JP2001523515A - Mammalian vaginal insertion device and method of manufacture and use - Google Patents

Abstract

(57) [Summary] This is an intravaginal device for injecting a drug (eg, progestin) into a receiving mammal. The ability of the active agent to provide the desired retention characteristics of the deformable retention device (even without the support projections), the proper release configuration for a defined insertion period, and biodegradability when removed from the mammal. (Eg, poly-ε-caprolactone or starchy polysaccharide).

Description

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to improvements in intravaginal devices or inserts (ie, charges) and
Or) improvement on the intravaginal device or insert.

PCT / NZ9 (issued as WO 97/40776) by the inventor
No. 7/00052 discloses various forms of an intravaginal device of a deformable type to be held in the vaginal cavity of an animal. Such devices have heretofore used the use of a silicone rubber component impregnated with an active agent (eg, progestin) as a matrix. In a device of the shape variable type called CIDR ^TM of CIDR,
The impregnated matrix is mainly supported by spines of a resilient material, e.g. nylon, and the resilience of such spines is usually such that the protrusions are completely covered by the impregnated matrix. Despite this, it is used because it has a shape variable holding characteristic.

[0003] Various polymers that possess the ability to provide biodegradability have been used to deliver active agents. Certain polymers that possess such properties and are widely used for the input of active agents are polyesters. Examples of these polymers include polylactic acid, polyglycolic acid, poly (ε-caprolactone) and various copolymers of lactic acid, glycolic acid and ε-caprolactone.

[0004] Pharmaceutical products using these polymers are typically formed as microspheres, microcapsules, films, rods or blocks. Retention in body cavities has been accomplished in a number of ways: by the addition of dense fillers, by injection, or by surgical implantation into the muscle or subcutaneous area.

[0005] The present invention is configured to administer luteinizing hormone for a long period of time (2 to 20 days) when inserted into the vagina of an animal such as a cow, sheep, horse, pig, goat, beef or deer. Device or insert. The device or insert is held in the vagina by a bendable device (eg, of an arm or body).

[0006] Upon completion of the procedure, the device is removed and treated in a manner that favors the biodegradability of the polymer.

The inventor of the present invention has found that biodegradable polymers, typically provided by poly (ε-caprolactone) or starchy saccharides, are readily biodegradable following withdrawal and subsequent to removal from animals. To provide suitable biorelease properties for the active agent over the vaginal retention time required by the particular procedure (e.g., a concentration of 5% to 70%).
% W / w) can be suitably impregnated with vaginal active agents such as progesterone.

Surprisingly, polymers such as, for example, poly (ε-caprolactone) not only provide an impregnated matrix but also change shape without forcing barbs or the like as in prior art devices. It has also been found that it is moldable, albeit impregnated with an activator, to provide the device. Similarly, it has been found that starchy saccharides can be formed to achieve the same effect.

Accordingly, the present invention provides in a first aspect, a device or insert insertable into a mammal's vagina, the device or insert comprising a biodegradable polymer containing an active agent. Is done.

[0010] The device or insert is preferably capable of being held in the vagina in the target species for at least 5 days (at least in part, preferably by the variable shape provided by the resiliency of the biodegradable polymer). .

[0011] Preferably, said active agent is a progestin with a concentration of 5 to 70% w / w.

The polymer preferably comprises or contains poly (ε-caprolactone).

[0013] Alternatively, the polymer consists of or contains a starchy polysaccharide.

In other forms, the polymer may be a mixture with any and / or another polymer.

[0015] The biodegradable polymer preferably contains both cyclodextrin and an active ingredient active in the vagina.

The term “vaginally active agent” refers to any compound that can be systematically absorbed by a mammal to achieve or inhibit a certain physiological effect upon introduction into the vaginal cavity of the mammal. , Components, or complexing agents. Examples include luteinizing hormones (eg, for estrous synchronization and other purposes) and oxytocin (eg, reduced milking).

The term “cyclodextrin” includes, for example, α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, and hydroxypropyl
including any suitable cyclodextrin or mixture thereof, such as (xypropyl) β-cyclodextrin.

Preferably, the cyclodextrin is from 5 to 70% w / w.

Preferably, the absorption enhancer is hydroxypropyl β-cyclodextrin at a concentration of 5 to 70% w / w.

Preferably, the device is shaped to facilitate retention in the vagina.

Preferably, the drug does not appear as fine powder or crystals on the surface of the device.

Another aspect of the present invention is a vaginal insert, holdable, and releasable that comprises at least one of poly (ε-caprolactone) and a moldable, biodegradable starchy polysaccharide or both. It is a massive lump, and because it is elastic, it is inserted into the vagina,
An intravaginal device or insert for a mammal of a target species comprising or containing a mass of variable shape that allows for holding and removal, wherein the mass is 2 ng / g for at least 5 days with respect to the target species. An intravaginal device containing enough progestin to allow the serum levels of progestin to continue after vaginal insertion and to remove the mass after removal from the animal; Insert.

Preferably, said target species is selected from cattle, sheep, horses, pigs, goats, wild cattle and deer.

The device or insert (eg, of nylon or polyester)
Preferably, it does not include a support barb.

The mass may optionally contain cyclodextrin.

In another aspect, the invention comprises the use or use of an apparatus as described above and any of the apparatuses according to the invention.

The invention also comprises a method of manufacturing an intravaginal device that provides any of the devices according to the invention. In another aspect, the invention comprises a method of making an intravaginal device that includes the step of including a cyclodextrin and an intravaginally active agent in a moldable biodegradable polymer matrix.

In a further aspect, the invention consists in using the device or insert according to the invention in estrus synchronization, in particular for a group of animals.

The use is preferably for intravaginal use, especially for 2 to 20 days, and the device provides serum levels of progestin hormone of 2 ng / ml or more (if inserted into the vagina for at least 5 days). It is preferred to have the ability to provide for at least 5 days in a mammal of the species targeted.

[0030] All polymers in the mass use conditions (if all are preferably molded) that adversely affect the active agent, and any polymer (other than the absorption-enhancing agent) Preferably, it can be molded without cyclodextrin.

In yet another aspect, the present invention is a method of achieving a serum level of progestin for an animal (or group of animals) of at least 2 ng / ml for at least 5 days in an animal (or group of animals), wherein the method comprises the steps of: The method comprises inserting and holding the device or insert for at least 5 days.

The inventor of the present invention has determined that certain biodegradable polymers can be effectively impregnated with drugs and, optionally, absorption enhancers, and that certain types of intravaginal devices require a variable shape for retention. That is, it can be effectively molded into the form of an insert and provides a suitable path to provide the desired pharmacological effect without being adversely affected by the tendency of the polymer to biodegrade over a defined insertion period. However, once removed, the drug content can be much lower (see WO 97/40776), eliminating the problem of prolonged processing due to the biodegradability of the polymer after removal from the animal. Was found.

Preferred embodiments of the present invention will be described below with reference to the accompanying drawings.

The selection of a resilient, moldable, ie, formable “polymer” that is biodegradable depends on the degradation of the impregnated matrix (but loaded with low residual active ingredients), preferably from 2 to 20 This is done to occur after a period of time (e.g., about 7 days) after removal from the animal after achieving its purpose while inserted into the vagina and after removal from the animal. The degradation, if any, that occurs during the insertion time is minimal.

In the apparatus shown in FIG. 1, the apparatus is free of any solid active agent which appears as fine powder or crystals on its surface and is impregnated with poly (ε) at a concentration of 5 to 70% w / w of progestin. -Caprolactone).

In FIG. 1, the wing 1 is resilient with respect to the body 2, which facilitates insertion in the vaginal insertion mode, and subsequently places the wing 1 in a state required for holding by the resilience. Can be deformed to a known shape or take a certain position. Its resiliency can later be used to withdraw the device from within the vagina.

A suitable source of poly (ε-caprolactone) is Union Carbide Specialty and Products, Dumbury, Connecticut, USA.
Specialty Polymers and Products, Danbury, Ct , a product called T ONE767 ^TM commercially available from USA).

Similarly, starchy polysaccharides that can be impregnated and used for some or all of the present devices include MTER-Bi ^™ , commercially available from Novamont, Italy, Italy. .

A preferred method of manufacturing the device is as follows. The polymer, which is poly-ε-caprolactone, and the starchy polysaccharide or a mixture of the two can be prepared by using a suitable compound such as a surfactant that adheres the activator to the surface of the polymer particles as well as the compound. Is mixed with the activator in a mixing vat using the extruded material. The polymer / activator mixture is then loaded into the hopper of the injection molding machine and the technical advice from the polymer supplier literature and the set point parameters of the machine relative to the standard method of injection molding are used for conventional methods. Treated similarly to thermoplastics.

The main set point for poly ε-caprolactone is that the injection pressure is 1600
The temperature range of the barrel in bar is 80-120 ° C. and the overall cycle time is about 55 seconds due to the need for a long cooling phase. The product is removed from the die and cooled to an equilibrium temperature before packaging.

The performance of the device during insertion, and the action when pulled out, is generally WO
97/40776, except that the device is (i) biodegradable after removal from the animal and (ii) the omission of the spines of the resilient material. It has the advantage that.

Suitable biodegradable polymers (typically poly (ε-caprolactone) or starchy saccharides) are effective in the vagina, such as progesterone (eg, at a concentration of 5 to 70% w / w). Over a period of time that can be adequately impregnated with an active enhancer and an absorption enhancer such as hydroxypropyl beta-cyclodextrin (e.g., at a concentration of 5 to 70% w / w) and retained in the vagina. To provide suitable release properties for the active agent.

A preferred device is made entirely from an impregnated matrix of poly (ε-caprolactone) impregnated with hydroxypropyl β-cyclodectrin at a concentration of 5 to 70% w / w.

A suitable source of hydroxypropyl β-cyclodextrin is Wacker Chemicals Austra, Victoria, Australia.
The product is BETAW 7HP, which is commercially available from lia, Victoria, Australia).

A preferred method for manufacturing the present apparatus is as follows. The polymer (poly (ε-caprolactone), starchy polysaccharide, or a mixture thereof is mixed with activator and absorbent in a mixing vat. The polymer / activator / absorbent mixture is then injection molded. It is loaded into the hopper of the machine and processed like a conventional thermoplastic with machine set point parameters according to the technical advice from the polymer supplier's literature and standard methods of injection molding. At an injection pressure of 1600 bar and a barrel temperature of 60 to 250 ° C., the overall cycle time is due to cool down to the equilibrium temperature before packaging.

FIG. 1 shows a device of variable shape (shape is variable as described in WO 97/40776), but spines of different materials (although optionally interposed if desired). There is no need for.

When an insert of the type shown in FIG. 1 made from poly (ε-caprolactone) was subjected to a biodegradation procedure to evaluate the release of progestin, the silicon CIDR-B ^{™ as} shown in FIG. It shows the same release characteristics as the insert.

FIG. 2 shows the cumulative progestin release status in vitro versus the square root of time. Inserts made from poly (ε-caprolactone) (thin line) or inserts made from silicon (thick line) are shown.

An insert of the type shown in FIG. 1 made from poly (ε-caprolactone) having a smaller surface area than the insert of the silicon CIDR-B ^™ was administered to cattle and the plasma collected for analysis of plasma luteinizing hormone concentration. In the sample, a slightly lower level was observed as shown in FIG.

FIG. 3 shows that both contain 10% w / w progestin and have a surface area of 134 c.
silicon insert or surface area m ² indicates the concentration of the average plasma progesterone against time after performing around 2 intravaginal processed by insert poly 105 cm ² (.epsilon.-caprolactone). Error bars are standard error means (n = 12 for silicon inserts, n = 9 for poly (ε-caprolactone) inserts).

When an insert of the type shown in FIG. 1 made from poly (ε-caprolactone) containing 10% w / w progestin has been stored in compost for 6 months, or If not stored, subsequent loss of mass was observed as shown in FIG.

FIG. 4 shows the percentage of initial mass loss versus time for drug loaded inserts (■) stored in compost and blank (□) poly (ε-caprolactone) inserts. The solid line shows the loss of mass as taught by the promotional literature supplied by the poly (ε-caprolactone) manufacturer. The error range display bar is the (n = 2) range.

An insert of the type shown in FIG. 1 made from poly (ε-caprolactone) containing 10% w / w progestin was stored in the compost for a period of 6 months, or no progestin was stored in the compost at all. If not, then a loss of tensile performance was observed as shown in FIG.

FIG. 5 shows drug-loaded inserts (■) and blanks (
The percentage of tensile loss for the poly (ε-caprolactone) insert of □) is shown over time. The solid line shows the tensile performance as taught by the promotional literature supplied by the manufacturer. The error range display bar is the (n = 2) range.

Cows were dosed with inserts of the type shown in FIG. 1 made from poly (ε-caprolactone) having a surface area similar to the silicon CIDR-B ^™ insert (disclosed in the aforementioned WO 97/40776), Similar levels were observed as shown in FIG. 6 when a sample of the plasma was collected to analyze the plasma progestin concentration.

FIG. 6 shows a silicon insert having a surface area of 134 cm ² (■) and a surface area of 115 cm ² (□
² ) shows the concentration of plasma luteinizing hormone over time after treatment in the vagina for 7 days using a poly (ε-caprolactone) insert or a lactose insert with a surface area of 115 cm ² ( ² ). . The final plasma specimen was collected 6 hours after removal on day 7. The error range indicator bar is a standard error average (n = 3).

When inserts of the type shown in FIG. 1 made from poly (ε-caprolactone) containing various excipients were stored in compost for 6 months, FIG.
The mass loss shown in FIG.

FIG. 7 shows the percentage of loss of initial mass of various poly (ε-caprolactone) formations stored in the compost over time. Poly (ε-caprolactone) (◆), Poly (ε-caprolactone) with 10% w / w progestin (■), 12.1% w / w lactose and 10.4% w / w progestin Poly (ε-caprolactone) with (), 37.2% w / w β-cyclodextrin and 10.3% w / w Poly (ε-caprolactone) with progestin
(X), 43.8% w / w hydroxypropyl β-cyclodextrin and 1
Poly (ε-caprolactone) (*) or 3% with 0% w / w progestin
Poly (ε-caprolactone) (●) with 9.9% w / w γ-cyclodectrin and 9.7% w / w progestin. The error range display bar is the (n = 2) range.

When inserts of the type shown in FIG. 1 made using polysaccharides were administered to cattle and plasma specimens were collected for plasma progestin concentration analysis, the levels shown in FIG. 8 were observed. Was.

FIG. 8 shows a Mater-Bi insert with a surface area of 58 cm ² , with 20% w / w NaCl added (■) and without (●) plasma following 7 days of intravaginal treatment. Is shown against the elapsed time. Error bars are in the (n = 2) range.

[Brief description of the drawings]

FIG. 1 is variable in shape (variable in shape as described in WO 97/40776), but without the need for barbs of foreign material (although optionally interposed as desired) It is a figure showing an apparatus.

FIG. 2 shows the release of in vitro cumulative progesterone over time as indicated by the square root of an insert made from poly (ε-caprolactone) (thin line) or an insert made from silicon (thick line).

FIG. 3: Both contain 10% w / w progestin (error bars are typically error average (n = 12 for silicon inserts, poly (ε-caprolactone))
Average plasma corpus luteum following two rounds of intravaginal treatment with a silicon insert (□) with a surface area of 143 cm ² or a poly (ε-caprolactone) insert (■) with a surface area of 105 cm ^2. It is a figure which shows the density | concentration of a hormone with respect to elapsed time.

FIG. 4: Percentage loss of initial mass of poly (ε-caprolactone) insert for drug loaded (■) and blank (□) stored in compost versus elapsed time (solid line). The loss of mass indicated by the promotional literature provided by the poly (ε-caprolactone) manufacturer (error bars are (n
= 2) Range).

FIG. 5 shows the percentage of loss of tensile performance of poly (ε-caprolactone) inserts against elapsed time for drug loaded (■) and blank (□) embedded in compost (solid line (Indicates the loss of tensile performance taught in the promotional literature provided by the manufacturer) (error bars are in the (n = 2) range.

[6] silicon surface area 134cm ² inserts (■), poly surface area 115cm ² (
FIG. 7 shows the concentration of progesterone in the plasma after a 7-day intravaginal treatment with an insert (□) of ε-caprolactone) or a lactose insert (○) with a surface area of 115 cm ² over time (final). Plasma specimens were collected 6 hours after removal on day 7. Error bars are standard error means (n = 3).

FIG. 7 shows the percentage of initial mass lost to the formation of various poly (ε-caprolactone) stored in compost versus elapsed time (poly (ε-caprolactone)).
Caprolactone) (◆), poly (ε-caprolactone) with 10% w / w progestin (■), 12.1% w / w lactose and 10.4% w / w progestin Poly (ε-caprolactone) (▲), poly (ε-caprolactone) (x) with 37.2% w / w β-cyclodextrin and 10.3% w / w progestin, 43.8% Poly (ε-caprolactone) (*) with w / w hydroxypropyl β-cyclodextrin and 10% w / w progestin or 39.9% w / w γ-cyclodextrin and 9.7% w / w Poly (ε-caprolactone) with progestin (●). Error bars are in the (n = 2) range. )

FIG. 8. Plasma progestin concentrations following a 7-day intravaginal treatment with Mater-Bi inserts having a surface area of 58 cm ² with (%) or without (•) 20% w / w NaCl. It is a figure shown with respect to elapsed time (error bar is a (n = 2) range).

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) // A61F 6/06 A61F 5/46 (31) Priority claim number 330596 (32) Priority date 1998 1998 March 5, 1998 (6.5.6.5) (33) Priority claiming country New Zealand (NZ) (81) Designated state EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG) , AP (GH, GM, KE, LS, MW, SD, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AL, AM, AT, AU , AZ, BA, BB, BG, BR, BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT , RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU, ZW (72) Inventor Berggraaf, Shan New Zealand Hamilton, Richmond Street 25 (72) Inventor Woodward, Bauguhan, Grant New Zealand Hamilton, Fox Street 3 (72) Inventor Ogle, Colin, Roger Newton, New Zealand Bidd Street 3F term (reference) 4C076 AA51 BB30 BB36 BB37 CC30 EE24 EE38 EE39 FF31 FF68 4C084 AA02 AA03 DC50 MA05 MA56 NA10 NA12 ZC112 4C098 AA06 EE21 EE23 EE30

Claims (22)

[Claims] 1. An insert for insertion into a mammal's vagina, wherein the insert comprises a biodegradable polymer containing an active agent. An insert that is a device. 2. The insert of claim 1, wherein the target seed can be held in the vagina for at least two days. 3. The method according to claim 1, wherein some of the biodegradable polymers can be held in the vagina by being able to take a variable shape determined by the elasticity of the biodegradable polymer. An insert as in the apparatus of claim 1. 4. The insert according to claim 1, wherein the active agent is a progestin. 5. The insert of claim 4, wherein said progestin is from 5 to 70% w / w. 6. The method according to claim 1, wherein the polymer comprises poly (ε-caprolactone) or contains the poly (ε-caprolactone).
An insert, which is the apparatus according to claim 1. 7. The insert according to claim 1, wherein the polymer comprises or contains a starch-like polysaccharide. 8. The vaginal cavity of a mammal, wherein the biodegradable polymer comprises both cyclodextrin and an active ingredient active in the vagina. 9. A compound, component or complex that is systematically absorbed by mammals by being introduced into the compound and can achieve or suppress a certain physiological effect. An insert as in the apparatus of claim 1. 9. The biodegradable polymer contains both cyclodextrin and an active ingredient active in the vagina, wherein the active agent active in the vagina is in the vaginal cavity of a mammal. 2. A compound, component or composite agent which is systematically absorbed by a mammal when introduced into a mammal, and is capable of achieving or inhibiting a certain physiological action. Item 10. The insert according to any one of items 8 to 8. 10. The insert of claim 9, wherein the cyclodextrin comprises 5 to 70% w / w. 11. The insert according to claim 1, wherein the active agent does not appear on the surface as a fine powder or crystals. 12. A vaginal device or insert for mammals of a target species, wherein the vaginal device comprises at least mainly one or both of poly (ε-caprolactone) and a moldable biodegradable starchy polysaccharide. An insertable, holdable, and removable mass, wherein the mass has a variable resilient shape so that it can be inserted, held, and removed into the vagina; Serum levels of luteinizing hormone of 2 ng / ml or higher for the species for at least 5 days are maintained after insertion into the vagina and sufficient to allow the mass to be biodegradable in vitro after removal from the vagina. An insert that is an intravaginal device characterized by containing progestin. 13. The insert of claim 12, wherein the target species is selected from cows, sheep, horses, pigs, goats, wild cattle, and deers. 14. The insert as claimed in claim 12, wherein no barbs for support are interposed. 15. The method according to claim 12, wherein the content of luteal hormone is sufficient to supply luteal hormone for a period of 2 to 20 days. The insert is a device. 16. The insert as claimed in claim 12, wherein the mass may contain cyclodextrin. 17. Use or use of an insert which is the device according to any one of claims 1 to 16. 18. A method of manufacturing an intravaginal device for providing an insert which is the device according to any one of claims 1 to 11. 19. A vagina comprising the step of including both a cyclodextrin and an intravaginally active agent in a moldable biodegradable polymer matrix, followed by forming said device or insert. A method of manufacturing an insert which is an internal device. 20. Use of an insert as claimed in any one of claims 1 to 6 in particular for the purpose of estrus synchronization of a group of animals. 21. Use intravaginally for a period of 2 to 20 days, wherein the device is 2 ng / ml for at least 5 days (if it has been inserted into the vagina for at least about 5 days).
The use according to claim 20, characterized in that the mammal has the ability to provide serum levels of the target species. 22. The method according to any one of claims 1 to 16, wherein the method achieves a serum level of progestin hormone in an animal (or a group of animals) of at least 2 ng / ml for at least 5 days. Inserting a device insert into each animal for at least 5 days and holding.