one embodiment of the present invention, the biodegradable drug delivery composition is suitable for parenteral administration.

In one embodiment of the present invention, the block copolymers have a solubility in aqueous solution of less than 5%, optionally less than 1% (w/w).

In one embodiment, the present invention provides a method of modulating the release kinetics of at least one active ingredient, said method comprising administering a biodegradable composition for delivering medicinal products to a subject as defined above, wherein the release kinetics of said at least one active ingredient from said biodegradable composition for drug delivery is modulated without having any effect on one or more physical properties of said biodegradable drug delivery composition; and where one or more of the physical properties are the injectability and pre-injection viscosity of the biodegradable drug delivery composition, and the depot stability after injection of the biodegradable drug delivery composition.

Brief description of drawings

Fig. 1 is a graph showing the percentage of total cumulative in vitro release of risperidone from three different dosage forms over time. Dosage form F28 (o) has a mass ratio of the sum of triblock to diblock equal to 5, i.e. contains 25.00% P1R6 triblock copolymer, 1.25% dP2R3 diblock copolymer, 1.25% dP0.35R8.5 diblock copolymer, 1.25% dP0.35R5 diblock copolymer, 1.25% diblock copolymer dP2R0.5, 10.00% active ingredient (API) and 60.00% dimethyl sulfoxide (DMSO). Dosage form F29 (®) has a mass ratio of the sum of triblock to diblock equal to 0.05, i.e. contains 1.50% P1R6 triblock copolymer, 7.125% dP2R3 diblock copolymer, 7.125% dP0.35R8.5 diblock copolymer, 7.125% dP0.35R5 diblock copolymer, 7.125% dP2R0.5 diblock copolymer, 10.00% active ingredient (API) and 60.00% DMSO. Dosage form F16 (□) has a mass ratio of the sum of triblock to diblock equal to 1, i.e. contains 1.00% P1R4 triblock copolymer, 1.50% P1R6 triblock copolymer, 1.50% dP2R3 diblock copolymer, 1.00% dP0.35R8.5 diblock copolymer, 60.00% active ingredient (API) and 35.00% DMSO. In table 1 below are specific dosage forms of block copolymers.

The weight ratio of the sum of triblock to diblock influences the modulation of release. Indeed, curves F28 and F29 show two different release profiles.

Interestingly, a significant amount of API (60.00%) associated with a small proportion of polymer content (5.00%) gave a pseudo-zero-order kinetic profile. Indeed, curve F16 shows a pseudo-zero order release profile.

Fig. 2 is a graph showing the percentage of total cumulative release of bupivacaine in vitro over time from four different dosage forms. Drug form F289 (o) has a mass ratio of the sum of triblock to diblock equal to 1, i.e. contains 20.00% P1R4 triblock copolymer, 20.00% dP1R4 diblock copolymer, 2.00% active ingredient (API) and 58.00% DMSO. Dosage form F290 (Δ) has a mass ratio of the sum of triblock to diblock equal to 1, i.e. contains 20.00% P1R4 triblock copolymer, 10.00% dP1R4 diblock copolymer, 10.00% dP0.35R8.5 diblock copolymer, 2.00% active ingredient (API) and 58.00% DMSO. Dosage form F291 (□) has a mass ratio of the sum of triblock to diblock equal to 1, i.e. contains 20.00% P1R4 triblock copolymer, 20.00% dP0.35R8.5 diblock copolymer, 2.00% active ingredient (API) and 58.00% DMSO. Dosage form F292 (◊) has a mass ratio of the sum of triblock to diblock equal to 1, i.e. contains 25.00% P1R4 triblock copolymer, 25.00% dP1R4 diblock copolymer, 2.00% active ingredient (API) and 48.00% DMSO. In table 2 below are specific dosage forms of block copolymers.

The addition of an additional biodegradable block copolymer affects the modulation of release without adversely affecting the injectability of the dosage form, as indicated in Table. 7. Indeed, curves F289 and F290 show two different modulated release profiles. Moreover, this additional biodegradable diblock copolymer allows for better controlled release. Indeed, curve F289 shows an uncontrolled explosion at the beginning of release, which is characterized by significant fluctuations between parallel trials. The standard deviation for F289 and F290 is 13.3 and 2.8, respectively, two days after depot formation.

The use of the above additional biodegradable block copolymer as a unique diblock copolymer results in modulated release compared to the original dosage form. Curves F289 and F291 show two different release profiles. However, the depot from the F291 dosage form exhibits suboptimal stability with significant fragmentation of the depot at an early time point. This suboptimal stability causes significant fluctuations between each parallel experiment due to unwanted and early fragmentation of the depot. Indeed, F290 and F291 show standard deviations of 5.7 and 9.7, respectively, ten days after depot formation.

Increasing the total polymer content affects the modulation of release. F292 shows a modulated release profile compared to F289. However, an increase in the total polymer content affects the injectability of the dosage form, as indicated in Table. 7. As a consequence, F289 and F292 have injectivity values of 4.8N and 14.5N, respectively.

Despite the modulation of F291 and F292, the composition change had a negative impact on the physical properties of the depot and dosage form, respectively. Thus, it is implied that adding additional biodegradable block copolymer, as in F290, is an effective way to provide predictable modulation.

Fig. 3 is a graph showing the percentage of total cumulative in vitro release of bupivacaine over time from four different dosage forms. Dosage form F289 (o) has a mass ratio of the sum of triblock to diblock equal to 1, i.e. contains 20.00% P1R4 triblock copolymer, 20.00% dP1R4 diblock copolymer, 2.00% active ingredient (API) and 58.00% DMSO. Dosage form F290 (Δ) has a mass ratio of the sum of triblock to diblock equal to 1, i.e. contains 20.00% P1R4 triblock copolymer, 10.00% dP1R4 diblock copolymer, 10.00% dP0.35R8.5 diblock copolymer, 2.00% active ingredient (API) and 58.00% DMSO. Dosage form F293 (®) has a mass ratio of the sum of triblock to diblock equal to 1, i.e. contains 20.00% P1R4 triblock copolymer, 20.00% dP1R4 diblock copolymer, 4.00% active ingredient (API) and 56.00% DMSO. Dosage form F294 (X) has a weight ratio of the sum of triblock to diblock equal to 1, i.e. contains 20.00% P1R4 triblock copolymer, 20.00% dP1R4 diblock copolymer, 6.00% active ingredient (API) and 54.00% DMSO. In table 2 below are specific dosage forms of block copolymers.

Increasing the total API load affects the modulation of release. F293 and F294, containing 4.00% and 6.00% API, respectively, exhibit different release profiles compared to F289 and F290. The release kinetics decreases as the amount of API in the dosage form increases. However, the resulting profiles show similar undesirable tendencies during the release process, characterized by a large burst effect at the beginning. Moreover, this is not a valid strategy since the injectability also increases as the API content increases, as shown in Table 1. 7.

Fig. 4 is a graph showing the percentage of total cumulative in vitro release of bupivacaine over time from four different dosage forms. Dosage form F45 (o) has a mass ratio of the sum of triblock to diblock equal to 5, i.e. contains 41.70% P1R4 diblock copolymer, 4.15% dP2R0.5 diblock copolymer, 4.15% dP0.35R8.5 diblock copolymer, 1.00% active ingredient (API) and 49.00% DMSO. The dosage form F46 (®) has a mass ratio of the sum of triblock to diblock equal to 0.05, i.e. contains 2.50% P1R4 diblock copolymer, 23.75% dP2R0.5 diblock copolymer, 23.75% dP0.35R8.5 diblock copolymer, 1.00% active ingredient (API) and 49.00% DMSO. Dosage form F49 (□) has a weight ratio of the sum of triblock to diblock equal to 0.05, i.e. contains 3.00% P1R4 triblock copolymer, 28.50% dP2R0.5 diblock copolymer, 28.50% dP0.35R8.5 diblock copolymer, 1.00% active ingredient (API) and 39.00% DMSO. Dosage form F64 (*) has a mass ratio of the sum of triblock to diblock equal to 0.05, i.e. contains 3.00% P1R4 triblock copolymer, 28.50% dP0.35R5 diblock copolymer, 28.50% dP0.35R8.5 diblock copolymer, 1.00% active ingredient (API) and 39.00% DMSO. In table 3 below are specific dosage forms of block copolymers.

The mass ratio of the sum of triblock to diblock influences the modulation of release. Indeed, curves F45 and F46 show two different modulated release profiles.

Replacing the block copolymer in the composition has a significant effect on release modulation. Indeed, curves F49 and F64 show two different modulated release profiles.

Thus, the results indicate that the addition of additional biodegradable block copolymer is an effective way to modulate the kinetics of the release process.

Fig. 5 is a graph showing the percentage of total cumulative in vitro release of ivermectin over time from six different dosage forms. Dosage form F105 (o) has a mass ratio of the sum of triblock to diblock equal to 0.67, i.e. contains 20.00% P2R3.5 triblock copolymer, 30.00% dP0.35R8.5 diblock copolymer, 1.00% active ingredient (API) and 49.00% DMSO. The dosage form F119 (®) has a mass ratio of the sum of triblock to diblock equal to 0.67, i.e. contains 10.00% triblock copolymer P12R0.7, 10.00% triblock

- 5 045044 P0.19R18 copolymer, 30.00% dP0.35R8.5 diblock copolymer, 1.00% active ingredient (API) and 49.00% DMSO. Dosage form F124 (Δ) has a mass ratio of the sum of triblock to diblock equal to 0.5, i.e. contains 4.20% P1R4 triblock copolymer, 4.20% P1R6 triblock copolymer, 5.50% dP0.35R5 diblock copolymer, 5.50% dP2R3 diblock copolymer, 5.50% dP0.35R8 diblock copolymer. 5, 1.00% active ingredient (API) and 74.10% DMSO. Dosage form F126 (V) has a mass ratio of the sum of triblock to diblock equal to 0.5, i.e. contains 2.80% P1R4 triblock copolymer, 2.80% P1R6 triblock copolymer, 2.80% P2R3.5 triblock copolymer, 5.50% dP0.35R5 diblock copolymer, 5.50% dP2R3 diblock copolymer and 5.50% dP0.35R8.5 diblock copolymer, 1.00% active ingredient (API) and 74.10% DMSO. Dosage form F115 (□) has a weight ratio of the sum of triblock to diblock equal to 0.5, i.e. contains 8.30% P2R3.5 diblock copolymer, 8.30% dP0.16R1 diblock copolymer, 8.30% dP2R10 diblock copolymer, 1.00% active ingredient (API) and 74.10% DMSO. The dosage form F110 (®) has a mass ratio of the sum of triblock to diblock equal to 0.5, i.e. contains 8.30% P2R3.5 triblock copolymer, 16.70% dP2R3 diblock copolymer, 1.00% active ingredient (API) and 74.10% DMSO. In table 4 below are specific dosage forms of block copolymers.

Substitution of the 12700 g/mol triblock P2R3.5 with an identical amount of a mixture of two triblock copolymers, P12R0.7 and P0.19R18, with molecular weights 25700 g/mol and 5800 g/mol, respectively, affects the release kinetics. Here, the molecular weight of the triblock sum from F119 is approximately in the same range as the sum from F115 (15800 g/mol and 12700 g/mol).

Similarly, replacing dP2R3 with a molecular weight of 11800 g/mol with an identical amount of a mixture of two diblock copolymers, dP2R10 and dP0.16R1 with a molecular weight of 34700 g/mol and 420 g/mol, respectively, affects the release kinetics. Indeed, curves F110 and F115 show two different modulated release profiles.

The addition of an additional biodegradable triblock copolymer causes a modulation of the release kinetics profile. Indeed, curve F126 shows a slower release than curve F124.

Thus, the data indicate that replacing one block copolymer with two others of approximately equivalent total molecular weight is an effective way to modulate release kinetics.

Fig. 6 is a graph showing the percentage of total cumulative in vitro release of octreotide acetate over time from three different dosage forms. Dosage form F163 (o) has a mass ratio of the sum of triblock to diblock equal to 1, i.e. contains 10.00% P1R4 triblock copolymer, 10.00% P1R6 triblock copolymer, 10.00% dP1R4 diblock copolymer, 10.00% dP0.35R8.5 diblock copolymer, 4.00% active ingredient (API) and 56 .00% DMSO. Dosage form F165 (Δ) has a mass ratio of the sum of triblock to diblock equal to 1, i.e. contains 20.00% P1R6 triblock copolymer, 20.00% dP0.35R8.5 diblock copolymer, 4.00% active ingredient (API) and 56.00% DMSO. Dosage form F166 (□) has a mass ratio of the sum of triblock to diblock equal to 1, i.e. contains 20.00% P1R4 triblock copolymer, 20.00% dP1R4 diblock copolymer, 4.00% active ingredient (API) and 56.00% DMSO. In table 5 below shows specific dosage forms of block copolymers.

F163 shows that the combination of two triblocks and two diblocks from F165 and F166 gives intermediate release kinetics, meaning that the observed modulation based on the four block copolymer composition appears to be due to the influence of F165 and F166.

In fig. Figure 7 shows the cumulative in vitro release of meloxicam over time from two different dosage forms. Dosage form F197 (□) has a weight ratio of the sum of triblock to diblock equal to 5, i.e. contains 50.00% triblock copolymer P0.19R2, 10.00% diblock copolymer dP0.35R8.5, 2.00% active ingredient (API) and 38.00% DMSO. Dosage form F199 (V) has a weight ratio of the sum of triblock to diblock equal to 5, i.e. contains 25.00% P0.19R2 triblock copolymer, 25.00% P2R3.5 triblock copolymer, 10.00% dP0.35R8.5 diblock copolymer, 2.00% active ingredient (API) and 38.00% DMSO. Dosage form F365 has a mass ratio of the sum of triblock to diblock equal to 5, i.e. contains 50.00% P2R3.5 triblock copolymer, 10.00% dP0.35R8.5 diblock copolymer, 2.00% active ingredient (API) and 38.00% DMSO. The F365 dosage form was not tested in vitro because it has a very high injectability (53.6 N), which prevents any manipulation with it. In table 6 below are specific dosage forms of block copolymers.

The release kinetics of F199 are modulated compared to those of F197. Substitution of 25.00% P0.19R2 originally present in 50.00% F197 with an identical amount of P2R3.5 causes a strong modulation of release kinetics. Indeed, adding the triblock copolymer P2R3.5 to F199 as an additional biodegradable block copolymer results in an increase in overall release duration. In addition, the initial burst release is significantly reduced and after 100 days of release there is no repeat in the F199 release profile

- 6 045044 significant acceleration of kinetics.

In fig. Figure 8 presents data on the injection capacity of F197, F199 and F365. Data show that complete substitution of P0.19R2 by P2R3.5 in F365 significantly affects the injectability of the parent formulation F197, making the form difficult to administer, while partial substitution of P0.19R2 by P2R3.5 in F199 gives an acceptable increase in injectability. Indeed, F365 has much more injection than F197. In table Table 8 shows the injectability values of these dosage forms.

These results confirm that the addition of additional biodegradable block copolymer is an effective way to modulate release kinetics without significantly changing the physical properties of the dosage form, such as injectability. These results also indicate that modulation of release kinetics can be very difficult when only two block copolymers are present at high loading. Therefore, adding at least one block copolymer to the dosage form may be beneficial in effectively achieving this modulation.

Description of the Preferred Embodiment of the Invention

As used herein, the term biodegradable means that polyesters undergo hydrolysis to form the constituent oligomers or monomers in vivo, for example, PLA undergoes hydrolysis to form lactic acid.

The term parenteral administration includes intramuscular, intraperitoneal, intraperitoneal, subcutaneous, intravenous and intra-arterial administration. The term also includes intradermal, intracavernosal, intravitreal, intracerebral, intrathecal, epidural and intraosseous administration.

The term animals covers all members of the kingdom Animalia. The animal may be a human or a non-human animal.

The term plant as used here covers all members of the plant kingdom.

Active ingredient means a drug or medicinal product for the treatment or prevention of various medical diseases. For the purposes of the present invention, the term active substance has the same meaning as active ingredient. Thus, the terms active ingredient, active substance, drug or drug are used interchangeably. The term active pharmaceutical ingredient, or API, is also used. As used herein, the term drug or active ingredient includes, without any limitation, physiologically or pharmacologically active substances that act locally or systemically in the animal or plant body. At least one active ingredient is present in the biodegradable drug according to the present invention.

As used herein, the term disease means any disorder in a person, animal or plant caused by infection, diet or abnormal process.

The term implant refers to any solid object formed outside the body and surgically placed into the body. Implants can be permanently installed or can be removed if necessary and depending on the circumstances. These procedures include, but are not limited to, making a small incision on the animal's body and inserting a solid object or trocar. A trocar is a medical device consisting of an obturator (which may have a pointed or non-sharp metal or plastic tip), a cannula and a seal. The trocar functions as a tool for placing the implant into the animal's body.

The term depot injection means the injection of a flowable pharmaceutical composition, typically subcutaneously, intradermally or intramuscularly, where the drug is administered as a localized, eg solid, mass called a depot. Depots, as defined here, are formed in situ upon injection. Thus, dosage forms can be prepared as liquids or microparticles and can be administered to the body by injection.

There are several ways to administer injections or infusions to humans, such as intradermal, subcutaneous, intramuscular, intravenous, intraosseous, intraperitoneal, intrathecal, epidural, intracardiac, intraarticular, intracavernous, and intravitreal.

The term bulk dosage form includes any dosage form that can be applied to or into the body of an animal or plant and is optionally administered by syringe.

The repeating units referred to herein are the basic repeating units of the polymer.

The term terminated polyethylene glycol refers to a PEG that has a single hydroxyl end group to react, and includes alkoxy-terminated PEG, urethane-terminated PEG, ester-terminated PEG, and the like. The end group is a chemical group that does not contain chemical compounds susceptible to reaction with cyclic esters such as lactide, glycolactide, caprolactone and the like, or other esters and mixtures thereof. As a result of the reaction of PEG-7 045044 end-group polymer with lactide, a diblock PEG-PLA copolymer is formed.

As used herein, the term polyethylene glycol, abbreviated as PEG throughout this document, is sometimes referred to as poly(ethylene oxide) or poly(oxyethylene), and these terms are used interchangeably within the scope of the present invention.

The abbreviation PLA stands for poly(lactide).

The abbreviation PLGA stands for poly(lactide-co-glycolide).

The abbreviation PCLA stands for poly(ε-caprolactone-co-lactide).

The abbreviation PLE means polyester.

The abbreviation T or TB stands for triblock copolymer(s), and the abbreviation D or DB stands for diblock copolymer(s).

As used herein, the term diblock means, for example, a polyether PEG copolymer with an end group. MPEG stands for methoxy polyethylene glycol.

The term triblock means, for example, PLE-PEG-PLE copolymer.

The molar ratio R refers to the number of polyester (PLE) units to the number of ethylene oxide (EO) units that are present in the biodegradable drug delivery composition. For example, the number of polyester units may refer to the number of lactoyl units (LA) or the number of glycolide units (G) or the number of caprolactone units (CL), or mixtures thereof.

This molar ratio R is determined experimentally using nuclear magnetic resonance (NMR). The molar ratio R of the triblock copolymer may be from 0.5 to 22.3, optionally from 0.5 to 10, optionally from 0.5 to 3.5. In another aspect, the molar ratio of R in the triblock may be from 0.5 to 2.5 in the biodegradable drug delivery composition described herein.

The molar ratio of R in the diblock may be from 0.8 to 15, optionally from 1 to 10, optionally from 2 to 6, optionally from 3 to 5, in a biodegradable drug delivery composition.

The degree of polymerization or DP is the number of repeating units in the middle polymer chain at time t during a polymerization reaction. For example, the degree of polymerization of PEG for triblock is from 3 to 300 and for diblock the degree of polymerization of PEG is from 2 to 250. In the case of PLA, the degree of polymerization for triblock is from 1 to 3000 and the same value is from 1 to 3000 for diblock.

As used herein, the term at least three block copolymers can mean a mixture of 3, 4, 5, 6, 7, 8, 9 or 10 different block copolymers in a biodegradable drug delivery composition. In one embodiment of the present invention, any combination of triblock and diblock copolymers from 3 to 10 can be formulated, provided that at least one triblock copolymer and at least one diblock copolymer are present in the mixture. Other examples include 3 to 5 or 4 to 8 or 4 to 6, 3 to 7, 4 to 9, and the like mixtures of triblock and diblock copolymers that can be used in biodegradable drug compositions as described in this document.

Modulating the release kinetics of at least one active ingredient means modulating the rate of release of at least one active ingredient from the depot after administration in vivo. In this regard, the kinetics may be first-order kinetics or pseudo-zero-order kinetics depending on the dosage form prepared.

The term release modulation as used herein is defined as a change in the amount of at least one active ingredient released from the depot over time. This desired change may be an increase or decrease in release compared to the original kinetics, immediate or prolonged over a period of time. Modification of the release profile may affect multiple periods; for example, in the very first hours of release, causing an increase or decrease in the initial explosion, or at later periods, to avoid re-acceleration or sharp decrease in release or during the release. Dosage form modulation is a process by which specific release profiles can be achieved and the overall duration of release can be optimized for a particular therapeutic application.

The term first order kinetics as used here means that the drug release process is directly proportional to the concentration of drug used in the process.

The term pseudo-zero order kinetics as used herein means that the drug release process occurs at a constant rate.

As used herein, the term physical properties is intended to refer to the physical properties of the composition that are important for the clinical use of the dosage form. Among them, viscosity, in particular the dynamic viscosity of the dosage form, swelling and stability of the depot after administration of the dosage form by injection are important parameters that need to be controlled during optimization of the dosage form composition. The key physical property is the injectability of the dosage form, that is, its suitability for

- 8 045044 administration by injection.

A depot has a disadvantage of stability if it is subjected to early fragmentation into many parts. This fragmentation can lead to unexpected and uncontrollable changes in release, such as burst effects and fluctuations. Such depot fragmentation can be determined visually in vitro. The lack of depot stability due to early physical fragmentation is different from the normal degradation of polymers in the depot, such as polymer hydrolysis, which is a key mechanism that provides release of the active ingredient along with diffusion of the active ingredient through the pores of the polymer matrix. Preferably, complete hydrolysis of the depot polymers does not occur until all or substantially all, for example 90 wt% or 99 wt% of the active ingredient is released from the depot.

As used herein, the term swelling means an increase in the volume of the formed depot associated with the absorption of water. The volume of the initial depot can increase 3-5 times or 1.1-3 times when introduced into the animal’s body. Swelling is determined visually in vitro.

The injectability of a dosage form herein is determined by the force, expressed in Newtons (N), that is required to inject the dosage form using predetermined parameters. These parameters include: injection speed, injection volume, injection duration, syringe type or needle type, and the like. These parameters may vary depending on the at least one pharmaceutically active ingredient used or the desired route of administration, such as subcutaneous, intraocular, intra-articular, and so on. These parameters will be adjusted depending on the at least one pharmaceutically active ingredient present in the dosage form so that differences and variations between dosage forms can be observed. The injection rate must be kept low so that the dosage form can be easily administered by a qualified healthcare professional within an acceptable time frame. The ideal injection value can be from 0.1 N to 10 N using the measurement method described below. An acceptable injection rate may be between 10 N and 20 N. A suboptimal injection rate may be between 20 N and 30 N. Dosage forms are difficult to inject at 30 to 40 N and cannot be injected above 40 N. Injectability can be measured with using a texture meter. preferably a Lloyd Instruments FT plus texturometer, using the following analytical conditions: 500 µl of the dosage form is injected through a 1 ml syringe and a 23G 1Terumo needle at a flow rate of 1 ml/min.

Viscosity, by definition and as used herein, is a measure of a fluid's resistance to flow and gradual deformation under shear stress or tensile strength. The term describes the internal friction of a moving fluid. For liquids, the term corresponds to the informal concept of thickness. Dynamic viscosity is a measure of the resistance to fluid flow under the influence of applied force. The dynamic speed can vary from 1 to 3000 mPa^s or from 5 to 2500 mPa^s, or from 10 to 2000 mPa^s, or from 20 to 1000 mPa^s. Dynamic viscosity is determined using an Anton Paar rheometer equipped with a cone-plate measuring system. Typically, 250 μl of the test dosage form is placed on the measuring plate. The temperature is maintained at + 25°C. The measuring system used is a 25 mm diameter disc and a 2° cone (CP25-2/S). The operating range is from 10 to 1000 s ^-1 . After shaking for 10 s, the dosage form is placed in the center of a temperature-controlled measuring plate using a spatula. The measuring system is lowered down and a gap of 0.051 mm is left between the measuring system and the measuring plate. Eleven viscosity measurement points are determined over a shear rate range from 10 s ^-1 to 1000 s ^-1 . The values given are those obtained at 100 s ^-1 .

The present invention relates to modulating the release kinetics of at least one active ingredient from a biodegradable three-/two-part pharmaceutical composition without negatively affecting critical characteristics of the dosage form, such as physical properties. The addition of at least one additional biodegradable block copolymer to the original TB/DB mixture allows the release kinetics to be adjusted without affecting its injectability, which may otherwise interfere with the administration of the composition using conventional devices. The combination of at least three block copolymers significantly increases the range of achievable release levels of at least one active ingredient and makes this a more effective modulation method.

Thus, the present invention relates to a biodegradable drug composition containing a mixture of at least three copolymers selected from triblock copolymers and diblock copolymers. A biodegradable triblock copolymer has the formula: A _v -B _w -A _x where A is a polyester, B is a polyethylene glycol, v and x are the number of repeat units ranging from 1 to 3000, and w is the number of repeat units ranging from 3 up to 300, with v=x or v^x. The degree of polymerization for DP-PEG is calculated by dividing the molecular weight of PEG by the unit molecular weight of EO (44 g/mol), v + x equals the degree of polymerization (number of repeating units) for PLA. DP-PLA is calculated by multiplying DP-PEG by the R factor.

- 9 045044

However, the number of v, w and x repeating units in a triblock composition may vary due to the target release time of the active ingredient and the type of active ingredient itself. Therefore, the number of repeating units in a triblock v, w and x can be from 1 to 3300 or from 60 to 2800, or from 300 to 1700, or from 500 to 1250, with v=x or v<x. For example, w may be 273 while v+x may be 682; or w could be 136 and v+x could be 273; or w could be 45.5 and v+x could be 546; or w could be 273 and v+x could be 136.

The molecular weight of PEG in the triblock can vary from 180 g/mol to 12000 g/mol.

The polyester in the triblock may be polylactide (PLA), polycaprolactone (PCL), polyethylene adipate (PEA), polyglycolide (PGA), polyhydroxyalkanoate (PHA), and mixtures thereof. In one embodiment of the present invention, the polyester used is a polylactide. In another embodiment of the present invention, the polyester is poly(lactide-co-glycolide).

Biodegradable triblock copolymers are then combined with biodegradable diblock copolymers having the formula: C _y -A _z where A is a polyester, C is a polyethylene glycol end group, and y and z are the number of repeating units, with y ranging from 1 to 3000, az ranging from 1 to 300. This combination has a weight ratio of triblock copolymer to diblock copolymer ranging from 1:19 to 5:1.

Terminated polyethylene glycol includes alkoxy-terminated PEGs, including methoxy-PEG or ethoxy-PEG, urethane-terminated PEG, ester-terminated PEG, amine-terminated PEG, and amide-terminated PEG. This list of end-group PEGs is not exhaustive, and one skilled in the art will recognize other end-group PEGs that are not listed here.

In addition, the number of repeating units (degree of polymerization (DP)) y and z in the diblock composition can also vary. Thus, y may be, for example, from 8 to 500, or from 150 to 850, or from 200 to 500, or from 30 to 1200, and z may be from 32 to 123, or from 7 to 250. For example, y is 32 The degree of polymerization of DP-PEG is calculated by dividing the molecular weight of the end group PEG by the unit molecular weight of EO (44 Da). The degree of polymerization of DP-PLA is calculated by multiplying DP-PEG by the R factor.

The polyester in the diblock may be polylactide (PLA), polycaprolactone (PCL), polyethylene adipate (PEA), polyglycolide (PGA), or polyhydroxyalkanoate (PHA), and mixtures thereof. In one embodiment of the present invention, the polyester used is a polylactide. In another embodiment of the present invention, the polyester is poly(lactide-co-glycolide).

Preferred embodiments of the present invention include any of the following combinations of polymers:

1) (a) a biodegradable triblock copolymer having the formula:

PLAu-PEGi-PLAx where v and x are the number of repeating units in the range from 1 to 3000, and w is the number of repeating units in the range from 3 to 300, with v=x or v/x; and (b) 2, 3 or 4 different biodegradable diblock copolymers, each having the following formula:

MPEGu-PLAG where y and z are the number of repeating units, while y varies from 2 to 250, and z varies from 1 to 3000;

and wherein the weight ratio between copolymers (a) and (b) is from 1:19 to 5:1.

2) (a) two different biodegradable triblock copolymers, each having the following formula:

PLAu-PEG _vd -PLAh where v and x are the number of repeating units in the range from 1 to 3000, and w is the number of repeating units in the range from 3 to 300, with v=x or t; and (b) 1, 2, 3 or 4 different biodegradable diblock copolymers, each having the following formula:

MPEGu-PLA _g where y and z are the number of repeating units, while y varies from 2 to 250, and z varies from 1 to 3000;

and wherein the weight ratio between copolymers (a) and (b) is from 1:19 to 5:1.

At least three block copolymers are combined by dissolving them together at room temperature in a pharmaceutically acceptable solvent. They are combined such that the at least three block copolymers are present in a final concentration of 2 to 60% (w/w) of the total composition, or optionally 10 to 50%, optionally 20 to 40% , optionally from 20 to 35%, optionally from 30 to 50% of the total weight of the composition. In one aspect, pharmaceutically

- 10 045044 a suitable solvent is an organic solvent. This organic solvent can be left in the composition or evaporated before administration.

The term small amount, as used herein, is defined as an amount of copolymer that is less than the sum of the other two block copolymers in the biodegradable drug composition. This small amount of at least one additional biodegradable block copolymer is not in addition to the total polymer content, but is added as a replacement block copolymer additive from an existing standard two-block copolymer composition. This addition of at least one additional biodegradable block copolymer to the dosage form, without changing the total amount of block copolymers in the dosage form or the TB/DB ratio, is a suitable way to change the release profile, which does not affect the associated physical properties. For example, the at least one additional biodegradable block copolymer may be less than 25% of the total block copolymer content, or may be, for example, less than 5%. In another embodiment of the present invention, the minor amount may be from 1 to 25% of the total block copolymer content, or from 2.5 to 15% of the total block copolymer content, or from 3.5 to 12% of the total block copolymer content.

The present invention relates to modulating the release kinetics of at least one active ingredient from a biodegradable three-/two-part pharmaceutical composition without adversely affecting the critical properties of the dosage form, including physical properties such as depot stability or injectability or viscosity of the dosage form. The presence of an additional biodegradable block copolymer in the original TB/DB mixture allows the release kinetics to be adjusted without affecting injectability, which might otherwise interfere with administration of the composition by conventional means.

In a preferred embodiment of the present invention, the combination of at least three block copolymers significantly expands the range of achievable release of at least one active ingredient and makes this a more effective modulation method.

This dosage form allows the release profile of at least one active ingredient to be modulated, causing an increase or decrease in release kinetics over time without significantly affecting the physical properties of the original dosage form. The total polymer content, as well as the total content of at least one active ingredient in the dosage form remains unchanged and gives it the same important parameters as injectability or depot stability. The goal of this approach is to change the release kinetics while maintaining the advantages provided by the original triblock and diblock copolymer PEGPLA (injectability, depot stability, etc.).

Modulation of release while maintaining a dosage form with two block copolymers differs from adding at least one additional block copolymer because the physical properties may differ significantly from those of a dosage form with two block copolymers. In this regard, influence on physical properties is possible.

Blends of at least three triblock copolymers and diblock copolymers may contain any polyester, for example, polylactide (PLA), polycaprolactone (PCL), polyethylene adipate (PEA), polyglycolide (PGA), polyhydroxyalkanoate (PHA), and mixtures thereof. Thus, the triblock may contain, for example, PCL-PEG-PCL or PEA-PEG-PEA, or PGA-PEG-PGA, or PGA-PEG-PGA, or PLA-PEG-PLA, or PLA-PEG-PCL, PCL _y -PEG _x -PCL _x or PGA-PEG-PEA. The diblock may contain, for example, a terminated PEG-PLA, or a terminated PEG-PCL, or a terminated PEG-PEA, or a terminated PEG-PGA, or a terminated PEG-PLGA, or a terminated PEG-PGA group, or PEG-PCLA with an end group.

Therefore, in certain embodiments of the present invention, a biodegradable drug delivery composition comprising mixtures of at least three triblock copolymers and diblock copolymers may comprise a PLA-PEG-PLA triblock copolymer and an MPEG-PLGA diblock copolymer mixed with a PCL triblock copolymer. -PEG-PCL and MPEG-PLA diblock copolymer. Another example is a PEA-PEG-PEA triblock copolymer and an MPEG-PEA diblock copolymer combined with a PLA-PEG-PLA triblock copolymer and an MPEG-PLGA diblock copolymer. Another example is a PLA-PEG-PCL triblock copolymer and a PEG-PCL-terminated diblock copolymer, as well as a PLA-PEG-PLA triblock copolymer or a PLA-PEGPLA triblock copolymer, and a PEG-terminated diblock copolymer -PLA, as well as a diblock copolymer of PEG-PLGA with an end group or a triblock copolymer of PCLA-PEG-PCLA, as well as a diblock copolymer of PEG-PLA with an end group and a diblock copolymer of PEG-PCLA with an end group.

The weight ratio of the sum of the biodegradable triblock copolymer and the biodegradable diblock copolymer in the biodegradable drug delivery composition is from 1:19 to 5:1, optionally from 1:5 to 3:1, optionally from 1:2 to 3:1. Therefore, this ratio can be, for example, 1:5, 1:10, 1:19, 4:1, 3:1 or 2:1.

The length of a polyester chain is determined by its molar ratio of polyester to

- 11 045044 ethylene oxide, which is from 0.5 to 22.3, optionally from 0.5 to 10, optionally from 0.5 to 3.5, optionally from 0.5 to 2.5 or for a triblock copolymer, and from 0.8 to 15, optionally from 0.8 to 13, optionally from 1 to 10, optionally from 3 to 5, optionally from 2 to 6 for the diblock copolymer. For example, if polylactide is used, the chain length is determined by the molar ratio of lactic acid to ethylene oxide. Likewise, if a polyglycolide is used, the chain length is determined by the molar ratio of polyglycolide to ethylene oxide, or the molar ratio of polycaprolactone to ethylene oxide, or the molar ratio of polyhydroxyalkanoate to ethylene oxide. When using poly(lactide-co-glycolide), the chain length is determined by the R-factor.

The mass of end-group polyethylene glycol can vary from 120 to 10,000 g/mol or from 164 to 2000 g/mol, or from 100 to 2 kg/mol, or from 200 to 8000 g/mol, or from 194 to 7500 g/mol, or from 100 to 6500 g/mol, or from 164 to 9500 g/mol. The mass may vary in the lower range from 130 to 300 g/mol or in the range from 125 to 800 g/mol.

The molecular weight of the polyethylene glycol chain varies from 180 g/mol to 12 kg/mol in a biodegradable drug delivery composition, or from 400 g/mol to 12 kg/mol, or from 194 g/mol to 12 kg/mol.

The total amount of polymer ranges from 2 to 60% (wt/wt), optionally from 1 to 50% (wt/wt%), optionally from 10 to 50%, optionally from 20 to 40%, optional from 20 to 35%, optionally from 30 to 50% of the total weight of the composition. In another embodiment of the present invention, the total weight of polymers present in the biodegradable drug composition is from 30 to 50% (wt./wt.%) or from 10 to 35% (wt./wt.%) of the total weight of the composition. In yet another embodiment of the present invention, the polymers are present in the biodegradable drug composition in an amount of from 40 to 50% (wt./wt.%) or from 20 to 45% (wt./wt.%) of the total weight of the composition.

Thus, the triblock copolymer is present in an amount of from 1 to 50% (wt./wt.%) or from 3 to 45% (wt./wt.%) of the total weight of the composition. In another aspect, the triblock copolymer is present in an amount of 6 to 10% (w/w) of the total weight of the composition. In yet another aspect, the triblock copolymer is present in an amount of from 20 to 40% (w/w) of the total weight of the composition. In yet another aspect, the triblock comprises from 5 to 40% (w/w) of the total weight of the composition.

Likewise, the diblock copolymer may be present in the biodegradable drug composition in an amount from 1 to 57% (w/w) of the total weight of the composition. In another aspect of the present invention, the diblock copolymer is present in an amount of from 2.5 to 45% (w/w) of the total weight of the composition. In yet another aspect of the present invention, the diblock copolymer is present in an amount of from 5 to 40% (w/w) of the total weight of the composition. In yet another aspect of the present invention, the diblock comprises from 8 to 20% (w/w) of the total weight of the composition.

The third or additional biodegradable block copolymer may be present in the biodegradable drug composition in an amount of at least 0.5 to 20, optionally 0.2 to 20 (wt/wt%) of the total weight of the composition. In another example, it may be present in an amount ranging from 1 to 10 (w/w%); in yet another example, it may be from 2 to 8 (wt./wt.%) of the total composition. In yet another aspect of the present invention, the at least one additional biodegradable block copolymer may comprise from 3 to 5 (wt/wt%) of the total weight of the composition.

At least one pharmaceutically active ingredient is enclosed in a mixture of at least three triblock and biblock biodegradable drug delivery compositions. Representative drugs and biologically active substances to be used according to the present invention include, but are not limited to, peptide drugs, protein drugs, desensitizing agents, antigens, vaccines, vaccine antigens, anti-infectives, antidepressants, stimulants, opiates, antipsychotics, atypical antipsychotics, glaucoma medications, sedatives, antiarrhythmics, antibacterials, anticoagulants, anticonvulsants, antidepressants, antiemetics, antifungals, anticancer drugs, antivirals, antibiotics, antimicrobials, antiallergic drugs, antidiabetic drugs, non-steroidal anti-inflammatory drugs, anti-edema, miotics, anticholinergics, sympathomimetics, sedatives, hypnotics, psychic agents, tranquilizers, androgenic steroids, estrogens, progestogens, humoral agents, prostaglandins, analgesics, corticosteroids, antispasmodics, antimalarials, antihistamines, cardioactive agents, non-steroidal anti-inflammatory drugs, antiparkinsonian drugs, antihypertensive drugs, beta-blockers, nutrients, gonadotropin-releasing hormones, insecticides, anthelmintics, or combinations thereof.

The pharmaceutically active ingredient may be risperidone, bupivacaine, ivermectin, octreotide, meloxicam, or combinations thereof.

Combinations of drugs can be used in the biodegradable drug delivery composition of the present invention. For example, if you need to cure lupus erythematosus, then nonsteroidal

- 12 045044 anti-inflammatory drugs and corticosteroids can be administered together according to the present invention.

Veterinary drugs such as anthelmintics or animal vaccines are also part of the present invention.

Antiviral agents for plants, for example against Potyviridae, Geminiviridae, Tospovirusgenus of Bunyaviridiae and Banana Streak, are also included in the present invention. Also, agents against tobacco mosaic virus, turnip mosaic virus, barley yellow dwarf virus, watermelon ringspot virus and cucumber mosaic virus can be used in the biodegradable drug delivery composition of the present invention.

Those skilled in the art may use other drugs or biologically active substances that can be released into the aqueous environment in the described delivery system. Various forms of 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 when administered to an animal or plant, or are used as a bulk dosage form so that it can be applied to the surface of the body of an animal or plant, or placed inside in the form of a rod-type implant.

The pharmaceutically effective amount of the active ingredient may vary depending on the active ingredient, the degree of health of the animal or plant, and the time required to deliver the active ingredient. There is no critical upper limit for the amount of active ingredient included in a polymer solution, other than the acceptable amount of such solution or the viscosity of the dispersion medium for administration through a syringe needle, and except that it can effectively treat a medical condition without exposing the animal or plant to overdose . The lower limit of the concentration of the active ingredient included in the delivery system simply depends on the activity of the active ingredient and the length of time required for treatment.

Typically, the pharmaceutically active ingredient is present in an amount of from 0.05% to 60% (w/w) of the total weight of the composition. In another embodiment of the present invention, the active ingredient is present in an amount of from 1 to 40% (w/w) of the total weight of the composition. In another embodiment of the present invention, the active ingredient is present in an amount of 2 to 4% (w/w) of the total weight of the composition. In yet another embodiment of the present invention, the active ingredient, which is a small molecule, is present in an amount of from 1 to 20% (w/w) of the total weight of the composition.

In the biodegradable drug delivery composition of the present invention, a pharmaceutically effective amount can be released gradually over an extended period of time. This sustained release may be continuous or intermittent, linear or non-linear, and may vary depending on the triblock copolymer and diblock copolymer composition.

The active ingredient may be released over a period of time ranging from 1 day to 1 year or longer depending on the type of treatment required and the biodegradable drug delivery composition used. In one embodiment, the biodegradable drug delivery composition may deliver the active ingredient over at least 1 day, optionally at least 3 days, optionally at least 7 days. In another embodiment of the present invention, the biodegradable drug delivery composition can deliver the active ingredient for at least 30 days. In one embodiment of the present invention, the biodegradable drug delivery composition can deliver the active ingredient for at least 90 days. In yet another embodiment of the present invention, the biodegradable drug delivery composition can deliver the active ingredient for 1 year or longer.

The biodegradable drug delivery composition may be an injectable liquid, preferably at room temperature, and can be administered through a syringe without much effort. Such biodegradable drug delivery compositions are also formed in situ and biodegradable, and are transformed into solid depots when injected into an animal or plant. They can also be prepared into microparticles that can be administered using a syringe.

Alternatively, the biodegradable drug composition is prepared as a solid, formulated into small particles (which cannot be injected due to their size) and formulated into a powder that is sprinkled on the injured area. Solid implants can have any desired shape for insertion into the body.

In another aspect of the present invention, the drug delivery composition is a rod-type implant that can be implanted subcutaneously or elsewhere in the body. In another aspect of the present invention, the drug delivery composition may be formulated and applied as a film. In another aspect of the present invention, the biodegradable drug delivery composition can be used as a bulk dosage form that can be applied to the surface of a plant or animal body or administered orally. Can be applied to any part of the body, including the eyes.

The biodegradable drug delivery composition may further comprise a pharmaceutically acceptable carrier, adjuvant or vehicle. Suitable carriers may be saline, buffered saline, or the like. It can be added to the biodegradable drug delivery composition after preparing its dosage form from a mixture of at least three copolymers taken from triblock copolymers and diblock copolymers.

The adjuvant can be prepared simultaneously by mixing the drug. In this regard, adjuvants that can be used are alum, aluminum phosphate, calcium phosphate, MPL™, CpG motifs, modified toxins, saponins, endogenous adjuvants such as cytokines, complete and incomplete Freund's adjuvants, ISCOM type adjuvants, muramyl peptides, etc. similar.

The binder can be any diluent, additional solvent, filler or binder that can optionally alter the delivery of the active ingredient in the biodegradable drug delivery composition. For example, small amounts of triglycerides such as triacetin or tripropionine. The amount that can be used in the described biodegradable drug delivery compositions of the present invention may vary from 12 to 20% (wt./wt.%). In one aspect of the present invention, triacetin can be added to the dosage form in an amount of 17% (w/w). In another aspect of the present invention, tripropionine (abbreviated as tripro) can be added in an amount of 16% (w/w).

In one embodiment of the present invention, the composition may contain an organic solvent. The organic solvent may be selected from the following group: benzyl alcohol, benzyl benzoate, dimethyl isosorbide (DMI), dimethyl sulfoxide (DMSO), ethyl acetate, ethyl benzoate, ethyl lactate, glycerol formal, methyl ethyl ketone, methyl isobutyl ketone, N-ethyl-2-pyrrolidone, N-methyl-2-pyrrolidinone ( NMP), pyrrolidone-2, tetraglycol, triacetin, tributyrin, tripropionine (Tripro) and mixtures thereof. In one embodiment of the present invention, DMSO, NMP, tripro, or mixtures thereof may be used as solvents.

In a further aspect of the present invention, there is provided a method for preparing a biodegradable drug delivery composition comprising a mixture of at least three block copolymers drawn from the triblock copolymers and diblock copolymers also included in the present invention. This method includes:

(i) dissolving in an organic solvent at least three triblock and diblock copolymers containing:

(a) a biodegradable triblock copolymer having the formula:

Av-B _w -Ax, where A is a polyester, B is a polyethylene glycol, v and x are the number of repeat units ranging from 1 to 3000, and w is the number of repeat units ranging from 3 to 300, with v = x or v^x; and (b) a biodegradable diblock copolymer having the formula:

C y-A _z , where A is a polyester, C is a polyethylene glycol end group, y and z are the number of repeating units, with y varying from 2 to 250, and z varying from 1 to 3000 to form a polymer mixture;

where the mass ratio between copolymers (a) and (b) is 1:19 to 5:1; and (ii) adding at least one pharmaceutically active ingredient to said polymer mixture.

Within the framework of this method, combinations of at least three block copolymers containing at least one diblock and at least one triblock, for example from 3 to 10 block copolymers, can be formulated. For example, two triblock copolymers can be combined with one diblock, or one triblock copolymer can be combined with two diblocks. Five triblock copolymers can be combined with five diblocks, or three triblock copolymers can be combined with seven diblock copolymers. Four triblocks can be combined with three diblocks, etc.

The polyester in the triblock may be polylactide (PLA), polycaprolactone (PCL), polyethylene adipate (PEA), polyglycolide (PGA), polyhydroxyalkanoate (PHA), and mixtures thereof. In one embodiment of the present invention, the polyester used is a polylactide.

The polyester in the diblock may be polylactide (PLA), polycaprolactone (PCL), polyethylene adipate (PEA), polyglycolide (PGA), or polyhydroxyalkanoate (PHA), and mixtures thereof. In one embodiment of the present invention, the polyester used is a polylactide. In another embodiment of the present invention, the polyester is a poly(lactide-co-glycolide).

The organic solvent that can be used in this described method can be selected from the group: benzyl alcohol, benzyl benzoate, dimethyl isosorbide (DMI), dimethyl sulfoxide (DMSO), ethyl acetate, ethyl benzoate, ethyl lactate, glycerol formal, methyl ethyl ketone, methyl isobutyl ketone, N-ethyl-2 -pyrrolidone, N-methyl-2-pyrrolidinone (NMP), pyrrolidone-2, tetraglycol, triacetin, tributyrin, tripropionine (Tripro) and mixtures thereof. In one embodiment of the present invention, DMSO, NMP, tripro, or mixtures thereof may be used as solvents.

The organic solvent is typically present in an amount of from 35 to 75% (w/w) of the total weight of the composition. In another embodiment of the present invention, the organic solvent used in the preparation of the biodegradable drug delivery composition is present in an amount of 50 to 60% (w/w) of the total weight of the composition. In yet another embodiment of the present invention, the solvent used in the preparation of the biodegradable drug delivery composition is present in an amount of from 25 to 90% (w/w) of the total weight of the composition. The amount of organic solvent in another embodiment of the present invention may be 0% if it is evaporated.

This organic solvent may be retained in the composition or evaporated prior to administration.

Some MPEG-OH may be contaminated with small amounts of OH-PEG-OH. According to the method of the present invention, when using contaminated MPEG-OH, the final product may be MPEG-PLA contaminated with a small amount of PLA-PEG-PLA, which is within the scope of the present invention.

In a further aspect, the present invention provides a method for modulating the release kinetics of at least one active ingredient, said method comprising administering a biodegradable drug delivery composition comprising a mixture of at least three different block copolymers, drawn from triblock and diblock copolymers, which includes:

(a) a biodegradable triblock copolymer having the formula:

Av-Bw-Ax where A is a polyester, B is a polyethylene glycol, v and x are the number of repeat units ranging from 1 to 3000, and w is the number of repeat units ranging from 3 to 300, with v = x or v^ x;

(b) a biodegradable diblock copolymer having the formula:

Cy-A _z where A is a polyester, C is a polyethylene glycol end group, and y and z are the number of repeating units, with y ranging from 2 to 250, and z ranging from 1 to 3000;

where the mass ratio between copolymers (a) and (b) is from 1:19 to 5:1; and (c) at least one pharmaceutically active ingredient.

In this method of modulating the release kinetics of at least one active ingredient, the polyester in the triblock and diblock may be selected from the group consisting of polylactide, polyglycolide, polycaprolactone, poly(ε-caprolactone-co-lactide), polyethylene adipate, poly(lactideco-glycolide) , polyhydroxyalkanoate and mixtures thereof, wherein the terminal polyethylene glycol may be methoxypolyethylene glycol. In one aspect of the present invention for biodegradable drug compositions, the triblock is PLA-PEG-PLA and the diblock is MPEG-PLA, as described herein.

In this method of modulating the release kinetics of at least one active ingredient, the molecular weight of the polyethylene glycol chain can vary from 180 g/mol to 12 kg/mol or from 194 g/mol to 12 kg/mol, and the molecular weight of the end group polyethylene glycol chain is from 100 g/mol to 4 kg/mol or from 164 g/mol to 10 kg/mol.

In another embodiment of the present invention, the at least one pharmaceutically active ingredient used in the present method is present in an amount of from 0.05 to 60% (w/w), optionally from 0.05 to 40%, optionally from 0 .05 to 30%, optionally from 0.05 to 10%, optionally from 0.05 to 7%, optionally from 0.05 to 2% of the total weight of the composition.

In one embodiment of the present invention, the biodegradable drug delivery composition is an injectable liquid and the at least one pharmaceutically active ingredient is present in an amount of from 0.05 to 60% (w/w).

In an alternative embodiment of the present invention, the biodegradable drug delivery composition is a rod-type implant and the at least one pharmaceutically active ingredient is present in an amount of from 50 to 80% (w/w%).

In a further embodiment of the present invention, the copolymers are present in an amount of from 2 to 60% (w/w%) of the total weight of the composition, optionally from 10 to 50%, optionally from 20 to 40%, optionally from 20 to 35%, optionally from 30 to 50%.

In one embodiment of the present invention, one or more triblock copolymers are present in an amount of from 1 to 50% (w/w), optionally from 5 to 40% of the total weight of the composition.

In one embodiment of the present invention, one or more diblock copolymers are present in an amount of from 1 to 57% (wt./wt.%), from 2.5 to 45% of the total weight of the composition.

In a further embodiment of the present invention, the weight ratio of the sum of biodegradable triblock copolymers (a) to the sum of biodegradable diblock copolymers (b) in said biodegradable drug delivery composition is from 1:5 to 3:1.

Typically, the molar ratio of polyester repeating units to ethylene oxide in the composition used in the described method is from 0.5 to 22.3, optionally from 0.5 to 10, optionally from 0.5 to 3.5 in the triblock, and also from 0.8 to 15, optionally from 1 to 10 in a diblock.

In a method as described herein modulating the release kinetics of at least one active ingredient, the composition may be an injectable liquid or microparticle and form a depot when administered into the body, or a solid or small solid particles, or a rod-type implant , or bulk dosage form, which may be in the form of solids and which can be introduced into the body, for example, using a trocar.

The use of a biodegradable drug delivery composition, as described herein, to modulate the release kinetics of at least one active ingredient is another aspect of the present invention.

A composition for drug delivery is proposed, containing: (i) a mixture of at least three different block copolymers, where each block polymer is:

(a) a triblock copolymer having the formula:

Ay-Bw-Ax where A is a polyester, B is a polyethylene glycol, v and x are the number of repeat units ranging from 1 to 3000, and w is the number of repeat units ranging from 3 to 300, with v = x or v^ x; or (b) a diblock copolymer having the formula:

Cy-Ar where A is a polyester, C is a polyethylene glycol end group, and y and z are the number of repeating units, with y ranging from 2 to 250, and z ranging from 1 to 3000; and where the mixture includes at least one copolymer (a) and at least one copolymer (b); and wherein the weight ratio between copolymers (a) and (b) is from 1:19 to 5:1; and (ii) at least one pharmaceutically active ingredient.

Also provided is a method of modulating the release kinetics of at least one active ingredient, said method comprising administering to a subject a drug delivery composition as defined above, wherein the release kinetics of said at least one active ingredient from said drug delivery composition is modulated without affecting affecting one or more physical properties of said drug delivery composition.

In addition, provision is made for the use of a drug delivery composition, as defined above, to modulate the release kinetics of at least one active ingredient.

A number of embodiments and/or aspects of the present invention have been described. However, it should be understood that various modifications may occur without affecting the spirit or scope of the invention.

Other aspects and embodiments of the present invention are set forth below or will be readily apparent from the following description of preferred embodiments.

A biodegradable composition for drug delivery is described, containing a mixture of at least three triblock copolymers and diblock copolymers, which includes:

(a) a biodegradable triblock copolymer having the formula:

Ау-Вш-Ах where A is a polyester, B is a polyethylene glycol, v and x are the number of repeating units in the range from 1 to 3000, and w is the number of repeating units in the range from 3 to 300, with v=x or v^ x;

(b) a biodegradable diblock copolymer having the formula:

Cy-Ar where A is a polyester, C is a polyethylene glycol with an end group, y and z are the number of repeating units, with y varying in the range from 2 to 250, and z varying from 1 to 3000, where the mass ratio of the amount of biodegradable triblock- copolymer (a) and biodegradable diblock copolymer (b) is from 1:19 to 5:1 in the specified biodegradable medicinal composition;

(c) at least one additional biodegradable block copolymer; And

- 16 045044 (d) at least one pharmaceutically active substance, wherein the release kinetics of said at least one active substance from said biodegradable drug delivery composition is modulated without having any effect on the physical properties of said biodegradable drug delivery composition funds.

A biodegradable composition for drug delivery is described, containing a mixture of at least three triblock copolymers and diblock copolymers, which includes:

(a) a biodegradable triblock copolymer having the formula:

Av- B _w -A _x where A is a polyester, B is a polyethylene glycol, v and x are the number of repeat units ranging from 1 to 3000, and w is the number of repeat units ranging from 3 to 300, wherein v=x or v+x;

(b) a biodegradable diblock copolymer having the formula:

Cy-A _z where A is a polyester, C is a polyethylene glycol end group, y and z are the number of repeat units, with y varying from 2 to 250, and z varying from 1 to 3000, where y is the number of repeat units ethylene oxide, and z is the number of polyester repeating units, where the mass ratio of the sum of the biodegradable triblock copolymer (a) and the biodegradable diblock copolymer (b) is from 1:19 to 5:1 in the specified biodegradable medicinal composition;

(c) at least one additional biodegradable block copolymer; and (d) at least one pharmaceutically active agent, wherein the release kinetics of said at least one active agent from said biodegradable drug delivery composition is modulated without any effect on the physical properties of said biodegradable drug delivery composition.

A biodegradable composition for drug delivery is described, containing a mixture of at least three triblock copolymers and diblock copolymers, which includes:

(a) a biodegradable triblock copolymer having the formula:

P LAu-PEG _vd -P LAx where v and x are the number of repeating units in the range from 1 to 3000, and w is the number of repeating units in the range from 3 to 300, with v=x or v+x;

(b) a biodegradable diblock copolymer having the formula:

MPEGy-PLA _g where y and z are the number of repeating units, with y varying from 2 to 250, and z varying from 1 to 3000, where the mass ratio of the sum of the biodegradable triblock copolymer (a) and the biodegradable diblock copolymer (b) is from 1:19 to 5:1 in the specified biodegradable medicinal composition;

(c) at least one additional biodegradable block copolymer; and (d) at least one pharmaceutically active agent, wherein the release kinetics of said at least one active agent from said biodegradable drug delivery composition is modulated without any effect on the physical properties of said biodegradable drug delivery composition.

A biodegradable composition for drug delivery is described, containing a mixture of at least three triblock copolymers and diblock copolymers, which includes:

(a) a biodegradable triblock copolymer in an amount of from 1 to 50% (w/w) of the total weight of the composition, having the formula:

P LAu-PEG _vd -P LA _X where v and x are the number of repeating units in the range from 1 to 3000, and w is the number of repeating units in the range from 3 to 300, with v=x or v+x;

(b) a biodegradable diblock copolymer in an amount of from 1 to 57% (w/w) of the total composition, having the formula:

MPEGu-PLAG where y and z are the number of repeating units, with y varying from 2 to 250, and z varying from 1 to 3000, where the mass ratio of the sum of the biodegradable triblock copolymer (a) and the biodegradable diblock copolymer (b) is from 1 :19 to 5:1 in said biodegradable medicinal composition;

(c) at least one additional biodegradable block copolymer; and (d) at least one pharmaceutically active substance in an amount of from 0.05 to 60% (w/w%), wherein the release kinetics of said at least one active substance from said biodegradable drug delivery composition is modulated, without having any effect on the physical properties of said biodegradable drug delivery composition.

A method is described for modulating the release kinetics of at least one active substance,

- 17 045044, wherein said method comprises administering a biodegradable drug delivery composition containing a mixture of at least three triblock copolymers and diblock copolymers, which consists of:

(a) a biodegradable triblock copolymer having the formula:

Av- Bw- Αχ, where A is a polyester, B is polyethylene glycol, v and x are the number of repeat units in the range from 1 to 3000, and w is the number of repeat units in the range from 3 to 300, wherein v=x or v ^x;

(b) a biodegradable diblock copolymer having the formula:

Cy-Az, where A is a polyester, C is a polyethylene glycol end group, y and z are the number of repeating units, with y varying from 2 to 250, and z varying from 1 to 3000, where the mass ratio of the amount of biodegradable triblock -copolymer (a) and biodegradable diblock copolymer (b) is from 1:19 to 5:1 in the specified biodegradable medicinal composition;

(c) at least one additional biodegradable block copolymer; and (d) at least one pharmaceutically active agent, wherein the release kinetics of said at least one active agent from said biodegradable drug delivery composition is modulated without any effect on the physical properties of said biodegradable drug delivery composition.

Examples

Example 1. Synthesis of polymers.

The block copolymers were synthesized in accordance with the method described in US Pat. No. 6,350,812, incorporated herein by reference with minor modifications. Typically, the required amount of PEG (in the triblock copolymer) or methoxy-PEG (in the diblock copolymer) was heated at 80°C and dried under vacuum for 30 minutes in the reactor. DL-lactide (according to the required UA/EO molar ratio) and zinc lactate (1/1000 of the amount of lactide) were added. The reaction mixture was first dehydrated with two short vacuum/N ₂ cycles. The reaction mixture was heated at 140°C under a constant flow of nitrogen (0.2 bar). After the reaction stopped, the block copolymer was unloaded from the reactor and left until solidification began at room temperature. The resulting product was characterized by 1H NMR as a function of lactate content. 1H NMR spectroscopy was carried out using a Brucker advance spectrometer with a power of 300 MHz.

For all 1H NMR spectrograms, MestReNova software was used for peak integration and analysis. Chemical shifts were referenced to a solvent value of Δ=7.26 ppm for CDCI3.

To determine the coefficient R, which describes the ratio of lactic acid units to ethylene oxide units (LA/EO), the areas of all peaks were calculated separately. The signal intensity (calculated value) is directly proportional to the number of hydrogen atoms that produce the signal. Thus, to determine the R factor (MK/EO ratio), the calculated values must be uniform and represent the same number of protons (for example, all signal values are determined for 1H). A standard PLA peak and one PEG peak were then used to determine the LA/EO ratio. This method is applicable to the calculation of PEG molecular weights above 1000 g/mol, where the signal obtained for the polymeric end groups can be neglected.

The triblock copolymers described herein have been designated PxRy, where x is the molecular weight of the PEG chain, expressed in kDa, and y is the molar ratio of polyester monomer to ethylene oxide, for example, the molar ratio of lactic acid to ethylene oxide (LA/EO). The MPEG-PLA diblock copolymers described herein are designated dPxRy, where x is the molecular weight of the PEG chain, expressed in kDa, and y is the molar ratio of polyester monomer to ethylene oxide, for example, the molar ratio of lactic acid to ethylene oxide (LA/EO).

Example 2. Preparation of a specific dosage form of meloxicam.

The F197 dosage form described herein is based on an organic block copolymer solution containing meloxicam as the API. 1800 mg of block copolymers corresponding to a mixture of diblock and triblock copolymers in a certain mass ratio of the sum of the triblock to the sum of the diblock, as indicated in the table. 6 was dissolved in 1140 mg of DMSO at room temperature overnight, stirring continuously with a magnetic stirrer. The next day, 60 mg of the drug was added to this block copolymer solution and stirred until the resulting solution was completely homogenized. The dosage form was placed in a syringe before use.

Example 3. Preparation of a dosage form.

Using Examples 1 and 2, the following dosage forms were obtained, listed in table. 1-6 below:

All compositions in the table. 1-6 were brought to 100% using DMSO as a solvent.

- 18 045044

Table 1

No. TB: DB Mass. COOT no Risperidone %(w/w) Triblock copolymer 1 PLA-PEG-PLA %(wt/ MPEG-PLA Diblock copolymer 1 Triblock copolymer 2 PLA-PEG-PLA Diblock copolymer 2 MPEG-PLA Diblock copolymer 3 Diblock copolymer 4 %(wt/may) Code %(wt/may) Code %(wt/may) Code %(wt/may) Code %(wt/may) Code May) Code 16 1.00 60 1.00 P1R4 1.50 dP2R3 1.50 P1R6 1.00 dP0.35R8.5 - - - - 28 5.00 10 25.00 P1R6 1.25 dP2R3 - - 1.25 dP0.35R8.5 1.25 dP0.35R5 1.25 dP2R0.5 29 0.05 10 1.50 P1R6 7.125 dP2R3 - - 7.125 dP0.35R8.5 7.125 dP0.35R5 7.125 dP2R0.5 table 2

Triblock copolymer 1 MPEG-PEG

No. TB:DB Mass ratio Bupivacaine PLA-PEG-PLA Diblock copolymer 1 Diblock copolymer 2 %(w/w) %(w/m as) Code %(w/w) Code %(w/w) Code 289 1.00 2.00 20.00 P1R4 20.00 dP1R4 - - 290 1.00 2.00 20.00 P1R4 10.00 dP1R4 10.00 dP0.35R8.5 291 1.00 2.00 20.00 P1R4 - - 20.00 dP0.35R8.5 292 1.00 2.00 25.00 P1R4 25.00 dP1R4 - - 293 1.00 4.00 20.00 P1R4 20.00 dP1R4 - - 294 1.00 6.00 20.00 P1R4 20.00 dP1R4 - Table 3 Triblock copolymer 1 MPEG-PLA

Bupivacaine PLA-PEG-PLA Diblock copolymer 1 Diblock copolymer 2

No. TB:DB Mass. correspondence %(w/w) %(wt/may) Code %(w/m as) Code %(w/m as) Code 45 5.00 1.00 41.70 P1R4 4.15 dP0.35R8.5 4.15 dP2R0.5 46 0.05 1.00 2.50 P1R4 23.75 dP0.35R8.5 23.75 dP2R0.5 49 0.05 1.00 3.00 P1R4 28.50 dP0.35R8.5 28.50 dP2R0.5 64 0.05 1.00 3.00 P1R4 28.50 dP0.35R8.5 28.50 dP0.35R5

- 19 045044

Table 4

No. TB:D B Mass. accordingly Iverme ktin %(wt/may) Triblock copolymer 1 MPEG-PLA Diblock copolymer 1 Triblock copolymer 2 MPEG-PLA Triblock copolymer 3 PLA-PEG-PLA %(wt/ PLA-PEG-PLA Diblock copolymer 2 Diblock copolymer 3 PLA-PEGPLA %(ma ss/ma c) Code %(wt/may) Code %(wt/°/ 'o (may/ May) Code %(wt/may) Code May) Code May) Code 10 0.67 1.00 20.00 P2R3. 30.00 dP0.35R8 5 5 .5 11 0 0.50 1.00 8.30 P2R3. 5 16.70 dP2R3 - - - - - - - - eleven 5 0.50 1.00 8.30 P2R3. 5 8.30 dP0.16R1 - - 8.30 dP2R10 - - - - eleven 0.67 1.00 10.00 P12R 30.00 dP0.35R8 10.00 P0.19R1 9 0.7 .5 8 12 dP0.35R8 dP0.35 4 0.50 1.00 4.20 P1R4 5.50 dP2R3 4.20 P1R6 5.50 .5 ^{S'S0 R5} - - 12 dP0.35R8 dP0.35 P2R 0.50 1.00 2.80 P1R4 5.50 dP2R3 2.80 P1R6 5.50 5.50 2.80„ _g 6 .5 R5 3.5 Table 5 Triblock Triblock copolymer 1 MPEG-PLA copolymer 2 MPEG-PLA Octreatide acetate PLA-PEG-PLA Diblock copolymer 1 PLA-PEG-PLA Diblock copolymer 2 TB:DB Mass. %(wt/ %(wt/ %(wt/ %(wt/ N ^{( 3} ratio %(w/w) May) CODE May) CODE May) Code May) Code 163 1.00 4.00 10.00 P1R4 10.00 dP1R4 10.00 P1R6 10.00 dP0.35R8.5 165 1.00 4.00 20.00 P1R6 20.00 dP0.35R8.5 - - - - 166 1.00 4.00 20.00 P1R4 20.00 dP1R4 - - - - Table 6

Triblock copolymer 1

Triblock copolymer 2

MPEGPLA

No. TB:DB Mass ratio Meloxicam %(w/m as) PLA-PEG-PLA Code Diblock copolymer 1 %(w/w) %(w/w) Code Code %(w/w) 197 5.00 2.00 50.00 P0.19R2 - - 10.00 dP0.35R8.5 199 5.00 2.00 25.00 P0.19R2 25.00 P2R3.5 10.00 dP0.35R8.5 365 5.00 2.00 50.00 P2R3.5 - - 10.00 dP0.35R8.5

Example 4. Injectability of various compositions.

The injection analysis is performed using a Lloyd Instruments FT plus texturometer using the following analytical conditions.

Scheme 1.

500 μl of the test dosage form is administered through a 1 ml Codan syringe and a 23G 1 Terumo needle at a flow rate of 1 ml/min. Samples were analyzed in six parallel assays.

The resulting value in N (Newtons) correlates with the force required to administer the dosage form under the conditions described.

Scheme 2.

500 μl of the test dosage form is administered through a 1 ml Codan syringe and a 23G 5/8 OD needle at a flow rate of 1 ml/min. Samples were analyzed in six parallel runs.

The resulting value in N (Newtons) correlates with the force required to administer the drug.

- 20 045044 new form under the described conditions.

Example from FIG. 2 and 3.

F289, F290 and F291 are mixtures of triblock (TB) P1R4 and diblock (DB) dP1R4 or mixtures of triblock (TB) P1R4, diblock (DB) dP1R4 and dP0.35R8.5, or mixtures of triblock (TB) P1R4 and diblock (DB) ) dP0.35R8.5 respectively in the case of a total polymer content of 40%, as indicated in table. 3. The average injectability of F289, F290 and F291 is 4.8 N, 4.4 N and 4.3 N, respectively, as shown in Table. 7. Injectability was analyzed in accordance with scheme 1.

The data show that the addition of additional biodegradable block copolymer causes modulation of release, as shown in FIG. 2, without affecting injection ability.

F292 is a mixture of triblock (TB) P1R4 and diblock (DB) dP1R4 in the case of a total polymer content of 50%, as indicated in table. 2. The average injectability of F292 is 14.5 N, as indicated in the table. 7.

The data shows that increasing the total polymer content from 40 to 50% causes modulation of release, as shown in FIG. 2. However, this increase leads to an increase in the injection value from 4.8 N to 14.5 N for F289 and F292, respectively.

F293 and F294 are a mixture of triblock (TB) P1R4 and diblock (DB) dP1R4 in the case of a total polymer content of 40% with 4% and 6% API loading, respectively, as indicated in table. 2. The average injectability of F293 and F294 is 4.8 N and 5.3 N, as indicated in table. 7.

The data show that increasing the total API loading from 4 to 6% causes modulation of release, as shown in FIG. 3. However, this modulation is suboptimal due to the high initial burst release.

Table 7

No. □upivacaine total polymer content (%) Number of copolymer in >o Number of injections Standard ^w/w) thorny (H) deviation 289 2.00 40.00 2 6 4.8 0.5 290 2.00 40.00 3 6 4.4 0.4 291 2.00 40.00 2 6 4.3 0.4 292 2.00 50.00 2 6 14.5 0.6 293 4.00 40.00 2 6 4.8 0.4 294 6.00 Example from FIG. 7 and 8 40.00 2 6 5.3 0.2

F197, F199 and F325 are mixtures of diblock (DB) dP0.35R8.5 and triblock (TB) P0.19R2 and/or P2R3.5 in the case of a total polymer content of 60%, as indicated in table. 8. The average injection properties of F197, F199 and F325 are 2.5 N, 8.6 N and 53.6 N, respectively, as shown in Table. 8.

The data show that the addition of additional biodegradable block copolymer causes modulation of release, as shown in FIG. 7, while the dosage form retains its injectability.

The injection assay was performed according to Scheme 2.

Table 8

/!eloxicam No. ^(w/w) Total polymer content (%) > Number of epolymers 4 number of repetitions eInjectionstandard yes (N) deviation 197 2.00 60.00 2 6 2.5 0.2 199 2.00 60.00 3 6 8.6 0.7 365 2.00 60.00 2 3 53.6 2.8

Example 5: Viscosity measurement.

Dynamic viscosity is determined using an Anton Paar rheometer equipped with a cone and disk. Typically, the following scheme is used to measure viscosity:

250 μl of the test dosage form is placed on the measuring plate. The temperature is maintained at +25°C. The measuring system used is a 25 mm diameter disc and a 2 degree cone (CP25-2/S).

The operating range is from 10 to 1000 s ^-1 .

After shaking for 10 s, the dosage forms are placed in the center of a temperature-controlled measuring plate using a spatula. The measuring system is lowered down, leaving between

-

Claims (28)

measuring system and measuring plate, the gap is 0.051 mm. Eleven viscosity measurement points are determined over a shear rate range from 10 to 1000 s ^-1 . The given values were obtained at 100 s ^-1 . Example 6: In vitro release assay. 50 mg of bupivacaine dosage form is added to 50 ml of physiological buffer. The physiological buffer used is KRT containing 50 ml of Krebs/Ringer/Tris (KRT) buffer solution, pH 7.4, which is 143 mM sodium chloride, 5.1 mM potassium chloride, 2.7 mM calcium chloride, 1. 34 mM magnesium sulfate, 25 mM Tris-Cl pH 7.4 and 0.1% sodium azide. Upon injection, the solvent diffuses from the dosage form and the remaining polymer forms an in situ depot in the aqueous environment. To maintain complete dissolution conditions for drug release, the release medium was shaken continuously at 180 rpm (Unimax 1010, Heidolph) at 37°C. At predetermined intervals, the medium is collected and analyzed by UHPLC. The amount of bupivacaine released from the dosage form is calculated from the calibration curve. The concentration of bupivacaine ranges from 0 to 150 mcg/ml. Bupivacaine included in the polymer solution is encapsulated in the polymer matrix as the polymer hardens. Although the present invention has been described in terms of various preferred embodiments, one skilled in the art will understand that various modifications, substitutions, omissions and changes may be made without departing from the scope of the invention. Accordingly, it is intended to limit the scope of the present invention to the scope of the claims, including their equivalents. CLAIM 1. Biodegradable composition for drug delivery, containing: (i) a mixture of at least three different block copolymers, each of these block copolymers being: (a) a biodegradable triblock copolymer having the formula: A _v -B _w -A _x where A is a polyester, B is a polyethylene glycol, v and x are the number of repeat units ranging from 4 to 3000, and w is the number of repeat units ranging from 3 to 300, with v=x or v^x; or (b) a biodegradable diblock copolymer having the formula: ^C y ^-A Z where A is a polyester, C is a polyethylene glycol end group, and y and z are the number of repeat units, with y ranging from 2 to 250, and z ranging from 4 to 3000; and where the mixture contains at least one copolymer (a) and at least one copolymer (b); and the weight ratio of the total amount of at least one copolymer (a) and the total amount of at least one copolymer (b) is from 1:19 to 5:1; and (ii) at least one pharmaceutically active ingredient. 2. The biodegradable drug delivery composition of claim 1, comprising a copolymer as defined in (a) or (b), wherein said polyester A is selected from the group consisting of polylactide (PLA), polyglycolide, polycaprolactone, polyethylene adipate, polyhydroxyalkanoate and mixtures thereof and, optionally, the end group polyethylene glycol is methoxy polyethylene glycol. 3. Biodegradable drug delivery composition according to any one of claims 1, 2, in which at least one biodegradable triblock copolymer (a) A is PLA and/or in which at least one biodegradable diblock copolymer (b) A represents PLA. 4. Biodegradable composition for drug delivery according to any one of claims 1-3, which additionally contains: (a) a biodegradable triblock copolymer having the formula: PLA _v -PEG _w -PLA _x where v and x are the number of repeating units in the range from 4 to 3000, and w is the number of repeating units in the range from 3 to 300, with v=x or v^x; and/or (b) a biodegradable diblock copolymer having the formula: MPEG _y -PLA _z where y and z are the number of repeating units, with y varying in the range from 2 to 250, and z varying in the range from 4 to 3000. 5. Biodegradable composition for drug delivery according to any one of claims 1-4, containing: (a) a biodegradable triblock copolymer having the formula: PLA _v -PEG _w -PLA _x - 22 045044 where v and x are the number of repeating units in the range from 4 to 3000, and w is the number of repeating units in the range from 3 to 300, with v=x or v^x; and (b) 2, 3 or 4 different biodegradable diblock copolymers, each of which has the formula: MPEGu-PLAG where y and z are the number of repeating units, with y varying in the range from 2 to 250, and z varying in the range from 4 to 3000; and wherein the weight ratio of the total amount of biodegradable triblock copolymer (a) to the total amount of 2, 3 or 4 different biodegradable diblock copolymers (b) is from 1:19 to 5:1. 6. Biodegradable composition for drug delivery according to any one of claims 1-4, containing: (a) two different biodegradable triblock copolymers, each having the formula: PLA _v -PEGw-PLAχ where v and x are the number of repeat units ranging from 4 to 3000, and w is the number of repeat units ranging from 3 to 300, in this case v=x or v^x; and (b) 1, 2, 3 or 4 different biodegradable diblock copolymers, each of which has the formula: MPEG _y -PLA _z where y and z are the number of repeating units, with y varying from 2 to 250 and z varying from 4 to 3000; and wherein the weight ratio of the total amount of two different biodegradable triblock copolymers (a) to the total amount of 1, 2, 3 or 4 different biodegradable diblock copolymers (b) is from 1:19 to 5:1. 7. Biodegradable composition for drug delivery according to any one of claims 1 to 6, characterized in that said composition is an injection liquid and is suitable for forming a depot when introduced into the body by injection or is solid particles or rod-type implants , or bulk dosage forms. 8. Biodegradable drug delivery composition according to any one of claims 1 to 7, in which the weight of the polyethylene glycol chain is in the range from 180 g/mol to 12 kg/mol, or from 194 g/mol to 12 kg/mol, or from 200 g/mol to 12 kg/mol, or 100 g/mol to 4 kg/mol, and the molecular weight of the end-group polyethylene glycol chain is in the range of 100 g/mol to 2 kg/mol, or 164 g/mol up to 10 kg/mol. 9. The biodegradable drug delivery composition according to any one of claims 1 to 8, further comprising a pharmaceutically acceptable carrier, wherein, optionally, the pharmaceutically acceptable carrier is a solvent, optionally an organic solvent. 10. Biodegradable composition for drug delivery according to any one of claims 1 to 9, in which the pharmaceutically active ingredient is hydrophobic; and/or the pharmaceutically active ingredient is risperidone, bupivacaine, ivermectin, octreotide, meloxicam, or combinations thereof. 11. Biodegradable drug delivery composition according to any one of claims 1 to 10, wherein at least one pharmaceutically active ingredient is present in an amount of from 0.05 to 60% (w/w), optionally from 0.05 up to 40%, optionally from 0.05 to 30%, optionally from 0.05 to 10%, optionally from 0.05 to 7%, optionally from 0.05 to 2% of the total weight of the composition. 12. The biodegradable drug delivery composition according to claim 11, wherein when said composition is an injection liquid, the at least one pharmaceutically active ingredient is present in an amount of from 0.05 to 60% (w/w) . 13. The biodegradable drug delivery composition according to claim 7, wherein when said composition is a rod-type implant, the at least one pharmaceutically active ingredient is present in an amount of from 50 to 80% (w/w). 14. Biodegradable drug delivery composition according to any one of claims 1 to 13, in which said mixture of at least three different block copolymers is present in an amount from 2 to 60% (w/w) of the total weight of the composition, optionally from 10 to 50%, optionally from 20 to 40%, optionally from 20 to 35%, optionally from 30 to 50%. 15. Biodegradable drug delivery composition according to any one of claims 1 to 14, wherein one or more triblock copolymer is present in an amount of from 1 to 50% (w/w), optionally from 5 to 40% of the total mass of the composition. 16. Biodegradable drug delivery composition according to any one of claims 1 to 15, wherein one or more diblock copolymer is present in an amount of from 1 to 57% (w/w), optionally from 2.5 to 45% from the total mass of the composition. 17. The biodegradable drug delivery composition according to any one of claims 1 to 16, wherein the weight ratio of the total amount of biodegradable triblock copolymers (a) to the total amount of biodegradable diblock copolymers (b) in said biodegradable delivery composition - 23 045044 medicines is from 1:5 to 3:1. 18. The biodegradable drug delivery composition according to any one of claims 1 to 17, wherein the molar ratio of polyester repeating units to ethylene oxide in the composition is from 0.5 to 22.3, optionally from 0.5 to 10, optionally from 0 .5 to 3.5 in the triblock copolymer, and from 0.8 to 15, optionally from 1 to 10 in the diblock copolymer. 19. The biodegradable drug delivery composition according to any one of claims 1 to 18, which contains three different block copolymers, as defined in any of the previous paragraphs, or four different block copolymers, as defined in any of the previous paragraphs, or five different block copolymers, as defined in any of the previous paragraphs, or six different block copolymers, as defined in any of the previous paragraphs. 20. The biodegradable drug delivery composition according to any one of claims 1 to 19, which contains one biodegradable triblock copolymer as defined in any of the claims, or two different biodegradable triblock copolymers as defined in any of the preceding claims, or three different biodegradable triblock copolymers as defined in any of the preceding paragraphs, or four different biodegradable triblock copolymers as defined in any of the preceding paragraphs. 21. The biodegradable drug delivery composition according to any one of claims 1 to 20, which contains one biodegradable diblock copolymer as defined in any of the preceding paragraphs, or two different biodegradable diblock copolymers as defined in any of the preceding paragraphs, or three different biodegradable diblock copolymers as defined in any of the preceding paragraphs, or four different biodegradable diblock copolymers as defined in any of the preceding paragraphs. 22. Biodegradable composition for drug delivery according to any one of claims 1 to 21, containing a triblock copolymer present in an amount from 1 to 50% (wt./wt.%) of the total weight of the composition, a diblock copolymer present in an amount from 1 to 57% (wt./wt.%) of the total weight of the composition and one or more additional diblock or triblock copolymers, each of which is present in an amount of from 0.2 to 20, optionally from 0.5 to 20 ( wt./wt.%) of the total weight of the composition. 23. Biodegradable composition for drug delivery according to any one of claims 1 to 22, which is a composition in accordance with composition No. 16, 28, 29, 290, 45, 46, 49, 64, 115, 119, 124, 126, 163 or 199, defined in example 3 in table. 1-6. 24. Biodegradable drug delivery composition according to any one of claims 1 to 23, wherein the release of at least one active ingredient can be modulated. 25. A biodegradable drug delivery composition according to any one of claims 1 to 24, which is suitable for delivering to a subject an active ingredient, optionally a therapeutically effective amount of the active ingredient, for at least 1 day, optionally for at least 3 days, optionally for at least 7 days, optionally for at least 30 days, optionally for at least 90 days, optionally for at least 1 year. 26. Biodegradable drug delivery composition according to any one of claims 1 to 25, which is suitable for parenteral administration. 27. The biodegradable drug delivery composition according to any one of claims 1 to 26, wherein the block copolymers have a solubility in aqueous solution of less than 5%, optionally less than 1% (w/w). 28. A method of modulating the release kinetics of at least one active ingredient, said method comprising administering a biodegradable composition for delivering medicinal products to a subject as defined in any one of claims 1 to 27, wherein the release kinetics of said at least one active ingredient from said the biodegradable drug delivery composition is modulated without having any effect on one or more physical properties of said biodegradable drug delivery composition; and wherein one or more of the physical properties are injectability and pre-injection viscosity of the biodegradable drug delivery composition, and depot stability after injection of the biodegradable drug delivery composition. -