DK174578B1 - Laminate for constraining rumen drug delivery device - comprises water-permeable low friction material bonded to repulpable tape doubly coated with water dispersible pressure-sensitive adhesive - Google Patents

Abstract

A laminate comprises a water-permeable material with a low friction surface in the presence of water the material being bonded by a water dispersible pressure sensitive adhesive to a repulpable tape which has the water dispersible pressure sensitive adhesive on both its surfaces. A device for controlled and prolonged release of an anthelmintic in a miminant comprises a resilient and flexible ethylene-vinyl acetate copolymer core sheet sandwiched between a pair of coextensive resilient films of the copolymer, the core sheet contg. 10-75% by wt. of a water-soluble morantel salt dispersed in it. The device has one or more circular macroperforations 0.5-10 mm in dia. symmetrically distributed across its face and extending through the films and core sheet. The dia. and arrangements of the macroperforations in relation to the thickness of the core sheet is selected to expose sufficient interior edge area of the sheet to give the required morantel release rate. The device is constrained in a rolled configuration by constraining means which are releasable in the animal's rumen, i.e. a laminate.

Description

in DK 174578 B1

BACKGROUND OF THE INVENTION 1. Field of the Invention The invention relates to improved means for holding devices for dispensing of wound medicaments in a rolled configuration. More particularly, it relates to laminates comprising a water-permeable material having a smooth surface in the presence of water, bonded to a resuspendable tape with a water-dispersible adhesive on both surfaces, laminates comprising a flexible water-permeable polymeric material bonded between the smooth-surface material and the resealable tapes, and thus compressed devices.

U.S. Patent Nos. 4,228,149 and 4,601,893 and U.S. Patent Applications Nos. 170,495 and 170,529, both filed March 21, 1988, relate to devices for delivery of our precursor drug in a rolled-up configuration of appropriate clamping agents.

It has been found that the known devices described above are sometimes ejected by the ruminant due to premature removal of the clamping means in the rumen. In addition, difficulty is often encountered after oral administration of the collapsed devices to young ruminants. Premature removal of the clamping means and subsequent rollout of the clamping device or slow review of the clamping device may lead to dosing problems. Thus, improved clamping means for dispensing drug delivery devices are needed which will facilitate dosing of ruminants with the devices and allow timely alteration of configurations in the rumen and eliminate ruminant vomiting of the device.

The clamping means of the invention provide a smooth surface to facilitate dosing of the device, provide timely change in geometry of the rolled device in the rumen and avoid premature roll-out of the devices after dosing, and are stable and non-toxic.

The improved clamping means of the invention are a laminate comprising a water-permeable material having a smooth surface in the presence of water, bonded by a water-dispersible pressure-sensitive adhesive to a resuspendable tape coated on both surfaces 10 by the adhesive. In one embodiment of the invention, the laminate described above comprises a flexible water-permeable polymeric material bonded between the smooth surface material and the resuspendable band. Yet another embodiment consists of a laminate comprising a flexible water-permeable polymeric material sandwiched between two sheets of a smooth-surface water-permeable material in the presence of water, one surface being bonded by a water-dispersible pressure-sensitive adhesive to a resealable is an adhesive tape coated on both surfaces (double coated) with the adhesive. The invention also includes rolled-up dispensing device dispensers compared to the improved clamping means described herein.

25 Water-dispersible pressure-sensitive tapes and resuspendable tapes coated with the water-dispersible pressure-sensitive adhesives are disclosed in U.S. Pat.

3,865,770, 3,441,430, 4,413,080 and 4,569,960. Such tapes are widely used in the papermaking industry.

The preferred smooth surface water permeable material in the presence of water is nitrocellulose. As the outermost or topmost layer of the laminates disclosed herein, the nitrocellulose facilitates oral administration of the interconnected devices, given the smooth surface it receives in the presence of saliva in the esophageal passage of the ruminant.

In one form of the clamping means described herein, the nitrocellulose film is bonded directly to one surface of the double adhesive coated resealable tape. The second adhesive-coated surface of the tape is, of course, bonded to the rolled-up device to hold it together in said configuration. This form 10 of clamping means, if increased flow of ambient fluid to the water dispersible adhesive is desired, may be perforated, especially with larger holes of about 0.5 to about 5 mm in diameter before being applied to the rolled device. The holes are usually circular, but can be of any kind, such as ovals, triangles, squares, hexagons, etc. The perforations tend to accelerate removal of the clamping member.

In a modified and preferred form of the improved clamping device according to the invention, a flexible water-permeable polymeric material, preferably cellophane, is bonded between the smooth surface material and the resuspendable band. The cellophane serves to increase the removal of the clamping means and the roll-out of the rolled-up device. In addition to cellophane, other water-permeable polymers such as polyvinyl acetate, polymethyl methacrylate, polyethyl methacrylate, polyvinyl chloride, cellulose acetate and polydimethylsiloxane can be used.

30

A preferred modification of the improved clamping member of the invention consists in a laminate comprising a flexible water-permeable polymeric material, such as the one described above, sandwiched between two sheets of a water-permeable material (e.g., nitrocellulose) having a smooth surface presence of water, one surface of which is bonded to a resuspendable band double coated with a water-dispersible pressure-sensitive adhesive. The thickness of the coated cellophane may be in the range of about 5 cm. 7.6 to approx. 76 μπι. Cellophane coated on both surfaces with nitrocellulose, ie. sandwiched between nitrocellulose sheets, commercially available from BCL America,

Inc., Malvern, PA. 19355, U.S.A., product grade 345 PS-41. It has a thickness of about 23 μιη.

10

Each of the types of clamping means described herein may optionally have macro perforations, especially in the portion where the member collides or overlaps when placed around the rolled-out delivery device 15 to increase the roll-out of the device in the application environment.

The laminates according to the invention are conveniently constructed by the individual layers of e.g. nitrocellulose 20 or cellophane coated on both sides with nitrocellulose is contacted with the resuspendable band which is double coated with a water dispersible pressure sensitive adhesive. Suitable water-dispersible pressure-sensitive adhesives are well known in the art.

25

Representative water dispersible pressure-sensitive adhesives are those comprising a copolymer of monomeric acrylic acid esters and vinyl carboxylic acid monomer, which copolymer is partially neutralized with a secondary or tertiary alkanolamine or an alkali metal hydroxide. Oily softening compounds such as water-soluble polyoxyethylenes and adhesives such as reaction products of acidic resins and alkanolamines are added to this material. Such adhesives and their use in the manufacture of resuspendable tapes are described in U.S. Patents Nos. 3,865,770, 4,413,080 and 4,569,960.

Illustrative of such adhesives disclosed in the aforementioned 5 patents are those comprising: I.

(a) a copolymer of monomers consisting essentially of 10 (1) from ca. 90 to approx. 20 parts by weight of non-tertiary alkyl alcohol monomer acrylic acid ester whose molecules contain 1-4 carbon atoms; and 15 (2) from ca. 10 to approx. 80 parts by weight of vinyl carboxylic acid monomer which is copolymerizable with the acrylic acid ester, a sufficient number of the carboxyl groups of the acidic monomers to constitute from ca. 3 to approx.

22% by weight of the copolymer has been neutralized by reaction with a secondary or tertiary alkanolamine containing at least 4 carbon atoms; and (b) 0-400 parts by weight of at least one water dispersible adhesive promoting material selected from oily softening water-soluble polyoxyethylene compounds and adhesion-promoting reaction products of acidic resins and alkanolamines; or II. the mixed reaction product of 30 (a) 100 parts by weight of a copolymer of monomers consisting mainly of DK 174578 B1 6 (1) from ca. 75 to approx. 85% by weight of at least one non-tertiary alkyl alcohol monomer-racrylic acid ester and correspondingly 5 (2) from ca. 25 to approx. 15% by weight of vinyl carboxylic acid, (b) from ca. 35 to approx. 100 parts by weight of acidic resin or acidic resin derivative; 10 (c) sufficient potassium hydroxide to neutralize from ca. 30 to approx. 45% of the combined carboxyl groups in the copolymer and resin or resin derivative; (d) sufficient sodium hydroxide, lithium hydroxide, or a combination thereof to neutralize from ca. 20 to approx. 45% of the carboxyl groups, and (e) from ca. 100 to approx. 225 parts by weight of oily softening water-soluble polyoxyethylene compound; or III. the mixed reaction product of (a) 100 parts by weight of a copolymer of monomers consisting principally of 25 (1) from ca. 60 to approx. 85% by weight of at least one monomeric racry acid ester of non-tertiary alkyl alcohol having 4-14 carbon atoms and correspondingly 30 (2) from about 40 to approx. 15% by weight of vinyl carboxylic acid.

(b) from ca. 50 to approx. 250 parts by weight of ethoxylated softening components, sufficient to provide adhesion values which cause the adhesive to delaminate kraft paper when tested as described below, and consisting essentially of at least one of the following: (1) up to about . 125 parts by weight, but not so much as to cause adhesive separation, of one or more OH-functional ethoxylated plasticizers and (2) one or more electrolyte-tolerant complex and acidic esters of phosphoric acid and an ethoxylated nonionic surfactant, and (c) alkaline hydroxide consisting mainly of (1) sodium hydroxide, lithium hydroxide or both sodium hydroxide and lithium hydroxide, in a sufficient quantity to increase shear strength and minimize bleeding, but insufficient to cause separation of any present OH-functional ethoxylated, since it does not exceed 20 approx. 0.07 hydroxyl equivalent if OH-functional ethoxylated plasticizer is the only softening component present, and (2) potassium hydroxide in a sufficient amount to promote water solubility.

The clamping means of the invention should not substantially increase the overall diameter of the clamped device at the clamping point to a thickness that would cause dosing problems when the clamped device is administered to an animal's rumen. This connection between the thickness (diameter) of the rolled-up device and the diameter of the clamping means will be recognized by those skilled in the art. These will recognize the need 35 to keep the thickness of the clamping member at a minimum thickness which is in accordance with acceptable times for removal of the clamping member in the application environment. In general, clamping means according to the invention provide a thickness of from about. 33 to approx. 254 mm 5 acceptable delivery times.

Using the improved clamping means of the invention, it is easy to prepare a device for controlled and prolonged delivery of veterinary drugs, e.g. anthelminthica, for the treatment of animals. The device comprises a resilient and flexible core of ethylene-vinyl acetate copolymer interposed between a pair of resilient films of the copolymer of the same extent. The core sheet can contain from approx. 10 to approx. 75 15% by weight of a water-soluble moran cell salt (e.g., moran tentartrate) dispersed in the core sheet. The device may have one or more circular macro perforations of approx. 0.5 to approx. 10 mm in diameter. These macro perforations are distributed symmetrically across the face of the device and extend through the resilient films and the core sheet. The diameter and arrangement of the macro perforations relative to the thickness of the core sheet is selected so as to expose sufficient inner edge area of the core sheet. Exposure of sufficient edge area will give the desired morantine salt release rate. The device is clamped in the rolled configuration of a clamping means which is releasable in an animal's rumen. Suitable clamping means include the laminate of the invention.

30

The point of greatest tension in the clamping member occurs at a segment of the roller where the clamping means bridges the gap formed by its contact with the end edge of the outer layer of the rolled-up device and the surface of the layer at the ends of said outer layer DK 174578 B1 9 . The effect of this tension can be minimized by doubling the thickness of the total length of the clamping means used. Alternatively, the effect can be minimized by applying a reinforcing strip of the clamping member having the above thickness across the segment.

As will be understood, the clamping means used may be of sufficient length to completely enclose the rolled-up device, the ends thereof forming a blunt joint. Alternatively, the clamping member may be of such length that its ends overlap to a greater or lesser extent when the member is placed on a rolled device. The degree of overlap should, for 15 economic reasons, be less than that which would result in a double thickness of the clamping member. Furthermore, the clamping means need not completely enclose the rolled device. It should at least be in contact with a terminal end of the outer layer 20 of the rolled-up device and the surface of the layer on which the outer layers end. The preferred length of the clamping means is that required to completely wrap around the rolled device.

The improved clamping member of the invention is readily prepared by laminating the adhesive-coated resuspendable tape to the water-permeable polymeric material with a smooth surface in the presence of water, e.g. nitrocellulose, or to the nitrocellulose-coated cellophane by known methods, taking care to avoid the formation of bubbles or wrinkles. The laminated tape is then cut to the desired size. Perforations may conveniently be produced either before or after cutting the laminated tape.

35 DK 174578 B1 10

The removability of the clamping member according to the invention in the application environment, e.g. an animal's rumen is determined by in vitro or in vivo methods. The in vitro method consists of placing the clamped device in water or properly mixing a synthetic rumen liquid at 40 ° C on an incubator shaker (approximately 80 rpm) and observing the time required for rolling it out. compressed device.

The in vivo method comprises administering the compressed device to a fistulated ruminant and observing the time required to roll out this compressed device.

To further minimize dosing problems, the clamped devices may desirably have plugs, e.g.

15 polyethylene plugs inserted at their open ends to transform the hollow tube into substantially a rod-like device.

EXAMPLE 1 20

A moranthel tartrate-containing device prepared according to Example 1 of US 4,601,893 was clamped in a rolled configuration with a clamping member according to the invention comprising an 8.9 x 7.6 cm laminate of 3M tape no.

25 900 and cellophane coated on both surfaces with nine trocellulose (product grade 345 PS-41). When the ends of the tape were wrapped around the device, they overlapped 0.635 cm.

When placed in water at 40 ° C as described above, the clamp was removed in 40 minutes.

A similar device, which had been stored at room temperature for 6 months, required 57 minutes for removal of the clamp when placed in water at 40 ° C.

EXAMPLE 2 When a clamped device made according to Example 1 was administered to a fistulated ruminant, the clamp was removed within 40 minutes, resulting in roll-out of the device.

EXAMPLE 3

The experiment of Example 1 was repeated, but using a band in which 50 perforations, 15 each 2 mm in diameter, were made at the overlapping ends.

The clamping device was removed in 15 minutes when the co-tensioned device was placed in water at 40 ° C.

EXAMPLE 4

A device made according to Example 2 of US 4,228,149 is clamped in a rolled configuration with an 8.9 x 7.6 cm laminate of 3M tape No. 405 and cellulose coated on both surfaces with nitrocellulose. The laminate was sufficiently long for the ends to overlap 0.635 cm.

EXAMPLE 5 30

The procedure of Example 3 is repeated, but using double-coated resuspendable bands made using the adhesives of Example 29 of US 4,569,960 and Example 7 of US 4,413,080.

EXAMPLE 6

Ten devices are prepared according to the procedure of Example 1, except that they are poured at 5 50 ° C for 24 hours before they are seam tightened. The devices are then tested at varying times for their ability to roll out. All devices, even those stored at room temperature for 6 months, were rolled out within an hour; i.e. the clamping means are removed from their original 2.5 cm cross-sectional diameter to a cross-sectional diameter sufficient to prevent their buildup of the ruminant.

EXAMPLE 7 Devices made according to Example 1 were administered to 100 young ruminants (weighing about 100 kg).

No difficulty was met in dosing the animals and no devices were engorged by any of the animals.

EXAMPLE 8

Twenty devices made essentially according to Example 1 were divided into two equal groups. Group A devices were placed in 40 ° C hot water as described above, and Group B devices were administered to fibrilated cattle, one device per day. animals. The times required for removal of the clamping means were recorded.

30

Average Range of Standard

Group Part Time Part Time Part A - In Vitro 31 min. 20-46 min. 8 min.

B - in vivo 51 min. 30-63 min. 9 min.

EXAMPLE 9

Nitrocellulose-coated cellophane (BCL 345 PS 41) was coated with "WASH-AWAY" adhesive (a trademark of Fitchburg Coated Products Inc., Scranton, PA 18501, USA, for a mixture of polyvinylmethyl ether, maleic anhydride and a phosphate ester) to manufacture of pressure-sensitive clamping device with water-soluble adhesive. A device of Example 1 of US 4,601,893,10 was clamped with the above clamping means.

When the clamped device was immersed in water at 40 ° C, the clamp was removed in 2 3 minutes.

Claims (2)

Device for controlled and extended release of anthelmintic in a ruminant, said device comprising a core sheet of resilient and flexible ethylene-vinyl acetate copolymer enclosed between a pair of resilient films of said copolymer of the same extent, the core sheet containing from about . 10 to approx. 75% by weight of a water-soluble morantine salt dispersed therein, and the device has one or more circular macroperforations of from approx. 0.5 to approx. 10 mm in diameter symmetrically distributed over the front of the device and extending through the films and the core sheet, the diameter and placement of the macro perforations relative to the thickness of the core sheet 15 being chosen so as to expose sufficient inner edge area of the sheet to provide the desired morale release rate. wherein the device is clamped in the rolled configuration of clamping means releasable in the animal's rumen, characterized in that the clamping means consists of a laminate comprising a water-permeable material having a smooth surface in the presence of water, bonded by means of a water-dispersible pressure-sensitive adhesive for a first surface of a resuspendable band having a first and a second surface, said band having a second layer of said water-dispersible pressure-sensitive adhesive on its second surface. Device according to claim 1, characterized in that the clamping means further contain a flexible water permeable polymeric material bonded between the smooth surface material and the resuspendable band, wherein the smooth surface material is nitrocellulose and the flexible water permeable polymeric material is flexible cellophane. .