Gnrh analogue-containing compositions with delayed release

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions relates to medicine and deals with a method of obtaining an elongated implant, where the ratio of the diameter to the length on the implant axis constitutes between 1:20 and 1:40, for the controlled and delayed release of a GnRH analogue of triptorelin acetate. In addition, the group of inventions deals with the elongated implant, obtained in accordance with the said method.

EFFECT: group of inventions provides good control over triptorelin release from the implant.

11 cl, 26 ex, 6 dwg, 11 tbl

 

The present invention relates to pharmaceutical compositions for controlled and sustained release of active substance comprising a biodegradable polymer or copolymer. In addition, the invention relates to pharmaceutical compositions for controlled and sustained release of at least one active substance, such as peptides or hormones and their analogs, and a method for producing such pharmaceutical compositions.

More specifically, the invention relates to pharmaceutical compositions in the form of small implants that include at least one active substance, such as analogues of gonadotropin releasing hormone (GnRH), such as triptorelin or its salts in the copolymer sleeve or polymer.

GnRH, also known as LHRH, is decapeptides the hormone responsible for the secretion folliclestimulating hormone (FSH) and luteinizing hormone (LH). The GnRH analogues are synthetic drugs modeled on GnRH. Analogues can be both agonists and antagonists. Agonists activate the GnRH receptor, resulting in increased release of FSH and LH. Antagonists, on the contrary, block the GnRH receptor, reducing the release of FSH and LH.

Triptorelin, also known as [D-Trp6], LHRH, is the active component�Ohm medicinal product DECAPEPTYL® and can be used for the treatment of diseases, including prostate cancer, in particular widespread metastatic prostate cancer, endometriosis, female infertility and is usually combined with other hormones during in vivo fertilization (IVF), early sexual maturation; fibroid tumors and endometriosis.

Peptides, such as GnRH analogues, are usually introduced parenterally, e.g. by subcutaneous injection. One reason for this introduction is that they usually break down in the GI tract. Treatment with GnRH analogue or requires constant or repeated administration to a patient over a long period of time.

However, repeated injections cause inconvenience and discomfort to the patient. Formulations with sustained release for prolonged delivery of GnRH analogues without the use of repeated injections now. Such compounds have a number of advantages, including improved precision of dosing and patient compliance with the treatment regimen.

This is a problem in many currently available formulations with sustained release over a long period has not been considered in the prior art. Moreover, for the treatment of many GnRH analogues requires the introduction of a patient for six months or more.

Many existing formulations is relatively difficult because the relevant IU�Odiah requires adding one or more excipients or additional stages, such as fusing and pressing.

The addition of additional excipients is often required to ensure the homogeneity, stability and improve pressuremost or solidification of the mixture, therefore there is a need in obtaining the desired properties without the addition of auxiliary substances.

Alloying and extrusion forms can be used to form the core with the active ingredient. Pressing in forms may be necessary, as the mixture needs to take a firm able to enable in the kernel. The problem of obtaining methods used at these stages, is that they are relatively complex and hard to reproduce on an industrial scale.

In international patent publication number 2005117934 device disclosed sustained release comprising at least one implant. The implant includes a base and a pharmaceutical composition comprising an agonist and/or antagonist hormone, luteinizing hormone releasing (LHRH). The implant may have dulaunoy structure with an outer layer formed of silicone material. An implant with one end open can be prepared by dipping one end of the drug in a solution for dissolving the substance of the outer layer.

The disadvantage of using silicone is that it decomposes after injection. This may have an adverse impact on the release profile of the component of the agonist and/or antagonist and LHRH to cause undesirable exhaust silicone material remains within the subject after the release.

In European patent number 1001743 reveals the core containing the active principle and a coating which completely surrounds the core. The core with a coating which completely surrounds it, degrades the properties so that the concentration of the active ingredient released shortly after the introduction, is low due to the coating that prevents release. The implant also has a second drawback consists in the difficulty of the method of producing.

In U.S. patent number 5851547 revealed the drug controlled release, which includes a swellable inner layer and a waterproof outer layer, which controls the swelling of the inner layer. The drug is released exclusively through at least one open end of the inner layer and the inner layer is not destroyed, and the original shape is retained during the period of release of the drug. The problem of such compositions is that the drug release can be controlled by only one pair�the ETP: the quantity of a medicine which can be released through the open end. This is because the inner layer does not break up, and this limits the period of release.

In one particular aspect, the invention provides controlled and sustained release of the GnRH analogue of triptorelin from poly(lactide-co-glycolide)acid (PLGA) coated with a biodegradable polymer or copolymer sleeve.

Therefore, the present invention is to provide a method that eliminates at least one drawback, providing, for example:

- prolonged release

- improved control of the release,

- a more complete release,

- a relatively simple production method, and/or

- improved Biodegradability.

In one aspect, the invention provides an elongated implant for the controlled and sustained release of at least one GnRH analogue, where the implant includes:

polymer or copolymer sleeve, and

polymer or copolymer core located in the sleeve comprising at least one GnRH analogue,

characterized by the fact that

at least one end of the sleeve is open, and

- the sleeve is destroyed by slow release.

In another aspect the invention provides a method of producing an elongated implant, comprising the stage

- function�of olenia biodegradable polymer or copolymer sleeves

- combining the GnRH analogue and the polymer or copolymer to obtain a polymer or copolymer core, and then,

- locating the core in the sleeve.

In an additional aspect, the invention provides an elongated implant for the controlled and sustained release of acetate of triptorelin, GnRH analogue, where the implant includes

polymer or copolymer sleeve having at least one open end, and

where the sleeve is a kernel that includes the acetate of triptoreline.

In another aspect the invention provides a method of producing an elongated implant, including the stage

- preparation of a polymer or copolymer sleeves

- preparation of a solution of acetate of triptorelin between 40 and 80% (wt./about.) in water

- placing the solution in his sleeve,

- soak solution for 2-48 hours at 20-30ºC, and

- drying within 6-24 hours under vacuum.

In yet another aspect, the invention further provides a method of producing an elongated implant "dual extrusion, incorporating the following stages:

- the introduction of pellets made of biodegradable polymer or copolymer and active substance into the extruder kernel;

- extrusion of the nucleus, is made of biodegradable polymer or copolymer and active substance (GnRH analogue), and then cooling;

- coating from BioRes�aguinaga polymer or copolymer.

Description of figures

Figure 1: comparison of the dissolution profiles in vitro implant comprising a polymeric core with acetate of triptorelin and PLGA polymeric sleeve of PLGA obtained in example 5 (represented by shaded squares), and polymer core with acetate of triptorelin and PLGA obtained in example 2 (represented by shaded circles).

Figure 2: shows the change in the concentration of triptorelin time in six dogs after injection of the implant obtained in example 5 (polymer core with 5.9 mg of the acetate of triptorelin sleeve 1.1 mm).

Figure 3: shows the change in the concentration of triptorelin time in six dogs after injection of the implant obtained in example 6 (polymer core with 6.4 mg of the acetate of triptorelin sleeve 0.85 mm).

Figure 4: shows the change in the concentration of triptorelin time in six dogs after injection of the implant obtained in example 7 (polymer core with 9.1 mg of the acetate of triptorelin sleeve 1.1 mm).

Figure 5: shows the change in the concentration of triptorelin in time after injection of the implant according to example 13 (a kernel with 6.3 mg of the acetate of triptorelin sleeve 0.85 mm) in six dogs.

Figure 6: shows the change in the concentration of triptorelin in time after injection of the implant according to example 14 (a kernel with 10.0 mg of the acetate of triptorelin sleeve 1,10 mm) in six dogs.

The following definitions of PR�conducted to elucidate and clarify the meaning and scope of various terms used here for invention disclosure.

As used herein, the term "controlled and sustained release" means the release of the active substance in the patient so that the patient receives an effective dose of the active substance for at least one month.

Used against GnRH "analog" means a natural, recombinant or synthetic peptide or derivative or fragment peptides, which exhibit essentially the same agonistic or antagonistic activity as unmodified or natural peptides.

The term "conformational change" in respect of conformational changes of acetate of triptorelin means a change in the spatial structure of the acetate of triptorelin when it is mixed with water. This change can be caused, for example, by the change of temperature or concentration.

The term "dual extrusion" means getting on one production line cylindrical Central body or core made of a copolymer and/or an active pharmaceutical ingredient (API) and a polymer coating or shell shaped tube, coated on the core after it has hardened.

Suitable for the compositions disclosed in the present invention, the GnRH analogs include leuprorelin, buserelin, nafarelin, histrelin, goserelin,deslorelin, gonadorelin, awarely, triptorelin and their salt forms.

In accordance with the present invention, the preferred GnRH analogue is a salt of triptorelin. More preferably, the GnRH analogue is a acetate of triptorelin or pamoat of triptoreline. Even more preferably, the GnRH analogue is a acetate of triptoreline.

In this application "acetate of triptoreline" means acetate salt form of triptoreline, which contains more than 95% by weight of pure acetate of triptorelin, and preferably more than 97 or 98% by weight pure acetate of triptoreline. This corresponds to a percentage, correspondingly, from about 80, 84, or 85% by weight of pure triptoreline.

In accordance with the invention, if the GnRH analogue is a acetate of triptorelin, the quantity of acetate of triptorelin in polymer core is in the range from 30 to 90% by weight relative to the total mass of the polymer core. Preferably, the number of triptorelin in polymer core is in the range from 35 to 65% by weight relative to the total mass of the polymer core.

In an additional aspect of the present invention sustained release of the active substance can occur through at least two mechanisms that provide improved control of the release. First, the analogue g�of RMON can be released through at least one open end of the sleeve. Secondly, hormone analogue may be released through the sleeve, since the sleeve and the core are destroyed. The elongated implant may include a cavity between the sleeve and the core, which may contribute to delayed release.

These polymers or copolymers are preferably used in purified form or form without the residual monomer fraction. Polymers or copolymers of this type are described, for example, in U.S. patent number 4728721.

In accordance with a preferred embodiment of the invention, the polymer or copolymer, the core can be in the form of a cylinder with a small diameter, preferably less than 1.5 mm, more preferably less than 1 mm and even more preferably between 0.6 and 0.9 mm.

Preferably, the polymer or copolymer formed from lactic and/or glycolic acids. More preferably, the polymer or copolymer is a polylactic acid (PLA), a polymer formed from lactic acid. More preferably, the polymer or copolymer are poly(lactide-co-glycolide), which is a copolymer of lactic acid and glycolic acid.

The copolymer PLGA degrades by hydrolysis of its complex ester linkages in the presence of water. The time required for degradation of PLGA polymer, in General, depends on the ratio of monomers used for its floor�countries so that the higher the number of residues of lactic acid, the greater the decomposition.

In accordance with the invention, the ratio of lactic acid and glycolic acid in PLGA is in the range from 70:30 to 90:10. Preferably, the ratio of lactic acid and glycolic acid in PLGA 85:15. The ratio of lactic acid and glycolic acid in PLGA comprising 85:15, for example, means that the PLGA polymer comprises 85% of the residues of lactic acid and 15% of the residues of glycolic acid. Pure polymers of lactic acid can also be used and are particularly suitable for securing the release for more than three months.

Preferably, the polymer or copolymer sleeve and a polymer or copolymer core is made of the same polymers or copolymers. Polymer or copolymer sleeve and a polymer or copolymer core can be made of PLGA prepared with a ratio of lactic acid and glycolic acid, a component of 85:15.

If the polymer or copolymer include PLGA, molecular weight is at least 60 kDa. More preferably, the molecular weight of PLGA is at least 100 kDa. Most preferably, the molecular weight of PLGA is in the range from 120 kDa to 170 kDa. If the polymer includes PLA, molecular weight of PLA is preferably mejdu kDa or 20 kDa and 30 kDa, or 40 kDa, or more preferably 25 kDa.

The implant releases a GnRH analog for a period of at least 3 months, preferably for at least 6 months.

If the GnRH analogue comprises the acetate of triptoreline, it preferably is present in amounts in the range from 0.5 to 50 mg. More preferably, the acetate of triptorelin is present in the range from 2 to 20 mg. Most preferably, the acetate of triptorelin is present in amounts of about 5, 6, 7, 8, 9, or 10 mg.

In addition, the length along the axis of the implant is between 1 and 4 cm. Preferably, the length along the axis of the implant is between 2 and 3 cm. More preferably, the length along the axis of the implant is approximately 2,5, 2,6, 2,7 or 2,8 cm Most preferably, the length along the axis of the implant is 2.6 cm

Preferably, the outside diameter of the elongated implant is in the range from 0.70 mm to 1.2 mm, more preferably in the range from 0.80 mm to 1.1 mm, Even more preferably, the outside diameter of the elongated implant is about 0.85, about 0.90, p = 0.95, and 1.0 or 1.1 mm.

Preferably, the ratio of diameter and length along the axis of the implant is between 1:20 and 1:40. More preferably, the ratio of diameter and length along the axis of the implant is between 1:22 and 1:30. Even more preferably, the ratio of diameter and length along the axis of the implant is 1:23, 1:25, 1:28 or 1:30.

�optimally size of the implant can be determined based on the dose volume, to be included, and enhance the discomfort that arises when increasing the size of the implant.

In addition, the percentage of GnRH analogue released from the elongate implant with a slow release, is more than 60%. Preferably, more than 80% of the GnRH analogue in the form of acetate of triptorelin is released from the elongate implant with a slow release. More preferably, more than 90% of the acetate of triptorelin released from the implant during slow release. Most preferably, 100% of the acetate of triptorelin released from the implant during slow release.

In yet another aspect, the invention relates to a method of treatment of a patient that requires constant introduction of at least one GnRH analogue, where the method consists of the introduction of the implant, as described above, to a patient by injection.

As mentioned above, in an additional aspect, the invention provides a method of producing an elongated implant, comprising the stage

- preparation of biodegradable polymer or copolymer sleeves

- Association of GnRH analogue and a polymer or copolymer of obtaining a polymer core, and

- subsequent placement of the core in the sleeve.

The advantages of this aspect of the invention is to simplify by IP�connections adding other excipients, in addition to PLGA, to hormonal analog.

The polymeric sleeve and the core polymer can be prepared, for example, extrusion or casting. Preferably the polymeric sleeve and the core polymer prepared by extrusion from the melt. Preferably, the first stage of obtaining a polymer sleeve polymer and the core is the formation of pellets by extrusion of PLGA. Obtaining pellets by extrusion is preferably performed at a temperature between approximately 130±10°C to 155±10°C, preferably at 145±10°C, and when the rotational speed of the extruder from about 25±10 Rev/min to 45±10 rpm, preferably at 35±10 Rev/min, Then the pellets can be ground in a cryogenic mill to obtain a powder. The particle size of the powder is preferably less than 1 mm, and more preferably less than 500 microns.

Preferably, the sleeve is produced by extrusion of polymer pellets. Such extrusion is preferably performed at a temperature in the range from 130 to 160°C, more preferably from 142 to 156°C. the rotation Speed of the extruder is preferably between 1 and 30 rpm, more preferably 2 and 6 rpm, and most preferably 4 rpm.

To prepare the core polymer, mix the powder and the GnRH analogue, preferably for about 30 minutes at 42 rpm. the Formation of a polymeric core �W powder preferably is a two extrusions. At the first extrusion, the mixture is extruded at a temperature preferably in the range from 110 to 130°C, more preferably from 116 to 124°C, and most preferably about 120°C, receive the pellets. The rotation speed of the extruder is preferably between 1 and 40 rpm, more preferably 15 and 25 rpm, and most preferably 21 rpm First extrusion improves the rheological properties of the mixture through the constant feed speed during the second extrusion and, therefore, obtaining a homogeneous extrudate diameter.

Residual moisture of the pellets of acetate of triptorelin and PLGA obtained after the first extrusion, preferably is less than 5% by weight of water relative to the total mass. However, the precise moisture content depends on the content of the GnRH analogue, which is the main source of moisture. In this respect, the residual moisture of the pellets, first obtained by extrusion, more preferably is less than about 1.5%, if the concentration of triptorelin is approximately 35%, and less than about 2%, if the concentration of triptorelin is approximately 50%. The pellets are preferably dried under vacuum prior to the second extrusion to reduce the moisture content below the required limit.

After drying, the pellets are subjected to a second extrusion at a temperature preferred�tive in the range from 120 to 160°C, more preferably from 130 to 150°C, and most preferably about 140°C.

The molten or liquid state of the peptide in the polymer makes possible the mixing process, bypassing the expensive pre-processing stage, which carriers are used for products, which are then removed.

The temperature can be selected depending on the polymer or copolymer; for example, it will be about 10°C below to about PLGA with lower internal viscosity or about 10°C higher in the case of PLGA with a higher internal viscosity.

In accordance with this variant of the polymeric core, the steps are performed without pretreatment of the mixture using aqueous or organic solvents, which are then removed. The method also eliminates the need for lyophilization mixtures and separate pre-heating for extrusion before extrusion.

A solid mixture of acetate powder of triptorelin and PLGA polymer can be melted at a temperature sufficient for obtaining unsteady condition of these two components to be mixed and then execute the extradition or molding to reduce the temperature and return to a solid state.

The device to perform the extrusion can work atambient temperature at the outlet of the extruder.

This continuous extrudate can be cut to produce the polymer cores of the desired size. Thus, the required dose can be obtained prior to placement of the polymer core in the sleeve.

Depending on the form, dose and the desired release profile, the method of obtaining the polymer core can also be used for forms with a small load of the active component. The indicators listed above in terms of residual moisture and the quantity of the active component, as well as the nature of the polymer, for example, can be applied to tracks with a load of less than 50%, as well as to those with a heavier workload. The necessary adaptation can be performed by a person skilled in the art with regard to the procedure outlined above, as well as examples of receipt.

In one embodiment, the implementation of checking the size of a polymer sleeve and a polymer core and placing the core in the sleeve is done manually or mechanically. Then the implant may be placed in the injection device and processed by gamma irradiation prior to the introduction.

Depending on the size of the implant physician to implement the administration may use such injection device as described in the PCT application WO2006/058745, or syringes standard size.

The person skilled in the art may use other polymers or a mixture of polymers, or other aspect]�sheniya of salt triptorelin and PLGA polymer; in this case, the molecular weight of the PLGA polymer and the mass of the polymer core should be adapted to achieve the desired release profile.

In an additional aspect, the invention provides a method of producing an elongated implant, comprising the stage

- combining the GnRH analogue and the polymer or copolymer, and

- subsequent joint extrusion combination and biodegradable polymer or copolymer,

to receive the implant comprising a GnRH analogue and a polymer or copolymer of a nucleus in a biodegradable polymer or copolymer sleeve.

Preferably, if combined GnRH analogue and a polymer, you get the pellets.

The temperature of the joint extrusion and the extrusion speed can be selected on the basis of the temperature of the softening point of the combination forming the core, and the polymer forming the sleeve. Preferably, the joint extrusion is carried out at the conditions described above for single extrusion.

In another aspect the invention provides the above-described implant, which is obtained as described above.

The invention provides another method of preparation of an elongated implant, comprising the stage

- the introduction of pellets made of biodegradable polymer or copolymer and active substance in a screw extruder,

- extrusion of the nucleus, made of BioRes�aguinaga polymer or copolymer and active substance, and subsequent cooling,

- coating of biodegradable polymer or copolymer.

The distance between the extrusion head and the head of the coating/deposition can be increased, and the melting trough is placed after the main extrusion head for the core cooled and hardened before serving in the channel coating.

The distance between the primary extrusion head and the coating/deposition is not necessarily adjust to from about 130 mm to 160 mm, preferably up to about 150 mm, to receive the implant is covered by the kernel. The choice of distance depends on the period of cooling.

In accordance with the method, the adhesion of the core and coating may be controlled by process parameters such as temperature, extrusion speed and coverage. Control of these parameters may result in permanent binding or rolling landing, allowing a small air gap between the core and the coating.

The final product obtained in this manner is a cylindrical elongated implant, consisting of a core made of the mixture of copolymer and active substance, and coating. The cover is made from a pure polymer or copolymer and may not necessarily be of the same or a different material as the copolymer in the composition for the kernel.

Ultimate receiving�tion product is a core, covered with a transparent coating: these two parts form a single product.

In this aspect of the invention and by means of this method it becomes possible to obtain a structured implant, similar to that obtained by the physical insertion of the cylindrical core in the tube.

A significant advantage of the above method is the lack of physical build of the kernel implant in the coating.

As noted earlier, in an additional aspect, the invention provides an elongated implant for the controlled and sustained release of acetate of triptorelin, GnRH analogue, where the implant includes

polymer or copolymer sleeve having at least one open end, and

- the core located in the sleeve, including the acetate of triptoreline.

Preferably, the acetate of triptorelin undergoes a conformational change that leads to increased viscosity of the kernel.

Preferably, the sleeve collapses during release.

The polymeric sleeve may be obtained according to the method described above.

Preferably, the humidity of the elongated implant according to this aspect of the invention is less than 1%.

Preferably, the gel acetate of triptorelin and water is injected directly into the sleeve, and therefore the method allows to avoid the necessity of casting or molding extrusi� kernel.

In one embodiment of the method of the invention, at least 40% of the acetate of triptorelin mixed with water and placed in a sleeve. Preferably, at least 50 or 60 or 70 or 80 or 90% of the acetate of triptorelin mixed with water and placed in the sleeve.

Preferred methods of obtaining kernel perform mixing from 40 to 80% (wt./mass.) acetate of triptorelin and water, preferably from 50 to 70% (wt./mass.) acetate of triptorelin or more preferably, 55, 60 or 65% (wt./mass.) acetate of triptoreline. The preferred concentration of the acetate of triptorelin should provide sufficient acetate content of triptorelin end elongated implant.

In one preferred method, the acetate of triptorelin and water are placed in separate vessels connected by a valve and creates a vacuum in the tank with acetate of triptoreline. Opening the valve causes the water in the container with acetate of triptorelin and fills in the gaps in acetate powder of triptoreline. The gel formed from water and acetate of triptoreline, can then be homogenized.

In an alternative preferred method, the acetate of triptorelin and water mixed with careful stirring.

Preferably, to obtain the kernel use water in the form of water for injection.

The temperature when mixing the acetate of triptorelin in�s preferably kept below 25°C, more preferably below 15°C and more preferably between 5 and 10°C. the Relatively low temperature slows down the crystallization or conformational change.

Then the acetate of triptorelin and water easily accommodated in the sleeve.

Once the semi-solid material as it appears in the tube, the gel may undergo a conformational change and to crystallize.

The first stage in this two-stage method may include incubation for 2-48 hours, at 20°C-40°C, preferably at 20-30°C, and atmospheric pressure to obtain a semi-solid compositions of acetate of triptorelin and water. Incubation of the nucleus can lead to conformational changes of acetate triptorelin. Solidifying thus the composition contributes to the retention of the composition in the sleeve and facilitates the drying of the composition in the second stage.

The second stage may include drying under vacuum for 6-24 hours at room temperature to reduce the moisture.

In a variant implementation, the implant may be placed manually in the device for administration by injection. The implant and the device are preferably treated with gamma-irradiation before administration of the injection. Alternatively, you can exclude the final sterilization, if the implants will be obtained under aseptic conditions.

In yet another aspect, the invention relates to a method of treatment of a patient,which requires periodic introduction of at least one GnRH analogue, where said method consists of the introduction of the implant, as described above, to a patient by injection.

The pharmaceutical compositions according to the invention can be applied by parenteral, such as subcutaneous or intramuscular injection.

Preferably, the introduction of pharmaceutical compositions in the form of an elongated implant containing 6, 9 or 10 mg of acetate of triptoreline, by subcutaneous injection, repeated every 6 months.

Preferably, the use of triptorelin in elongated implant, as disclosed in the present invention, adapted for the treatment of diseases, including prostate cancer, in particular widespread metastatic prostate cancer, endometriosis, female infertility and is usually associated with other hormones during in vivo fertilization (IVF), early sexual maturation; fibroid tumors and endometriosis.

All publications, patent applications, all patents and all other references mentioned herein are incorporated by reference.

The following examples illustrate the invention and is in no way ohraniaiut it.

Example 1

Method preparation of polymer core

Examples 1-12 are to receive the implant in accordance with the invention, the polymer comprising the core of acetate of triptorelin and PLGA polymeric sleeve of PLGA in the form of a tube.

To ISP�lzovat to obtain both sleeveless and polymeric cores, PLGA was subjected to initial training. Stage involves the extrusion of PLGA at 145±10°C and 35±10 rpm and the grind of the obtained pellets in a cryogenic mill to obtain PLGA powder with a particle size of less than 500 microns for receiving the implant.

To produce the polymer core is consistently weighed the GnRH analogue in the acetate form of triptoreline powder and PLGA. The acetate of triptorelin was passed through a sieve to remove lumps from the mixture. Then the mixture was stirred for 30 minutes and then extrudible at 120±4°C and 21±1 Rev/min.

The pellets were dried under vacuum prior to the second extrusion to reduce humidity to less than 2% or 1.5%. The pellets were extrudible from the melt at 138±2°C and 9±2 rpm.

The extrudate was cut during the second extrusion and received individual polymer core.

Example 2

The results of the polymeric core

The polymer core is received in accordance with the General methodology described in example 1.

Polymer core contained a dose of 6 mg, the measured size was 0.85 mm in diameter and approximately 26 mm in length, and included 40% by weight of acetate of triptoreline (purity>97,5%) and 60% by mass of 85:15 PLGA (internal viscosity iv in chloroform: 1,2 DL/g <iv <a 1.7 DL/g).

Example 3

A method of producing a polymer sleeve

To obtain the sleeves PLGA powder, after initial preparation of example 1, was extrudible of isreplace at 149±7°C and 4±2 rpm and extruded tube is cut to receive the sleeves.

Example 4

A method of producing a polymeric core in polymeric sleeve

A large number of polymer cores and polymeric sleeves were obtained in accordance with examples 1 and 3 respectively. Checked the size of the polymer cores and sleeves, and cores were placed in sleeves. The resulting implants were placed into the injection device and treated with gamma radiation 25 kGy prior to administration.

Example 5

Results 1 polymeric core in polymeric sleeve

Chose the six implants obtained in example 4, corresponding to the parameters set forth in table 1 below.

Table 1
Polymer core with 5.9 mg of triptorelin acetate sleeve 1.1 mm
SleeveSleeve length (mm)26,0
The outer diameter of sleeve (mm)1,10
The inner diameter of sleeve (mm)0,82
CoreThe content of triptorelin acetate (mg/mg)0,342
Average dose (mg)5,9
The average purity (%) 97,3
Load acetate of triptorelin in the core of the implant (%)40,2

Example 6

The results of the polymeric core in polymeric sleeve 2

Chose the six implants obtained in example 4, corresponding to the parameters set forth in table 2 below.

Table 2
Polymer core with 6.4 mg of triptorelin acetate sleeve 0.85 mm
SleeveSleeve length (mm)26,1
The outer diameter of sleeve (mm)0,85
The inner diameter of sleeve (mm)0,65
CoreThe content of triptorelin acetate (mg/mg)0,597
Average dose (mg)6,4
The average purity (%)97,6
Load acetate of triptorelin in the core of the implant (%)70,3

Example 7

The results of the polymeric core in polymeric sleeve 3

Chose the six implant�in, obtained in example 4, corresponding to the parameters set forth in table 3 below.

Table 3
Polymer core with 9.1 mg of triptorelin acetate sleeve 1.1 mm
SleeveSleeve length (mm)26,0
The outer diameter of sleeve (mm)1,10
The inner diameter of sleeve (mm)0,82
CoreThe content of triptorelin acetate (mg/mg)0,486
Average dose (mg)9,5
The average purity (%)97,8
Load acetate of triptorelin in the core of the implant (%)57,2

Example 8

The results of the polymeric core in polymeric sleeve 4

Chose the six implants obtained in example 4, corresponding to the parameters set forth in table 4 below.

Table 4
Polymer core with 4.2 mg of triptorelin acetate sleeve 0,87 m�
SleeveSleeve length (mm)26,3
The outer diameter of sleeve (mm)of 0.87
The inner diameter of sleeve (mm)0,70
CoreThe content of triptorelin acetate (mg/mg)0,352
Average dose (mg)4,2
The average purity (%)97,4
Load acetate of triptorelin in the core of the implant (%)41,4

Example 9

Results 5 the polymeric core in polymeric sleeve

Chose the six implants obtained in example 4, corresponding to the parameters set forth in table 5 below.

Table 5
Polymer core with 6.2 mg of triptorelin acetate sleeve 1,08 mm
SleeveSleeve length (mm)26,2
The outer diameter of sleeve (mm)1,08
The inner diameter of sleeve (mm)0,90
CoreThe content of triptorelin acetate (mg/mg)0,345
Average dose (mg)6,2
The average purity (%)97,5
Load acetate of triptorelin in the core of the implant (%)40,6

Example 10

The results of the polymeric core in polymeric sleeve 6

Chose the six implants obtained in example 4, corresponding to the parameters set forth in table 6 below.

Table 6
Polymer core with 4.1 mg of triptorelin acetate sleeve 0.85 mm
SleeveSleeve length (mm)26,1
The outer diameter of sleeve (mm)0,85
The inner diameter of sleeve (mm)0,65
CoreThe content of triptorelin acetate (mg/mg)0,394
Average dose (mg)4,1
The average purity (%)97,6
Load acetate of triptorelin in the core of the implant (%)46,3

Example 11

The results of the polymeric core in polymeric sleeve 7

Chose the six implants obtained in example 4, corresponding to the parameters set forth in table 7 below.

Table 7
The polymer core from 4.9 mg of triptorelin acetate sleeve 0.85 mm
SleeveSleeve length (mm)26,1
The outer diameter of sleeve (mm)0,85
The inner diameter of sleeve (mm)0,65
CoreThe content of triptorelin acetate (mg/mg)0,464
Average dose (mg)4,9
The average purity (%)97,7
Load acetate of triptorelin in the core of the implant(%) 54,6

Example 12

A method of producing sleeves with triptoreline nucleus

Examples 12-16 are receiving the implant according to the invention, comprising a core of acetate of triptorelin in polymer sleeve PLGA in the form of a tube.

Forty parts of water for injections and 60 parts of acetate of triptorelin weighed in two separate tanks connected by a valve. Used a pump to create a vacuum in the tank with acetate of triptoreline. The spray device was opened and water was supplied into the free space between the particles of the powder.

The gel formed from water and acetate of triptoreline, homogenized with stirring.

The resulting aqueous gel acetate of triptorelin filled the sleeve obtained in accordance with example 3. Sleeve were weighed before and after filling to confirm the correct quantity of acetate of triptorelin in water for dosing.

The acetate of triptorelin and water placed in the tube, dried in two stages. The mixture was incubated for 2-48 hours at 20-30°C and atmospheric pressure for changes in the conformation and then dried for 6 hours - 24 hours under vacuum to reduce the moisture.

Example 13

The results of retrieval sleeves with triptoreline core 1

Chose the six implants obtained in example 12 with the parameters set forth�bubbled in table 8 below.

Table 8
Polymer core with 6.3 mg of triptorelin acetate sleeve 0.85 mm
SleeveSleeve length (mm)26
The outer diameter of sleeve (mm)0,85
The inner diameter of sleeve (mm)0,65
CoreAverage dose (mg)6,3
The average purity (%)98,6

Example 14

The results of retrieval sleeves with triptoreline core 1

Chose the six implants obtained in example 12 with the parameters set forth in table 9 below.

Table 9
Polymer core with 10.0 mg of triptorelin acetate sleeve 1,10 mm
SleeveSleeve length (mm)26
The outer diameter of sleeve (mm)1,10
The inner diameter of sleeve (mm)0,85
CoreAverage dose (mg)10,0
The average purity (%)98,4

Example 15

The results of retrieval sleeves with triptoreline core 1

Chose the six implants obtained in example 12 with the parameters set forth in table 10 below.

Table 10
Polymer core with 10.0 mg of triptorelin acetate sleeve 1,10 mm
SleeveSleeve length (mm)26,0
The outer diameter of sleeve (mm)1,10
The inner diameter of sleeve (mm)0,82
CoreAverage dose (mg)6,3
The average purity (%)98,6

Example 16

The results of retrieval sleeves with triptoreline core 1

Chose the six implants obtained in example 12 with the parameters set forth in table 11 below.

Table 11
Polymer core with 7.2 mg of triptorelin acetate sleeve 1.2 mm
SleeveSleeve length (mm)28
The outer diameter of sleeve (mm)1,2
The inner diameter of sleeve (mm)0,8
CoreAverage dose (mg)7,2
The average purity (%)98,8

Example 17

The double extrusion

First, PLGA 85:15 in the powder was extrudible into pellets. Approximately 600 g of PLGA powder was extrudible and received 586,88 g pellets (corresponding to a yield of 86%). Pellets were obtained with different properties.

The extrusion parameters were as follows:

ParametersTarget valueTechnical specifications
MaxMin
Thermal zone 1148°C155°C125°C
Tempera�örn zone 2 148°C155°C125°C
Temperature zone 3155°C175°C145°C
Temperature zone 4130°C145°C115°C
The screw speed30 rpm45 rpm25 rpm
Humidity457515
Pressure/325/
Torque/20/
The rate of tension/40/
Oxygen/4010
The length of the cut1 mm/ /
Diameter1000 µm1500 µm500 microns
Temperature baths20°C23°C17°C
Serving temperature/27°C17°C

The samples were obtained on separate set of equipment placed in series in a production line of the extruder for kernels and system of a coating in the form of a tube/coating.

Example 18

Pellets kernel with PLGA/acetate of triptorelin containing 34% acetate of triptorelin

This study was performed with the PLGA pellets and acetate of triptoreline (PLGA+active substance). The concentration of acetate of triptorelin in the pellets was approximately 34%.

The parameters of the method

tr>
ParametersThe actual value
Extrusion of the nucleus And
Temperature zone 1 (°C)130
Temperature zone 2 (°C)130
Temperature zone 3 (°C)130
The material temperature (°C)130
Material pressure (Bar)105
The auger speed (rpm)8
Screw torque (km/H)64,7
System of a coating/coating application (kernel)
Temperature zone 1 (°C)140
Temperature zone 2 (°C)150
Temperature zone 3 (°C)140
The material temperature (°C)145
Material pressure (Bar)45
The auger speed (rpm)20
Screw torque (km/H)
The speed of the carousel machinery (m/min)

These two parts, the core and the coating was shown to have high adhesion�Oia and stayed United together.

Example 19

The technique of in vitro release polymeric core and a polymeric core in polymeric sleeve

Examples 19 and 20 relate to the in vitro studies of the polymer cores of example 2 and the polymeric core in polymeric sleeve in example 6.

The following methodology was used to study the in vitro release of the implant according to examples 2 and 6. The apparatus consisted of a modified dissolution camera I (c a system of baskets) according to the USP connected with an automatic device for sampling (MAXIMIZER™) printer for recording data in an operational mode and a spectrophotometer in the UV and visible region with multicellular system, programmable thermostat reverse camera. Revolving cycle of this camera includes a capacity of 2 litres, which is maintained at a Wednesday release for the second part of the study. The spectrophotometer is connected to PC with installed software CHEMSTATION™, and during the study, supervised the sampling, analysis and the state of the cameras.

Below shows the additional terms.

- Temperature gradient: 56 hours at 37°C, increasing to 55°C in 24 hours, and 55°C until the end.

Environment release: PBS pH 7.4 in a period of 44 hours. Then eight assists (one every 4 hours): consisting of extraction with 25 ml of PBS environment and the introduction of a 20 mm pre-heated lactic acid pH 3. Then CP�do release supported after those innings. Both environments were degassed prior to use.

- The mixing speed: 75 rpm.

- The volume of dissolution medium: 100 ml.

- Duration: 7 days for implants/10 days for microrobot (not fully defined).

- Operational research: the ultraviolet and visible region of the spectrum (280 nm).

Example 20

The results of in vitro release polymeric core and a polymeric core in polymeric sleeve

The release profile in vitro polymer cores of example 2 and the implant according to example 6 were obtained in accordance with the procedure of example 19. The release profile in vivo is shown in figure 1.

The release profile in vitro noticeably slower if the core polymer acetate of triptorelin and PLGA coated with a polymer sleeve PLGA than without coverage.

Example 21

The in vivo study of polymeric core in polymeric sleeve

Examples 21-22 relate to the in vivo study of implants according to the invention, comprising a polymeric core of acetate of triptorelin and PLGA polymeric sleeve PLGA in the form of a tube.

The following methodology was used to study in vivo implant according to the invention.

Chose the six males hounds and every dog in the back of the neck subcutaneously injected with one implant.

The implant obtained in accordance with example 4, was placed manually in the device for administration by injection. The implant device and�istwo was treated with gamma radiation 25 kGy. The device in the form of a syringe was weighed before and after injection to confirm full insertion.

Blood samples were collected through the parent vein. The schedule for sampling within 6 months was as follows: before injection (time 0), 15 and 30 minutes, 1, 2, 4, 8 and 12 hours and then 1, 2, 3, 7, 10, 15, 20, 24, 27, 30, 37, 44, 51, 60, 69, 76, 83, 90, 105, 120, 135, 150, 165, 180 day. Once the concentration of triptorelin found and castrated dogs, the samples then were collected once every 14-16 days before until the number of triptorelin repeatedly was below the detection limit concentration, and testosterone level was above the limit of castration.

Samples were collected in a syringe with a coagulant and preservative. The content of each syringe was gently stirred. The blood samples were left on a cold water bath before centrifugation (1600 g for 20 minutes at 4°C). Finally, 1 ml plasma was transferred into polypropylene cryovials for analysis of testosterone, and the remaining plasma was transferred into polystyrene tubes for analysis of triptorelin. They were quickly frozen to below -20°C, at this temperature, allowed to analyze.

The concentration of triptorelin in plasma was determined by RIA. This method, previously validated, includes the preparation of a calibration standard curves, and the addition of quality control samples. The limit of quantification (defined�tion is 20 ng·ml -1.

In addition, the concentration of testosterone in plasma samples of dogs were analyzed after solid-phase extraction online 0.3 ml plasma samples of dogs with LC-MS/MS using trilaterally testosterone as an internal standard, and the net plasma female dogs to prevent interaction with the basal testosterone, which is present in healthy males. This method, previously validated, includes the preparation of a calibration standard curves, and the addition of quality control samples of pure plasma female dogs to prevent interaction with the basal testosterone, which is present in healthy males.

Implants according to examples 6-8, described above, was administered to the dogs in accordance with examples 22-24.

The introduction was carried out using needles with an outer diameter of 1.2 or 1.4 mm or through Retroinjector.

Example 22

Results for in vivo polymeric core in polymeric sleeve 1

Implants according to example 6 was administered to six dogs in accordance with the procedure of example 21. The release profile in vivo is shown in figure 2.

The concentration of drug in plasma after subcutaneous injection was measured for at least 8 months all dogs. Average ± S. D. concentration of triptorelin in plasma at 6 months was $ 0,34±0.08 ng/ml. graph To the end�the ations in plasma from the time of sampling shown very good control explosive release (mean ± SD C max1,9±0,87 ng/ml) with a median tmax4 hours. Then, after a slight decrease in the concentration of triptorelin to 30 day, saw the release of zero order on the 90th day (rounded value median C30-90dare 0.127 ng/ml). Peak plasma concentration was observed in all dogs during the period between 90 and 180 days with concentrations of triptorelin within 0,379 to 1,395 ng/ml.

Example 23

Results for in vivo polymeric core in polymeric sleeve 2

The implant according to example 7 was administered to six dogs in accordance with the procedure of example 21. The release profile in vivo is shown in figure 3.

The concentration of drug in plasma after subcutaneous injection was measured for at least 7 months in five of the six dogs. Average ± S. D. concentration of triptorelin in plasma for 6 months amounted to 0.13±0.11 ng/ml. the graph of dependence of plasma concentration against time of sampling shown very good control explosive release (mean ± SD Cmax6,0±1.6 ng/ml) with a median tmax2.5 hours. Then, after a slight decrease in the concentration of triptorelin to 30 day, saw the release of the pseudo zero-order 90 day (rounded value median C30-90d0,341 ng/ml). Then the concentration declined rapidly to 105 day (mean value C90d0,42 ng/ml and the mean value C105d0.10 ng/ml). Finally, the peak plasma concentration was observed in all the dogs in the period between 105 and 150 days with a concentration of triptorelin within 0,226 to 0,678 ng/ml.

Example 24

Results for in vivo polymeric core in polymeric sleeve 3

The implant according to example 8 was administered to six dogs in accordance with the procedure of example 21. The release profile in vivo is shown in figure 4.

The concentration of drug in plasma after subcutaneous injection was measured for at least 8 months in five of the six dogs. Average ± S. D. concentration of triptorelin in plasma at 6 months was 0.24±0.26 ng/ml. the graph of dependence of plasma concentration against time of sampling shown very good control explosive release (mean ± SD Cmax7,4±1,7 ng/ml) with a median tmax4 hours. Then, after a slight decrease in the concentration of triptorelin to 20 day, watched the release of the pseudo zero-order 150 day (rounded value median C20-150dof 0.36 ng/ml).

Example 25

Results in vivo for the kernel of triptorelin in polymer sleeve 1

Examples 25 and 26 relate to the in vivo study of implants according to the invention, comprising a core of triptorelin in polymeric sleeve in the form of tubes made from PLGA.

The implant according to example 13 was administered to six dogs in accordance with the procedure of example 21. The release profile in vivo is shown in figure 5.

The concentration of drug in plasma after subcutaneous injection was measured for a period of at least 6 months, all dogs. Wed�of water ± S. D. the concentration of triptorelin in plasma at 6 months was 0.09±0.05 ng/ml. the graph of dependence of plasma concentration against time of sampling shown very good control explosive release (mean ± SD Cmaxof 6.4±2.3 ng/ml) with a median tmax1 hour. Then, after a rapid decrease in the concentration of triptorelin in the period from 1 hour to 12 hours, observed the zero-order release 40 day (rounded value median C0,5-40d0,633 ng/ml). Two peak plasma concentrations was observed in most dogs between 40 and 90 during the day and from 98 to 180 days, with concentrations of triptorelin within 0,414 up to 2,164 20 ng·ml-1and from 0,307 to 1,311 ng/ml, respectively.

Example 26

Results in vivo for the kernel of triptorelin in polymer sleeve 2

The implant according to example 14 was administered to six dogs in accordance with the procedure of example 21. The release profile in vivo is shown in figure 6.

The concentration of drug in plasma after subcutaneous injection was measured for a period of at least 6 months, five of the six dogs. Average ± S. D. concentration of triptorelin in plasma at 6 months was 0.12±0.15 ng/ml. the graph of dependence of plasma concentration against time of sampling shown very good control explosive release (mean ± SD Cmax8,9±5.0 ng/ml) with a median tmax1 hour. Then, after a rapid decrease� " s concentration of triptorelin in the period from 1 hour to 1 day observed zero-order release for 30 day (rounded value median C0,5-30dthe value 0,552 ng/ml). After that the two peak plasma concentrations was observed in most dogs between 30 and 90 day and 90 to 180 days, with concentrations of triptorelin within 0,323 to 3,709 ng·ml-1and from 0,457 to 2,247 ng/ml, respectively.

1. A method of producing an elongated implant, where the ratio of diameter to the length axis of the implant is between 1:20 and 1:40 for the controlled and sustained release of the GnRH analogue acetate of triptorelin, which includes stages
- preparation of a polymer or copolymer sleeves,
- preparation of the solution between 40 and 80% (wt./wt.) acetate of triptorelin in water,
- host the solution in his sleeve,
incubation of the solution for 2-48 hours at 20-30°C and
- drying for 6 to 24 hours under vacuum.

2. The elongated implant, where the ratio of diameter to the length axis of the implant is between 1:20 and 1:40 for the controlled and sustained release of the GnRH analogue acetate of triptorelin received in accordance with the method according to claim 1, wherein the implant includes
polymer or copolymer sleeve with at least one open end, and
- the core comprising the acetate of triptoreline, located in
sleeve.

3. The elongated implant, where the ratio of diameter to the length axis of the implant�and is between 1:20 and 1:40, for controlled and sustained release of the GnRH analogue acetate of triptorelin obtained by the method according to claim 1.

4. The implant according to claim 3, wherein the polymer or copolymer sleeve formed from lactic and/or glycolic acids.

5. The implant according to claim 4, wherein the polymer or copolymer sleeve are a copolymer of lactic acid and glycolic acid (PLGA).

6. The implant according to claim 5, wherein the ratio of lactic acid and glycolic acid in PLGA is in the range from 70:30 to 90:10.

7. An implant according to any one of claims. 2 or 3, which is able to be released slowly for at least 3 months, preferably for at least 6 months.

8. An implant according to any one of claims. 2 or 3, where the number of acetate of triptorelin is in the range from 0.5 to 50 mg, preferably the amount is in the range from 2 to 20 mg, more preferably the number is 5, 6, 7, 8, 9, or 10 mg.

9. An implant according to any one of claims. 2 or 3, where the long axis of the implant is between 2 and 3 cm, preferably a length along the axis of the implant is approximately 2.6 cm

10. An implant according to any one of claims. 2 or 3, where the ratio of diameter to the length axis of the implant is 1:30.

11. The implant according to claim 5, where the molecular weight of PLGA is at least 60 kDa, preferably the molecular weight of PLGA is �ENISA least 100 kDa.



 

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