Release control formulation in a delivery device

Abstract

The present invention provides an intraluminal device comprising: a body substantially impermeable to luminal fluid, the body comprising a barrel, at least one outlet, and at least one matrix within the barrel; a compression mechanism within the body adapted to bias an array of matrices within the barrel toward the at least one outlet; and at least one variable geometry device dependent on the body to assist in lumen retention, wherein the at least one matrix within the barrel comprises at least one active ingredient and at least one polymer selected from the group consisting of nonionic polymers and crosslinked anionic polymers. The present invention also provides methods of making and using the device.

Description

Technical Field

[0001] The present invention relates to an intraruminal device comprising a formulation that enables controlled release delivery of one or more active therapeutic or beneficial components to a ruminant animal.

Background Art

[0002] It is desirable to deliver a pharmaceutically active ingredient or other substance to an animal in a sustained and controlled manner. Various devices and methods for delivering active ingredients to ruminant animals are known in the art.

[0003] The inability to effectively control the dispensing rate continues to limit the effectiveness of these devices and can lead to problems such as underdosing and the development of drug resistance.

[0004] There is a need for a new dosing device that overcomes, avoids, or at least partially ameliorates one or more of the foregoing disadvantages. The object of the present invention is to take some measures to meet this need and / or to provide at least generally useful options to people.

Summary of the Invention

[0005] In a first aspect, the present invention relates to an intraruminal device, the intraruminal device comprising · a body substantially impermeable to rumen fluid, the body comprising a barrel, at least one outlet, and at least one matrix within the barrel; · a compression mechanism within the body adapted to urge a column of the matrix within the barrel towards at least one outlet; · at least one variable profile device dependent on the body for assisting in the retention of the rumen; At least one matrix within the barrel comprises at least one active ingredient and at least one polymer selected from the group consisting of a nonionic polymer and a crosslinked anionic polymer.

[0006] In a further aspect, the present invention relates to an intravaginal device, the intravaginal device comprising: · A body substantially impermeable to the vaginal fluid, the body comprising a barrel, at least one outlet, and at least one matrix within the barrel; · A compression mechanism within the body adapted to urge a column of the matrix within the barrel towards the at least one outlet; · At least one variable outer profile device dependent on the body for assisting in the retention of the vagina. At least one matrix within the barrel includes at least one active ingredient and at least one polymer selected from the group consisting of a non-ionic polymer and a crosslinked anionic polymer, and the anionic polymer is a block polymer of polyethylene glycol.

[0007] In a further aspect, the present invention relates to an intravaginal device, the intravaginal device comprising: · A body substantially impermeable to the vaginal fluid, the body comprising a barrel, at least one outlet, and at least one matrix within the barrel; · A compression mechanism within the body adapted to urge a column of the matrix within the barrel towards the at least one outlet; · At least one variable outer profile device dependent on the body for assisting in the retention of the vagina. At least one matrix within the barrel includes at least one active ingredient and at least one polymer selected from the group consisting of a non-ionic polymer and a crosslinked anionic polymer, and the anionic polymer comprises a long-chain alkyl acid ester.

[0008] In a further aspect, the present invention relates to an intravaginal device, the intravaginal device comprising: · A body substantially impermeable to the vaginal fluid, the body comprising a barrel, at least one outlet, and at least one matrix within the barrel; · A compression mechanism within the body adapted to urge a column of the matrix within the barrel towards at least one outlet, · At least one variable outer shape device dependent on the body for assisting in the retention of the lumen, and At least one matrix within the barrel comprises at least one active ingredient and at least one polymer selected from the group consisting of a non-ionic polyol polymer and a crosslinked anionic polymer.

[0009] In a further aspect, the invention relates to an intraluminal device, the intraluminal device comprising · A body substantially impermeable to the luminal fluid, the body comprising a barrel, at least one outlet, and at least one matrix within the barrel, · A compression mechanism within the body adapted to urge a column of the matrix within the barrel towards at least one outlet, · At least one variable outer shape device dependent on the body for assisting in the retention of the lumen, and At least one matrix within the barrel comprises at least one active ingredient and a) A non-ionic polyol polymer, b) A crosslinked anionic polymer comprising a long-chain alkyl acid ester, c) A crosslinked anionic polymer that is a block polymer of polyethylene glycol, and d) At least one polymer selected from any combination of (a) to (c).

[0010] In a further aspect, the invention relates to an intraluminal device, the intraluminal device comprising · A body substantially impermeable to the luminal fluid, the body comprising a barrel, at least one outlet, and at least one matrix within the barrel, · A compression mechanism within the body adapted to urge a column of the matrix within the barrel towards at least one outlet, · At least one variable outer shape device dependent on the body for assisting in the retention of the lumen, and At least one matrix within the barrel comprises at least one active ingredient and a) a nonionic polymer, wherein i) a nonionic polyol polymer, and ii) a nonionic polyethylene oxide homopolymer, and iii) a nonionic polyethylene oxide homopolymer having a molecular weight of from about 0.9 to about 7 million, and iv) a nonionic polyethylene oxide homopolymer having a viscosity greater than about 7,500 cP, and v) a nonionic polyethylene oxide homopolymer that is readily crosslinkable, or b) a crosslinked anionic polymer, wherein vi) a crosslinked anionic polymer containing a long-chain alkyl acid ester, and vii) a crosslinked anionic polymer that is a block polymer of polyethylene glycol, and viii) an anionic poly(acrylic acid) interpolymer (copolymer), and ix) an acrylic acid interpolymer crosslinked with an allyl ester of a polyalcohol, and x) a water-insoluble anionic acrylic acid interpolymer, and xi) an anionic acrylic acid interpolymer having a viscosity greater than about 45,000 cP, and xii) a polymer in which the polymerization process is benzene-free, and xiii) a polymer in which the polymerization solvent used is ethyl acetate or cyclohexane, or a cosolvent containing a combination thereof, and xiv) a nonionic acrylic acid interpolymer that is substantially benzene-free, and xv) a nonionic acrylic acid interpolymer, or c) at least one polymer selected from any combination of (i) to (xv).

[0011] In some embodiments, the nonionic polymer is p) q) A crosslinked anionic polymer containing a long-chain alkyl acid ester, r) A crosslinked anionic polymer that is a block polymer of polyethylene glycol, s) Having any one or more of the characteristics of any combination of (a) to (c).

[0012] In a further aspect, the present invention is a method for treating a ruminant in need of treatment, comprising administering to the ruminant a rumen device according to any one of the preceding claims.

[0013] In a further aspect, the present invention relates to a method of assembling a controlled delivery rumen, the method comprising: · Granulating a mixture comprising at least one active ingredient, and at least one polymer selected from the group consisting of a nonionic polymer and a crosslinked anionic polymer, and optionally one or more excipients; · Drying the granules; · Passing the granules through a sieve; · Tableting the granules in at least one matrix; · Loading at least one matrix into the body of the rumen device.

[0014] In a further aspect, the present invention relates to the use of a controlled release rumen device for delivering at least one active ingredient at an effective concentration to a ruminant in need thereof.

[0015] The following embodiments may relate to any of the above aspects.

[0016] Preferably, the nonionic polymer and the crosslinked anionic polymer limit interaction with cationic species in the rumen.

[0017] Preferably, the nonionic polymer is selected from the group consisting of polyethylene oxide polymers and polyvinylpyrrolidone.

[0018] Preferably, polyvinylpyrrolidone has a molecular weight in the range of 35,000 to 60,000 g / mol L-1.

[0019] Preferably, the polyethylene oxide polymer has a molecular weight in the range of 800,000 to 7,250,000 g / mol L-1.

[0020] Preferably, the polyethylene oxide polymer has a viscosity in the range of 5,000 to 15,000 cP.

[0021] Preferably, the crosslinked anionic polymer contains less than 65% of the monomers having free anionic groups compared to the total number of monomers.

[0022] Preferably, the crosslinked anionic polymer is polyacrylic acid or a polyacrylic acid derivative.

[0023] Preferably, the crosslinked anionic polymer is crosslinked with allyl sucrose or allyl pentaerythritol.

[0024] Preferably, the crosslinked anionic polymer has a viscosity in the range of 40,000 to 67,000 cP.

[0025] Preferably, the crosslinked anionic polymer contains a block copolymer of polyethylene glycol and a long-chain alkyl acid ester.

[0026] Preferably, the anionic polymer has an anionic poly(acrylic acid) interpolymer (copolymer).

[0027] Preferably, the anionic polymer has an acrylic acid interpolymer crosslinked with an allyl ester of a polyalcohol.

[0028] Preferably, the anionic polymer has an anionic acrylic acid interpolymer that is water-insoluble.

[0029] Preferably, the anionic polymer has an anionic acrylic acid interpolymer with a viscosity exceeding 45,000 cP.

[0030] Preferably, the polymerization process in the formation of the anion is benzene-free.

[0031] Preferably, during the formation of the anionic polymer, the polymerization solvent is a co-solvent that may include ethyl acetate and cyclohexane.

[0032] Preferably, the anionic polymer has a nonionic acrylic acid interpolymer that is substantially (i.e., 95, 96, 97, 98 or 99%) benzene-free.

[0033] Preferably, the anionic polymer has a nonionic acrylic acid interpolymer that is Carbopol Ultrez 10.

[0034] Preferably, the non-anionic polymer includes a nonionic polyethylene oxide homopolymer.

[0035] Preferably, the non-anionic polymer includes nonionic polyethylene oxide homopolymer(s) with a molecular weight of 0.9, 2, 3, 4, 5, 6, 7 million.

[0036] Preferably, the non-anionic polymer includes a nonionic polyethylene oxide homopolymer with a viscosity exceeding about 7,500.

[0037] Preferably, the non-anionic polymer includes a nonionic polyethylene oxide homopolymer that is easily crosslinked.

[0038] Preferably, the intraruminal device may be for use in a method of treating ruminants.

[0039] Preferably, the treatment method is not affected by the pH and ionic effects in the rumen of ruminants.

[0040] Preferably, the treatment method is not affected by the pH and ionic effects resulting from changes in the diet of ruminants.

[0041] Preferably, at least one active ingredient or beneficial ingredient is selected from the group consisting of antibiotics, antifungal agents, antiviral agents, steroid hormones, antihistamines, metabolic regulators, such as rumen methane inhibitors / regulators, productivity regulators, corticosteroids, antithyroid agents, antiparasitic agents (ectoparasiticides and / or endoparasiticides) such as anthelmintics, non-steroidal anti-inflammatory agents, nutraceuticals, rumen fermentation regulators, or combinations thereof. The intraruminal device according to any one of the preceding claims, wherein at least one active ingredient is an antiparasitic agent.

[0042] Preferably, at least one active ingredient is an antiparasitic agent.

[0043] Preferably, the antiparasitic agent is an anthelmintic selected from the group consisting of benzimidazoles, imidazothiazoles, tetrahydropyrimidines, macrocyclic lactones, salicylanilides, substituted phenols, aromatic amides, isoquinolines, aminoacetonitriles, and spiroindoles, or combinations thereof.

[0044] Preferably, the treatment method is not affected by the pH and ionic effects in the rumen of ruminants.

[0045] Preferably, the treatment method is not affected by the pH and ionic effects resulting from changes in the diet of ruminants.

[0046] Preferably, the effective concentration is not affected by the pH and ionic effects in the rumen of ruminants.

[0047] Preferably, the effective concentration is not affected by the pH and ionic effects resulting from changes in the diet of ruminants.

[0048] Preferably, the ruminant animal is selected from the group consisting of cows, goats, sheep, and deer.

[0049] Other aspects of the present invention may become apparent from the following description given by way of example only with reference to the accompanying drawings.

[0050] As used herein, the term "and / or" means "and" or "or", or both.

[0051] As used herein, "(s)" following a noun means the plural and / or singular form of the noun.

[0052] As used in this specification and the claims, the term "comprising" means "consisting of at least a part of". When interpreting the descriptions in this specification and the claims containing this term, all the features preceded by this term in each description must be present, but other features may also exist. Related terms such as "comprise" and "comprised" are interpreted in the same way.

[0053] References to numerical ranges disclosed herein (e.g., 1 to 10) are intended to incorporate references to all rational numbers within that range (e.g., 1, 1.1, 2, 3, 3.9, 4, 5, 6, 6.5, 7, 8, 9, and 10), and also any range of rational numbers within that range (e.g., 2 to 8, 1.5 to 5.5, and 3.1 to 4.7).

[0054] The entire disclosures of all applications, patents, and publications cited above and below are incorporated herein by reference, if any.

[0055] The present invention also includes parts, elements and features individually or collectively mentioned or shown in the specification of this application, and any two or more or all combinations of any of these parts, elements or features, and when specific integers having equivalents known in the technical field to which the present invention pertains are mentioned herein, such known equivalents are considered to be incorporated herein as if individually described.

Brief Description of the Drawings

[0056] Here, with reference to the accompanying drawings, the present invention will be described by way of example only.

[0057]

Figure 1

Figure 2

Modes for Carrying Out the Invention

[0058] The inventors consider that one of the parameters that can affect the dispensing rate of rumen devices known in the art is the concentration of one or more minerals and / or ions, such as calcium ions in the rumen of ruminants.

[0059] Compared to different pastures, such as ryegrass, lucerne may have a different mineral composition, and as a result, the amount of minerals in the rumen of animals grazing on that particular type of pasture will be different.

[0060] Large amounts of certain minerals or ions, such as calcium, in the diet of ruminants can have an adverse effect on rumen devices, for example, by restricting the delivery of one or more active ingredients from the rumen device and / or by causing a non-linear or unpredictable dispensing from the rumen device.

[0061] The inability to effectively control the dispensing rate for different concentrations of minerals and / or ions continues to limit the effectiveness of rumen devices in the art and can lead to problems such as underdosing and the development of drug resistance.

[0062] The present invention generally relates to a rumen device for the controlled release of one or more active ingredients to non-human animals, preferably ruminants.

[0063] 1. Rumen device The present invention relates to a rumen device, which is a body substantially impermeable to rumen fluid, comprising a barrel, at least one outlet, and at least one matrix within the barrel, a compression mechanism within the body adapted to urge the at least one matrix within the barrel towards the at least one outlet, and at least one variable geometry device that depends on the body to assist in retaining the rumen.

[0064] A compression mechanism within the body adapted to urge at least one matrix within the barrel towards at least one outlet.

[0065] At least one variable geometry device that depends on the body to assist in retaining the rumen. At least one matrix within the barrel comprises at least one active ingredient and at least one polymer selected from the group consisting of a nonionic polymer and a crosslinked anionic polymer.

[0066] The device of the present invention can be used to deliver one or more active therapeutic or beneficial components to non-human animals.

[0067] Preferably, the non-human animal can be a ruminant, such as, for example, cattle, goats, sheep, deer, yaks and giraffes, preferably cattle or sheep.

[0068] In some embodiments, the body of the intraluminal device is rigid and can maintain its shape when at least one matrix containing one or more active ingredients is inserted into the barrel of the device and when the device is administered to an animal.

[0069] The body of the intraluminal device can be formed into several suitable shapes. The body of the intraluminal device is preferably cylindrical, and the cross-section of the body is preferably circular. Preferably, one end of the body can be tapered and the diameter reduced to assist the passage of the intraluminal device down the esophagus and into the lumen.

[0070] The diameter of the body of the intraluminal device is small enough to easily pass through the esophagus of a ruminant and large enough to accommodate at least one matrix within the barrel. The diameter of the barrel depends, for example, on the thickness of the body of the intraluminal device. In some embodiments, the diameter of the intraluminal device and the diameter of the barrel may be substantially the same, the difference being the result of the thickness of the body.

[0071] In some embodiments, the diameter of the intraluminal device can be less than or equal to about 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, or 4.5 cm. A useful range can be selected from any of these values (e.g., the diameter of the intraluminal device can be from about 1 to about 4.5, about 1 to about 4 cm, about 1 to about 3.5 cm, about 1 to about 3, about 1 to about 2.5, about 1 to about 2, about 1 to about 1.5, about 1.2 to about 4.5, about 1.2 to about 4, about 1.2 to about 3.5, about 1.2 to about 3, about 1.2 to about 2.5, about 1.2 to about 2, about 1.2 to about 1.5, about 1.5 to about 4.5, about 1.5 to about 3.5, about 1.5 to about 3, about 1.5 to about 2.5, or about 1.5 to about 2).

[0072] The length of the body of the intraluminal device is short enough so as not to impede the progression into the reticular lumen along the esophagus.

[0073] The length of the body of the device can vary, for example, to accommodate more or less matrix. The length of the body can also vary, for example, depending on the target species to which the intraluminal device is administered, the size of the animal, the dosage, and the duration of the dosing period.

[0074] The length of the body can be about 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175 or 180 mm or more. The useful range can be selected from any of these values (e.g., about 40 mm to about 180 mm, 40 mm to about 150 mm, about 40 mm to about 120 mm, about 40 mm to about 100 mm, about 40 mm to about 75 mm, about 70 mm to about 180 mm, about 70 mm to about 160 mm, about 70 mm to about 160 mm, about 70 mm to about 140 mm, about 70 mm to about 120 mm, about 70 mm to about 100 mm, about 75 mm to about 180 mm, about 75 mm to about 165 mm, about 75 mm to about 145 mm, about 75 mm to about 125 mm, or about 75 mm to about 105 mm). For example, in some embodiments, the length of the body of the intraruminal device administered to sheep and other small ruminants can be about 76 mm to about 90 mm, and the length of the body of the intraruminal device administered to cattle and other similarly sized ruminants can be about 97 to about 170 mm.

[0075] In some embodiments, the body of the intraruminal device can be impermeable to intraruminal fluid but can allow gas permeation. In some cases, the permeability of the wall of the intraruminal device may require additional features to improve gas permeability and prevent the formation of a partial vacuum above the compression mechanism that can affect the smooth operation of the biasing system. The additional features can further include an opening above the starting position of the compression mechanism that increases gas permeation but prevents or substantially prevents the intrusion of rumen fluid. This portion of the intraruminal device can include a region of a modified polymer or pores incorporating a membrane such as a semipermeable membrane. In various embodiments, the body of the intraruminal device can be made from a pharmaceutical grade polymer or copolymer. Suitable polymers and copolymers will be apparent to those skilled in the art.

[0076] The in-vessel device includes holding means for holding the device in the lumen and helping to prevent backflow. This can be achieved in several ways. For example, the holding means may comprise weighted components or parts. The weighted component can be, for example, a region of the body made of a material with a higher density than the material used to make the rest of the body. Thus, the weighted component can ensure that the in-vessel device stays at the bottom of the lumen cavity and avoid backflow.

[0077] In various embodiments, the holding means may preferably comprise, at one end of the body, a deformable device, preferably a retractable wing or pair of wings. The deformable device, preferably the wing, is pressed against the side of the body during administration and pops out after administration to prevent backflow. In some embodiments, the in-vessel device may include a plurality of holding means, such as deformable devices like wings or pairs of wings, and one or more weighted components.

[0078] The deformable device, such as a wing, can be pressed against the side of the body using several means. For example, a water-soluble tape or adhesive can be used to hold the wing against the body.

[0079] In some embodiments, the deformable device, such as a wing, can be pressed against the side of the body by an applicator during dosing.

[0080] In some embodiments, a variable shape device, such as a wing, can be pressed against the side of the body using a pharmaceutical grade polymer or copolymer that is readily dissolved by the contents of the lumen, or a polymer or copolymer that melts at the temperature of the lumen, for example, from about 37.5, 38, 39, 39.5, 40, 40.5 or 41 °C, and the useful range can be selected from any of these values (e.g., from about 39 to about 40 °C, or from about 38 to about 41 °C), a polymer that melts at a temperature. Preferably, the melting point of the polymer or copolymer is from about 38.5 to about 40.5 °C to avoid the polymer melting in the esophagus of the ruminant and releasing the wing from the side of the body before the device enters the lumen.

[0081] In some embodiments, a variable shape device, such as a wing, may be made from the same polymer material as the body or from a different polymer material. In various embodiments, a variable shape device, such as a wing, may be made from a polymer material that is less rigid than the polymer used to make the body in order to allow the wing to be held against the side of the body during administration to the animal. Suitable polymer materials will be apparent to those skilled in the art and may include, for example, any pharmaceutical grade polymer that is flexible enough to be held against the side of the device within the lumen when administered. In various embodiments, the wing or a portion of the wing may be made from polypropylene or a copolymer thereof.

[0082] In some embodiments, the body and the variable shape device, such as the wing(s) of the device within the lumen, can be manufactured from one or more parts molded from a plastic material (e.g., polypropylene) and assembled together by adhesives and / or welding.

[0083] The lumen device includes a compression mechanism located within the barrel of the device, and compresses a composition containing the active ingredient(s) toward at least one outlet for discharging into the lumen. In various embodiments, the at least one outlet is located at one end of the body, and the compression mechanism biases at least one matrix within the barrel of the lumen device toward the at least one outlet. The force applied by the compression mechanism is intended to ensure a consistent linear delivery of at least one matrix beyond the frictional force generated between the core and the inner wall of the device over the entire distance the compression mechanism moves.

[0084] In some embodiments, the compression mechanism may include a plunger and a biasing means. In various embodiments, the biasing means may be a spring.

[0085] In some embodiments, the biasing means such as a spring can be made of materials such as alloys of steel, such as stainless steel, carbon steel, oil tempered wire, chrome silicon steel or chrome vanadium steel. Other alloys such as Inconel, Monel, beryllium, copper or phosphor bronze can also be used. Other suitable materials will be apparent to those skilled in the art.

[0086] In various embodiments, the compression mechanism can be adapted to be expandable up to at least about 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or 100% of the length of the body, and suitable ranges can be selected from any of these values (e.g., about 45% to about 100%, about 45 to about 75%, about 45 to about 60%, about 50% to about 100%, about 60 to about 80%, about 50 to about 80%, about 50 to about 60%, about 60 to about 100%, about 60 to about 80%, about 70 to about 100%, about 70 to about 80%, or about 80% to about 100%).

[0087] In an exemplary embodiment, the compression mechanism may include a spring adapted to push the plunger to expand the compression mechanism to at least about 80, 85, 90, 95 or 100% of the length of the body.

[0088] In various embodiments, the pressure exerted by a compression mechanism, such as a biasing means like a spring, can remain substantially constant over the entire dosing period, and the substantially constant pressure leads to a linear or substantially linear (>0.95) sustained release of one or more active ingredients described herein.

[0089] Without wishing to be bound by theory, the inventors believe that the pressure exerted by the compression mechanism, i.e., the pressure biasing at least one matrix towards at least one outlet, contributes to the control of the dosing period.

[0090] In various embodiments, the barrel of the intraluminal device comprises at least one matrix containing at least one active ingredient.

[0091] In some embodiments, the barrel of the intraluminal device can comprise only one matrix, or two or more matrices, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 or more matrices. The useful range can be selected from any of these values, for example, 1 - 30 matrices, 1 - 25, 1 - 20 matrices, 1 - 15, 1 - 10 matrices, 1 - 5, 5 - 30, 5 - 25, 5 - 20, or 5 - 15 matrices. At least one matrix can be of any shape adapted to fit inside the barrel of the device. In various embodiments, the barrel of the intraluminal device can contain two or more matrices. The form of at least one matrix can be, for example, a tablet, capsule, caplet or wafer.

[0092] In some embodiments, at least one matrix can be shaped to allow stacking along the longitudinal axis of the body of the intraluminal device, such that the matrices can be sequentially presented to the lumen, as first proposed for the Laby device. Preferably, at least one matrix is a tablet, preferably in the shape of a disc.

[0093] In some embodiments, the diameter of at least one matrix can be about 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 mm. The useful range can be selected from any of these values (e.g., the diameter of the matrix can be about 9 to about 40 mm, about 9 to about 30 mm, about 9 to about 20 mm, about 9 to about 10 mm, about 10 to about 35 mm, about 10 to about 25 mm, about 10 to about 15 mm, about 11 to about 40, 11 to about 38, 11 to about 36, 11 to about 34, 11 to about 32 mm, 11 to about 30 mm, 11 to about 28 mm, 11 to about 26 mm, 11 to about 24 mm, 11 to about 22 mm, 11 to about 20 mm, 11 to about 19 mm, 11 to about 18 mm, 11 to about 17 mm, 11 to about 16 mm, 11 to about 15 mm, 11 to about 14 mm, 12 to about 40 mm, 12 to about 38, 12 to about 36, 11 to about 34, 12 to about 32 mm, 12 to about 30 mm, 12 to about 28 mm, 12 to about 26 mm, 12 to about 24 mm, 12 to about 22 mm, 12 to about 20 mm). For example, in some embodiments, at least one matrix for use in an intraluminal device administered to a sheep can have a diameter of about 11 to about 15 mm, and at least one matrix for use in an intraluminal device administered to a cow can have a diameter of about 15 to about 32 mm.

[0094] The diameter of at least one matrix containing one or more active ingredients must be small enough to fit into the barrel of the device. For example, if the diameter of the barrel of the device is 30 mm, the matrix can have a diameter of, for example, about 29.5 mm. In various embodiments, the diameter of the matrix can be sufficiently administered to the inner diameter of the barrel to substantially prevent the intrusion of the lumen fluid between the core and the barrel without preventing the movement of the matrix within the barrel.

[0095] In some embodiments, the device may include a plurality of matrices, e.g., a plurality of compressed tablets, and the number of matrices depends on the length of the body of the device, the thickness of the matrix, the desired dosing period, and the amount of active ingredient present in at least one matrix. For example, in some embodiments, the thickness of at least one matrix may be at least about 3, 3.25, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.25, 5.5, 5.75, 6, 6.25, 6.5, 6.75, 7, 7.25, 7.5, 7.75, 8, 8.25, 8.5, 8.75, 9, 9.25, 9.5, 9.75 or 10 mm or more. Useful ranges can be selected between these values, e.g., about 1 to about 10 mm, about 1 to about 8 mm, about 1 to about 6 mm, about 1 to about 4 mm, about 2 to about 10 mm, about 2 to about 8 mm, about 2 to about 6 mm, about 2 to about 4 mm, about 3 to about 10 mm, about 3 to about 9 mm, about 3 to about 7 mm, about 3 to about 5 mm, about 5 to about 10 mm, about 5 to about 9 mm, about 5 to about 8 mm, about 5 to about 7 mm, about 7 to about 10 mm, or about 7 to about 9 mm.

[0096] In some embodiments, the barrel may comprise only one matrix, e.g., one solid core containing at least one active ingredient and optionally one or more excipients. In such embodiments, the matrix can extend substantially the length of the barrel from an end of the body having at least one outlet from the compression mechanism.

[0097] In some embodiments, the solid core can be continuous or composed of individual compressed matrices or units (tablets) arranged in a stack.

[0098] In some embodiments, the active ingredient(s) can be released into the lumen in a controlled manner by contacting the matrix containing the active ingredient(s) with the intraluminal fluid, allowing erosion or dissolution of the matrix into the lumen.

[0099] In some embodiments, there is a seal between the end of the matrix containing the active ingredient(s) facing the lumen and the barrel of the in-lumen device. Without wishing to be bound by theory, the inventors believe that an ineffective seal between the barrel of the matrix containing the active ingredient(s) and the end facing the lumen can swell other surfaces of the matrix or other matrices in the stack, which can negatively affect or halt the reliable dispensing of one or more active ingredients.

[0100] In various embodiments, at least one outlet can be located at one end of the body. The outlet can be from about 1, 2, 3, 4, 4, 5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5, 20, 20.5, 21, 21.5, 22 mm or more in diameter. The useful range can be selected between any of these values (e.g., from about 1 to about 22 mm, from about 1 to about 20 mm, from about 1 to about 18.5 mm, from about 1 to about 15 mm, from about 1 to about 12 mm, from about 1 to about 10 mm, from about 1 to about 5 mm, from about 3 to about 22 mm, from about 3 to about 20 mm, from about 3 to about 18.5 mm, from about 3 to about 15 mm, from about 3 to about 12 mm, from about 4 to about 22 mm, from about 4 to about 20 mm, from a diameter of about 4 to about 18.5 mm, from about 4 to about 15 mm, or from about 4 to about 12 mm). One of ordinary skill in the art will understand that the size of the outlet depends on factors such as, for example, the intended dispensing rate.

[0101] In various embodiments, the diameter of at least one outlet can be selected to ensure that there is sufficient protrusion to seal against at least one matrix within the barrel of the in-lumen device.

[0102] In various embodiments, the in-lumen device can comprise an end cap provided at one end of the body.

[0103] In various embodiments, the end cap is provided at the end of the body that comprises at least one outlet.

[0104] In various embodiments, the end cap comprises at least one outlet.

[0105] In various embodiments, the end cap may be permanently fixed to the body of the in-vessel device, for example, may be integral with the body of the in-vessel device.

[0106] In various embodiments, the end cap can be removably attached to the body of the in-vessel device.

[0107] In some embodiments, the end cap may comprise only one outlet.

[0108] In some embodiments, the end cap may comprise two or more outlets, for example, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more outlets. The useful range can be selected from these values, for example, either 2 to 6 outlets or 3 to 8 outlets. Preferably, one or more outlets are located at or near the center of the end cap. Preferably, when the end cap comprises a plurality of outlets, the outlets are substantially equidistant from each other.

[0109] In some embodiments, the end cap may be made of the same material as the body or a different material. In various embodiments, the end cap is made of a polymeric material that is stable under the conditions present in the animal's lumen.

[0110] The end cap, if present, can be fixed to the end of the body by any suitable means. For example, the end cap may be welded or adhered to the end of the barrel, preferably welded.

[0111] 2. Contents of the matrix The rumen device of the present invention comprises at least one matrix. The at least one matrix may comprise one or more active ingredients and one or more polymers and excipients in a ratio that enables delivery of a therapeutically effective amount of one or more active ingredients to non-human animals, preferably ruminants.

[0112] 2.1. Polymer The inventors have advantageously discovered that the release rate and / or linearity of release of nutritional or pharmaceutically active ingredient(s) from at least one matrix in a rumen device can be adjusted or controlled using one or more polymers selected from the group consisting of one or more polymers, preferably nonionic and crosslinked anionic polymers, within the matrix.

[0113] A nonionic polymer is a polymer that does not contain charged groups. A crosslinked anionic polymer is a polymer that contains negatively charged (anionic groups), for example carboxylic acid groups, and contains one or more bonds between different polymer chains. The bonds can be covalent or ionic bonds, and the crosslinked anionic polymer can be a natural or synthetic polymer.

[0114] Without wishing to be bound by theory, nonionic polymers and crosslinked anionic polymers limit interactions with cationic species in the rumen that can affect important attributes of the polymer(s).

[0115] In various embodiments, the polymer, preferably a nonionic polymer or a crosslinked anionic polymer for use in the matrix of the rumen device, is a polymer that forms a strong gel and / or has a low swelling capacity.

[0116] The strength of the gel can be determined in several ways. For example, use the Bloom test, which includes determining in grams the weight required to push the surface of the gel 4 mm down using a plunger 0.5 inches in diameter at a specified temperature.

[0117] In some embodiments, the nonionic polymer and crosslinked anionic polymer in the matrix and intraluminal device of the present invention can produce a Bloom strength in the range from about 1, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490 or 500 or more. A useful range can be selected from any of these values (e.g., about 1 to about 500, 10 to about 500, 100 to about 500, 200 to about 500, about 300 to about 500, about 400 to about 500, about 50 to about 450, about 50 to about 350, about 50 to about 350, or about 50 to about 250).

[0118] The swelling ability of the polymer can be calculated in several ways. For example, the swelling ability of the polymer can be calculated by taking a certain amount (e.g., 0.1 g) of the polymer and exposing it to 100 ml of deionized water. After 20 minutes, the weight of the polymer is measured and the weight change rate is calculated according to Equation 1 below. ((Final weight (after swelling) - Initial weight (before swelling) / Initial weight (before swelling)) × 100%

[0119] In some embodiments, the swelling ability of the polymer is calculated using Equation 1 and can be from about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 180, 185, 190, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, 400, 405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480, 485, 490, 495, or 500% or more. Useful ranges can be selected from any of these values (e.g., the swelling ability is from about 1 to about 500%, 5 to about 500%, 10 to about 500%, 100 to about 500%, 200 to about 500%, 300 to about 500%, 400 to about 500%, 1 to about 400%, 1 to about 300%, 1 to about 200%, 1 to about 100%, 1 to about 90%, 1 to about 75%, 1 to about 50%, 1 to about 25%, or about 1% to about 10%). In some embodiments, the polymer, such as a nonionic or crosslinked anionic polymer, is present in an amount from about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12.5, 15, 17.5, 20, 22.5, 25, 27.5, 30, 32.5, 35, 37.5, 40, 42.5, 45, 47.5, 50, 52.5, 55, 57.5, 60, 62.5, 65, 67.5, 70, 72.5, 75, 80, 85 or 90 by weight % of the matrix.The useful range can be selected from any of these values (e.g., about 1 to about 50 wt% or about 2 to about 45 wt% of the matrix, preferably about 0.5 to about 90, about 0.5 to about 70, about 0.5 to about 50, about 0.5 to about 30, about 0.5 to about 10, about 0.5 to about 8, about 0.5 to about 6, about 1 to about 90, about 1 to about 60, about 1 to about 40, about 1 to about 10, about 1 to about 8, about 1 to about 6, about 1 to about 4, about 2 to about 90, about 2 to about 70, about 2 to about 50, about 2 to about 30, about 2 to about 10, about 2 to about 8, or about 2 to about 6).

[0120] In some embodiments, the nonionic polymer may be a homopolymer or a copolymer containing two or more polymers. Each of these is nonionic and preferably a homopolymer. In some embodiments, the nonionic polymer can be an alternating, branched, or block copolymer.

[0121] In various embodiments, the nonionic polymer can be a homopolymer containing an acyclic polymer backbone.

[0122] In some embodiments, the nonionic polymer may be crosslinked.

[0123] In various embodiments, the polymer is a crosslinked anionic polymer containing a long-chain alkyl acid ester.

[0124] In various embodiments, the polymer is a crosslinked anionic polymer that is a block polymer of polyethylene glycol.

[0125] In various embodiments, the nonionic polymer with an acyclic polymer backbone can be polyvinylpyrrolidone or polyethylene oxide.

[0126] In an exemplary embodiment, the nonionic polymer can be polyvinylpyrrolidone having a molecular weight from about 35,000, 36,000, 37,000, 38,000, 39,000, 40,000, 41,000, 42,000, 43,000, 44,000, 45,000, 46,000, 47,000, 48,000, 49,000, 50,000, 51,000, 52,000, 53,000, 54,000, 55,000, 56,000, 37,000, 58,000, 59,000 or 60,000 g / mol-1. Suitable ranges can be selected from any of these values (e.g., from about 35,000 to about 60,000, from about 35,000 to about 50,000, from about 35,000 to about 40,000, from about 40,000 to about 60,000, from about 40,000 to about 50,000, from about 42,000 to about 60,000, from about 42,000 to about 50,000, from about 44,000 to about 60,000, from about 44,000 to about 58,000, from about 44,000 to about 65,000, from about 44,000 to about 54,000, from about 44,000 to about 52,000, from about 44,000 to about 50,000, from about 42,000 to about 60,000, from about 42,000 to about 58,000, from about 42,000 to about 56,000, from about 44,000 to about 54,000, from about 42,000 to about 52,000, or from about 42,000 to about 50,0000, from about 35,000 to about 60,000, from about 35,000 to about 55,000, from about 35,000 to about 50,000, or from about 35,000 to about 45,000 g / mol-1).

[0127] In an exemplary embodiment, the nonionic polymer can be polyvinylpyrrolidone consisting of monomer units of about 310, 320, 330, 340, 350, 360, 370, 380, 385, 390, 395, 400, 405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480, 485, 490, 495, 500, 505, 510, 515, 520, 530, 535 or 540. The useful range can be selected from any of these values (e.g., about 540, 310 to about 500, about 310 to about 400, about 350 to about 540, about 350 to about 500, about 350 to about 400, about 380 to about 540, about 380 to about 500, about 380 to about 400, about 395 to about 540, about 395 to about 500, about 395 to about 485, about 395 to about 450, about 395 to about 430, about 395 to about 400 monomer units).

[0128] In some embodiments, the anionic polymer has any one or more of the following characteristics. · Anionic poly(acrylic acid) interpolymer (copolymer). · An acrylic acid interpolymer crosslinked with an allyl ester of a polyalcohol. · The anionic acrylic acid interpolymer is water-insoluble. · An anionic acrylic acid interpolymer having a viscosity exceeding about 45,000 cP. · Formed such that the polymerization process is benzene-free. · Formed such that the polymerization solvent is a co-solvent containing ethyl acetate and cyclohexane. · The anionic acrylic acid interpolymer is essentially benzene-free. · The anionic acrylic acid interpolymer is Carbopol Ultrez 10.

[0129] In some embodiments, the nonionic polymer has any one or more of the following characteristics. · Nonionic polyethylene oxide homopolymer. · The molecular weight of the nonionic polyethylene oxide homopolymer is about 0.9 to 7 million. · The viscosity of the nonionic polyethylene oxide homopolymer is greater than about 7,500. · The nonionic polyethylene oxide homopolymer is easily crosslinked.

[0130] In various embodiments, the polymer is a nonionic polyol polymer.

[0131] In various embodiments, the nonionic polymer is a polyethylene oxide polymer, for example, a polymer commercially available under the name of POLYOX™ 301, POLYOX™ 303, or POLYOX™ 1105.

[0132] In various embodiments, the polyethylene oxide polymer can have a molecular weight from about 800,000, 850,000, 900,000, 950,000, 1,000,000, 1,250,000, 1,500,000, 1,750,000, 2,000,000, 2,250,000, 2,500,000, 2,750,000, 3,000,00, 3,250,000, 3,500,000, 3,750,000, 4,000,000, 4,250,000, 4,500,000, 4,750,000, 5000,000, 5,250,000, 5,500,000, 5,750,000, 6,000,000, 6,250,000, 6,500,000, 6,750,000, 7,000,000 or 7,250,000 g / mol-1. Useful ranges can be selected from any of these values (e.g., molecular weights of about 800,000 - 7,000,000, about 800,000 - about 6,000,000, about 800,000 - about 5,000,000, about 800,000 - about 4,000,000, about 800,000 - about 3,000,000, about 800,000 - about 2,000,000, about 900,000 - about 7,000,000, m about 900,000 - about 6,000,000, about 900,000 - about 5,000,000, about 900,000 - about 4,000,000, about 900 - about 3,000,000, about 900,000 - about 2,000,000, about 1,000,000 - about 5,000,000, about 1,000,000 - about 4,000,000, about 1,000,000 - about 3,000,000, about 1,000,000 - about 2,000,000 g / mol-1). In an exemplary embodiment, the nonionic polymer can be a polyethylene oxide polymer consisting of about 15,000, 20,000, 25,000, 30,000, 35,000, 40,000, 45,000, 50,000, 55,000, 60,000, 65,000, 70,000, 75,000, 80,000, 85,000, 90,000, 95,000, 100,000, 105,000, 110,000, 115,000, 120,000, 125,000, 130,000, 135,000, 140,000, 145,000, 150,000, 155,000, 160,000, or 165,000 monomer units.The useful range can be selected from any of these values (e.g., monomer units of about 15,000 to about 165,000, about 15,000 to about 150,000, about 15,000 to about 10,000, about 15,000 to about 75,000, about 15,000 to about 50,000, about 20,000 to about 165,000, about 20,000 to about 155,000, about 20,000 to about 100,000, about 20,000 to about 80,000, about 20,000 to about 60,000, or about 20,000 to about 40,000).

[0133] In various embodiments, the nonionic polymer, preferably a nonionic polymer containing an acyclic backbone, can have a viscosity from about 5,000, 5,250, 5,500, 5,750, 6,000, 6,250, 6,500, 6,750, 7,000, 7,250, 7,500, 7,750, 8,000, 8,250, 8,500, 8,750, 9,000, 9,250, 9,500, 9,750, 10,000, 10,250, 10,500, 10,750, 11,000, 11,250, 11,500, 11,750, 12,000, 12,250, 12,500, 12,750, 13,000, 13,250, 13,500, 13,750, 14,000, 14,250, 14,500, 14,750, or 15,000 cP (0.5 wt% at pH 7.5). The useful range can be selected from these values (e.g., viscosities from about 5,000 to about 15,000, about 5,000 to about 12,000, about 5,000 to about 10,000, about 7,500 to about 15,000 cP, or about 7,500 to about 10,000 cP).

[0134] In some embodiments, the crosslinked anionic polymer can contain anionic groups such as carboxylates, sulfates, sulfonates, and phosphates, preferably carboxylates such as acrylates.

[0135] In various embodiments, the crosslinked anionic polymer can be a modified polyacrylic acid polymer with a high density of crosslinking that forms a strong gel.

[0136] In some embodiments, the crosslinked anionic polymer can include a percentage of monomers having free anionic groups, such as free acid groups, as a percentage of the total number of monomers of less than about 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, or 65%. Useful ranges can be selected from any of these values (e.g., about 50 to about 65, about 50 to about 60, about 50 to about 59, about 50 to about 58, about 50 to about 57, about 50 to about 56, about 50 to about 55, about 50 to about 54, about 50 to about 53, about 50 to about 52, about 50 to about 51, about 55 to about 65, about 55 to about 64, about 55 to about 63, about 55 to about 62, about 55 to about 61, about 55 to about 60, about 55 to about 59, about 55 to about 58, about 55 to about 57, about 55 to about 56, about 56 to about 65, about 56 to about 64, about 56 to about 63, about 56 to about 62, about 56 to about 61, about 56 to about 60, about 56 to about 59, about 56 to about 58, about 56 to about 57, about 57 to about 65, about 57 to about 64, about 57 to about 63, about 57 to about 62, about 57 to about 62, about 57 to about 61, or about 57 to about 60%).

[0137] The crosslinked polymer can be crosslinked, for example, with allyl sucrose or allyl pentaerythritol.

[0138] In various embodiments, the crosslinked anionic polymer, preferably a crosslinked polyacrylic acid polymer, can have a viscosity from about 40,000, 40,250, 40,500, 40,750, 41,000, 41,250, 41,500, 41,750, 42,000, 42,250, 52,500, 42,750, 43,000, 43,250, 43,500, 43,750, 44,000, 44,250, 44,500, 44,750, 45,000, 45,250, 45,500, 45,750, 46,000, 46,250, 46,500, 46,750, 47,000, 47,250, 47,500, 47,750, 48,000, 48,250, 48,500, 48,750, 49,000, 49,250, 49,500, 49,750, 50,000, 51,000, 51,250, 51,500, 51,750, 52,000, 52,250, 52,500, 52,750, 53,000, 53,250, 53,500, 53,750, 54,000, 54,250, 54,500, 54,750, 55,000, 55,250, 55,500, 55,750, 56,000, 56,250, 56,500, 56,750, 57,000, 57,250, 57,500, 57,750, 58,000, 58,250, 58,500, 58,750, 60,000, 60,250, 60,500, 60,750, 61,000, 61,250, 61,500, 61,750, 62,000, 62,250, 62,500, 62,750, 63,000, 63,250, 63,500, 63,750, 64,000, 64,250, 64,500, 64,750, 65,000, 65,125, 65,250, 65,500, 65,750, 66,000, 66,250, 66,500, 66,750, or 67,000 cP. A useful range can be selected from these values (e.g., a viscosity from about 45,000 to about 60,000 cP).

[0139] In various embodiments, the crosslinked anionic polymer can be a high crosslink density polymer such as, for example, a polymer sold under the name Carbopol® Ultrez 10NF.

[0140] 2.2. Active ingredient At least one matrix within the luminal device of the present invention delivers a therapeutically effective amount of one or more active ingredients. The active ingredient(s) is / are delivered from the luminal device and may have a local effect, for example, in the gastrointestinal tract, and / or may be active within the lumen containing the microbiota or enzyme environment, and / or may be absorbed into the systemic circulation to provide a therapeutic response to other body compartments, for example, including major organs and tissues.

[0141] A wide range of active ingredients can be delivered from at least one matrix within the luminal device of the present invention.

[0142] The luminal device of the present invention comprises at least one matrix, and the at least one matrix defines a core. In some embodiments, the core may contain a single therapeutic agent or a combination of combined therapeutic agents. In some embodiments, the therapeutic agents can be separated throughout the core using individual matrices.

[0143] In some embodiments, the at least one matrix may contain one or more antibiotics, antifungal agents, antiviral agents, steroid hormones, antihistamines, metabolic regulators, for example, lumen methane inhibitors / regulators, productivity regulators, corticosteroids, antithyroid agents, for example, anthelmintics such as antiparasitic agents (ectoparasitic agents and / or endoparasitic agents), non-steroidal anti-inflammatory agents, nutraceuticals, lumen fermentation regulators, or combinations thereof. In some embodiments, the at least one matrix may contain, for example, one or more vitamins, for example, vitamin A, vitamin E, vitamin B l2 , vitamin B3, D-pantothenic acid (vitamin B5), folic acid, vitamin B6, vitamin B1, vitamin D3, vitamin C, vitamin B2, vitamin B7 or H. As another example, the nutraceutical may be a provitamin, for example, beta-carotene or panthenol.

[0144] In some embodiments, the nutritional active substance can be an amino acid. Suitable amino acids include, but are not limited to, the 20 naturally occurring L-amino acids, such as arginine, isoleucine, leucine, lysine, etc.

[0145] In some embodiments, the nutritional active substance can be a coenzyme, such as coenzyme Q.

[0146] In some embodiments, the nutritional active substance can be a mineral. Non-limiting examples of minerals include potassium, sodium, manganese, zinc, iron, calcium, copper, cobalt, iodine, chlorine, and selenium. In some embodiments, the mineral can be in the form of a suitable salt.

[0147] In some embodiments, at least one matrix can contain one or more antibacterial components, such as antibiotics, antifungal agents, antiviral agents, anthelmintics, etc.

[0148] Suitable antibiotics can be substances that act as inhibitors of cell wall synthesis (e.g., penicillin, cephalosporin, bacitracin, and vancomycin), inhibitors of protein synthesis (aminoglycosides, macrolides, lincosamides, streptogramins, chloramphenicol, tetracycline), inhibitors of membrane function (e.g., polymyxin B and colistin), inhibitors of nucleic acid synthesis (e.g., quinolone, metronidazole, and rifampin), or inhibitors of other metabolic processes (e.g., antimetabolites, sulfonamides, and trimethoprim).Non-limiting examples of antibiotics include polyethers, ionophores such as monensin and salinomycin, beta-lactams such as penicillin, aminopenicillins (e.g., amoxicillin, ampicillin, hetacillin, etc.), penicillinase-resistant antibiotics (e.g., cloxacillin, dicloxacillin, methicillin, nafcillin, oxacillin, etc.), extended-spectrum antibiotics (e.g., amoxicillin, carbenicillin, mezlocillin, piperacillin, ticarcillin, etc.), cephalosporins (e.g., cephradine, cefazolin, cephalexin, cephalothin, cephapirin, cephradine, cefaclor, cefamandole, cefmetazole, cefonicid, ceforanide, cefotetan, cefoxitin, cefprozil, cefuroxime, loracarbef, cefixime, cefprozil, cefuroxime, loracarbef, cefixime, ceftriaxone, moxalactam, etc.), monobactams such as aztreonam, carbapenems such as imipenem and ertapenem, quinolones (e.g., ciprofloxacin, enrofloxacin, difloxacin, orbifloxacin, marbofloxacin, etc.), chloramphenicols (e.g., chloramphenicol, thiamphenicol, florfenicol, etc.), tetracyclines (e.g., chlortetracycline, tetracycline, oxytetracycline, doxycycline, minocycline, etc.), macrolides (e.g., erythromycin, tylosin, trimicosin, clarithromycin, azithromycin, etc.), lincosamides (e.g., lincomycin, clindamycin, etc.), aminoglycosides (e.g., gentamicin, amikacin, kanamycin, apramycin, tobramycin, neomycin, dihydrostreptomycin, paromomycin, etc.), sulfonamides (e.g., sulfadimethoxine, sulfamethazine, sulfachinoxaline, sulfamerazine, sulfathiazole, sulfasalazine, sulfadiazine, sulfabromomethazine, sulfisoxazole, etc.), glycopeptides (e.g., vancomycin, teicoplanin, ramoplanin, and decaplanin), and other antibiotics (e.g., rifampin, nitrofurans, virginiamycin, polymyxin, tobramycin, etc.).

[0149] In some embodiments, at least one matrix may comprise one or more antifungal active ingredients, such as one or more polyenes, azoles, allylamines, morpholines, antimetabolites, and combinations thereof. For example, in some embodiments, at least one matrix may comprise one or more of fluconazole, itraconazole, clotrimazole, ketoconazole, terbinafine, 5-fluorocytosine, and amphotericin B, or combinations thereof.

[0150] Non-limiting examples of antiviral drugs that may be present within at least one matrix may include didanosine, lamivudine, stavudine, zidovudine, indinavir, and ritonavir.

[0151] In some embodiments, at least one matrix may comprise one or more steroid hormones, such as steroid hormones including growth promoters and production promoters. In some embodiments, the steroid hormones may be, for example, natural steroid hormones such as estradiol, progesterone, and testosterone, or synthetic steroid hormones such as trenbolone acetate, estradiol benzoate, estradiol 17β, and melengestrol acetate, and / or geraniol.

[0152] Steroid hormones that may be present in at least one matrix may include, for example, natural and synthetic steroid hormones, steroid hormone precursors, steroid hormone metabolites, and their derivatives structurally derived from cholesterol. Steroid hormones can be synthesized from cholesterol via pathways involving the cytochrome P450 (cP450) enzyme, a heme-containing protein.

[0153] In some embodiments, at least one matrix can include one or more steroid hormones such as, for example, androgen, estrogen, progesterone, mineralocorticoid, and glucocorticoid. Exemplary androgens include, but are not limited to, testosterone, dehydroepiandrosterone, dehydroepiandrosterone sulfate, dihydrotestosterone, androstenedione, androstenediol, androstanedione, androstanediol, and any combination thereof. Exemplary estrogens include, but are not limited to, estrone, estradiol, estriol, estetrol, equilin, and any combination thereof. Exemplary progesterones include, but are not limited to, progesterone, 17-hydroxy-progesterone, pregnenolone, dihydroprogesterone, allopregnanolone, 17-hydroxy-pregnenolone, 17-hydroxy-dihydroprogesterone, 17-hydroxy-allopregnanolone, and any combination thereof. Exemplary mineralocorticoids include, but are not limited to, aldosterone, 11-deoxycorticosterone, fludrocortisone, 11-deoxycortisol, pregnenedione, and any combination thereof. Exemplary glucocorticoids include, but are not limited to, cortisol (hydrocortisone), corticosterone, 18-hydroxy-corticosterone, cortisone, and any combination thereof.

[0154] In some embodiments, at least one matrix can include one or more antihistamines such as, for example, clemastine, clemastine fumarate (2(R)-[2-[1-(4-chlorophenyl)-1-phenylethoxy]ethyl)-1-methylpyrrolidine), dexmedetomidine, doxylamine, loratadine, desloratadine, and promethazine, and diphenhydramine, or a pharmaceutically acceptable salt, solvate, or ester thereof.

[0155] In some embodiments, at least one matrix may include one or more active ingredients adapted to modify the in-rumen fermentation process.

[0156] In some embodiments, at least one matrix may include one or more metabolic regulators, such as, for example, one or more methane inhibitors / modulators, or fermentation regulators / modifiers.

[0157] In some embodiments, at least one matrix may include one or more productivity regulators, such as polyethers such as monensin. In some embodiments, the productivity regulator may be a productivity enhancer.

[0158] In an exemplary embodiment, at least one matrix may include one or more anthelmintics, such as, for example, one or more benzimidazoles, imidazothiazoles, tetrahydropyrimidines, macrocyclic lactones, salicylanilides, substituted phenols, aromatic amides, isoquinolines, aminoacetonitriles, spiroindoles, isoxazolines, or combinations thereof.

[0159] Anthelmintic benzimidazoles include, for example, mebendazole, flubendazole, fenbendazole, oxfendazole, albendazole, albendazole sulfoxide, thiabendazole, thiophanate, febantel, netobimin, and triclabendazole. Further examples include mebendazole, and ricobendazole.

[0160] Without wishing to be bound by theory, the inventors believe that benzimidazole-based anthelmintics may interfere with the energy metabolism of worms at the cellular level by binding to a specific building block called beta-tubulin and preventing its uptake into a specific cellular structure called microtubules, which are essential for energy metabolism.

[0161] Both imidazothiazole and tetrahydropyrimidine are nicotinic agonists. In some embodiments, one or more anthelmintics within at least one matrix may include imidazothiazoles such as levamisole, tetramisole, and butamisole. Tetrahydropyrimidine anthelmintics that can be used in the matrices of the present invention include, for example, morantel, oxantel, and pyrantel.

[0162] Without wishing to be bound by theory, the inventors believe that tetrahydropyrimidine may mimic the activity of acetylcholine, a naturally occurring neurotransmitter that initiates muscle contraction. This may lead to worms that cannot be fed or starved.

[0163] Without wishing to be bound by theory, the inventors believe that imidazothiazole has a similar mechanism of action to tetrahydropyrimidine and may cause spastic paralysis of worms. For example, levamisole is thought to have a broad antibacterial spectrum and may therefore be effective against the larval stages of parasites.

[0164] In various embodiments, at least one matrix may include one or more macrocyclic lactones such as abamectin, doramectin, eprinomectin, ivermectin, selamectin, milbemycin such as milbemycin oxime, moxidectin, or combinations thereof.

[0165] In some embodiments, at least one matrix may include one or more salicylanilides such as brotianide, clioxanide, closantel, niclosamide, oxyclozanide, rafoxanide, substituted phenols such as bithionol, disophenol, hexachlorophene, nitroxynil, and aromatic amides such as diamphenethide (diamphenethide), or combinations thereof.

[0166] In some embodiments, at least one matrix can include one or more isoquinoline anthelmintics such as praziquantel and eprinanthel. In some embodiments, the matrix and intraluminal device of the present invention can include one or more aminoacetonitrile derivatives such as monepantel.

[0167] In some embodiments, at least one matrix can include one or more active ingredients such as piperazine, derivatives of piperazine such as piperazine and diethylcarbamazine (DEC, a derivative of piperazine), benzenesulfonamides such as chlorothalonil, amidines such as bunamidine, isothiocyanates such as nitrosocanate, and phosphoric acid esters such as dichlorvos, and spiroindoles such as derquantel (2-deoxoparaherquamid).

[0168] In various embodiments, one or more active ingredients within at least one matrix of the intraluminal device are stable and do not react with other components within the at least one matrix or otherwise degrade or decompose.

[0169] In various embodiments, the dispensing rate of the active ingredient(s) can be measured as a function of the width of the matrix that is discharged into the lumen through one or more outlets within the end cap. In some embodiments, the dispensing rate of the in-lumen device of the present invention is about 0.1, 0.125, 0.15, 0.175, 0.2, 0.225, 0.025, 0.275, 0.3, 0.325, 0.35, 0.375, 0.4, 0.425, 0.45, 0.475, 0.5, 0.525, 0.55, 0.575, 0.6, 0.625, 0.65, 0.675, 0.7, 0.725, 0.75, 0.775, 0.8, 0.825, 0.85, 0.875, 0.9, 0.925, 0.95, 0.975, 1, 1.1, or 1.2 mm or more per day in an aqueous medium, such as lumen fluid or water. Suitable ranges can be selected from any of these values (e.g., about 0.1 to about 1.2, about 0.1 to about 1, about 0.1 to about 0.75, 0.1 to about 0.6, 0.1 to about 0.5, 0.2 to about 1.2, about 0.2 to about 0.75, about 0.2 to about 0.6, about 0.2 to about 0.5 mm / day). Those skilled in the art will understand that the dispensing rate as a function of the width of the matrix can depend on the size of the in-lumen device.

[0170] Preferably, the dispensing of one or more active ingredients is linear or substantially linear. In various embodiments, the linearity can be greater than about 0.95, 0.955, 0.96, 0.965, 0.97, 0.975, 0.98, 0.985, 0.99, 0.995, 0.996, 0.997, 0.998, 0.999 or more. Suitable ranges can be selected from any of these values, e.g., about 0.95 to about 0.999, about 0.99 to about 0.995, about 0.99 to about 0.996, about 0.99 to about 0.997, about 0.99 to about 0.998, about 0.99 to about 0.999.

[0171] In various embodiments, the dispensing rate of one or more active ingredient(s) is minimally affected, preferably not affected, by the pH and ionic composition of the lumen.

[0172] In some embodiments, at least one matrix of the intraluminal device can include two or more active ingredients. For example, in some embodiments, the matrix of the present invention can include 2, 3, 4, 5, 7, 8, 9, or about 10 or more active ingredients. The useful range can be selected from any of these values (e.g., 2 to about 10 or 2 to about 5 active ingredients).

[0173] In some embodiments, at least one matrix can include two or more active ingredients, and some or all of the active ingredients can belong to different pharmacodynamic classifications, such as antibiotics, antifungals, antivirals, steroid hormones, antihistamines, metabolic regulators, productivity regulators, corticosteroids, antithyroid agents, anthelmintics, e.g., analgesics and / or nutraceuticals. For example, the matrix can include three active substances, one of which is an anthelmintic, one is an antibiotic, and the third is a nutraceutical, e.g., a vitamin.

[0174] In various embodiments, at least one matrix of the intraluminal device can include two or more active ingredients, each belonging to the same pharmacodynamic classification, preferably anthelmintics. In some embodiments, the matrix can include two or more anthelmintic active substances belonging to the same classification of anthelmintics, such as benzimidazoles, imidazothiazoles, tetrahydropyrimidines, macrocyclic lactones, salicylanilides, substituted phenols, aromatic amides, isoquinolines, aminoacetonitriles, and spiroindoles. For example, at least one matrix can include two or three active substances, each of which can be a macrocyclic lactone.

[0175] In various embodiments, at least one matrix of the intraluminal device may each be an anthelmintic active substance, and each may contain two or more active ingredients belonging to different anthelmintic classes such as, for example, benzimidazoles, imidazothiazoles, tetrahydropyrimidines, macrocyclic lactones, salicylanilides, substituted phenols, aromatic amides, isoquinolines, aminoacetonitriles, and spiroindoles. For example, the matrix may contain two anthelmintics, one of which may be a macrocyclic lactone and the other may be an imidazothiazole.

[0176] In some embodiments, at least one matrix may contain one or more active ingredients in an amount of at least about 5, 7.5, 10, 12.5, 15, 17.5, 20, 22.5, 25, 27.5, 30, 32.5, 35, 37.5, 40, 42.5, 45, 47.5, 50, 52.5, or 55% or more by weight of each matrix. Useful ranges can be selected from any of these values (e.g., about 5 to about 55, about 5 to about 50, about 5 to about 25, about 5 to about 10, about 6 to about 55, about 6 to about 50, about 6 to about 25, about 6 to about 10, about 7 to about 55, about 7 to about 50, about 7 to about 35, about 7 to about 10, about 8 to about 55, about 8 to about 50%, about 8 to about 50, about 8 to about 25, about 8 to about 10, about 9 to about 55, about 9 to about 50, about 9 to about 25, about 10 to about 55, about 10 to about 50, about 10 to about 40, about 10 to about 30, about 10 to about 25, or about 10 to about 25% by weight).

[0177] In various embodiments, the matrices (tablets (plural)) of the present invention and the intraluminal devices comprising these tablets contain one or more active ingredients, the polymers described herein, and the ratios of other ingredients that enable delivery of one or more therapeutically effective amounts of the active ingredients to non-human animals, preferably ruminants.

[0178] 2.3. Other Materials At least one matrix containing one or more active ingredients and a polymer may further contain several excipients. Examples of suitable excipients may include, but are not limited to, fillers, diluents, lubricants, surfactants, glidants, gelling agents, binders, and stabilizers, or combinations thereof.

[0179] In some embodiments, at least one matrix of the present invention may further contain one or more fillers or diluents. Examples of suitable fillers or diluents may include, but are not limited to, sugars such as lactose, sucrose and mannitol, inorganic salts such as calcium phosphate and calcium carbonate, cellulose, methylcellulose, ethylcellulose, aluminum silicate, kaolin or combinations thereof.

[0180] In some embodiments, the at least one matrix may contain one or more fillers and / or diluents in an amount, by weight of the matrix, of about 0, 0.1, 0.25, 0.5, 0.75, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12.5, 15, 17.5, 20, 22.5, 25, 27.5, 30, 32.5, 35, 37.5, 40, 42.5, 45, 47.5, 50, 52.5, 55, 57.5, 60, 62.5, 65, 67.5, 70, 72.5, 75, 77.5, 80, 82.5, 85, 87.5, 90, 92.5, 95 wt%. A useful range can be selected from any of these values (e.g., about 0.1 to about 95, 0.1 to about 80, 0.1 to about 50, 0.1 to about 20, 0.1 to about 15, 0.1 to about 10, 0.1 to about 5, 5 to about 95, 5 to about 90, 5 to about 75, 5 to about 50, 5 to about 25, or about 5 to about 10 wt% of the matrix).

[0181] For example, in some embodiments, the filler / diluent may contain lactose and / or another filler such as sucrose or mannitol, or combinations thereof, in an amount of about 0.1 to about 35% of the matrix.

[0182] In some embodiments, the filler / diluent may comprise cellulose or a cellulose derivative such as, for example, methylcellulose and / or ethylcellulose, or any combination of two or more thereof, in an amount of about 0.1 to about 80% by weight of the matrix, regardless of the presence or absence of one or more other fillers / diluents.

[0183] In some embodiments, the filler / diluent may comprise a filler / diluent selected from the group consisting of aluminum silicate, kaolin, calcium phosphate, and calcium carbonate, or any combination of two or more thereof, in an amount of about 0.1 to about 80% by weight of the matrix, regardless of the presence or absence of one or more other fillers / diluents.

[0184] In some embodiments, at least one matrix may comprise one or more surfactants or lubricants. Examples of surfactants or lubricants may include, but are not limited to, stearates such as magnesium stearate and calcium stearate, and stearyl fumarate, glycerol stearates such as glyceryl monostearate, glycerol derivatives, sodium lauryl sulfate, sucrose fatty acid esters, poloxamers, mineral clays such as kaolin, aluminum silicate, or combinations thereof. In some embodiments, one or more surfactants and / or lubricants may be present in the matrix of the present invention in an amount of about 0.01, 0.05, 0.075, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90% by weight of the matrix. Useful ranges can be selected from any of these values (e.g., about 0.01 to about 90, about 0.01 to about 75, about 0.01 to about 50, about 0.01 to about 25, about 0.01 to about 10, about 0.5 to about 90, about 0.5 to about 75, about 0.5 to about 50, about 0.5 to about 25, about 5 to about 80, about 5 to about 60, about 5% to about 40, or about 5 to about 20%).

[0185] For example, in some embodiments, the lubricant / surfactant may comprise a stearate such as magnesium stearate or calcium stearate, stearyl fumarate, glyceryl stearate such as glyceryl monostearate, a diclycerin derivative, or combinations thereof, in an amount of about 0.05 to about 3 wt% of the matrix.

[0186] In some embodiments, the lubricant / surfactant may comprise sodium lauryl sulfate in an amount of about 0.01 to about 5 wt% of the matrix.

[0187] In some embodiments, the lubricant / surfactant may comprise one or more sucrose fatty acid esters in an amount of about 5 to about 80 wt% of the matrix.

[0188] In some embodiments, the lubricant / surfactant may comprise one or more poloxamers in an amount of about 0.01 to about 10 wt% of the matrix.

[0189] In some embodiments, the lubricant / surfactant may comprise one or more fillers such as one or more mineral clays and / or an aluminum silicate such as kaolin, in an amount of about 0.1 to about 80 wt% of the matrix.

[0190] In some embodiments, at least one matrix may further comprise one or more flow promoters. Examples of flow promoters include colloidal silicon dioxide, talc, magnesium stearate, calcium stearate and metal stearates such as stearyl fumarate, and glyceryl monostearate such as glyceryl stearate, or combinations thereof, but are not limited thereto. In some embodiments, the flow promoter(s) may be present in an amount from about 0.01, 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, or 5 weight % of the matrix within at least one matrix. Useful ranges can be selected from any of these values (e.g., about 0.01 to about 5, about 0.01 to about 4, about 0.01 to about 2, about 0.01 to about 1, about 0.25 to about 5, about 0.25 to about 4, about 0.25 to about 3, about 0.25 to about 1, about 0.5 to about 5, about 0.5 to about 3, about 0.5 to about 2, about 0.5 to about 1 weight % of the matrix).

[0191] In some embodiments, the flow promoter may comprise colloidal silicon dioxide, metal stearates such as magnesium stearate, calcium stearate and stearyl fumarate, and / or glyceryl stearate such as glyceryl monostearate, or combinations thereof, in an amount from about 0.01 to about 2 weight % of the matrix.

[0192] In some embodiments, at least one matrix may include one or more additional gelling agents. Examples of additional gelling agents that can be used include, but are not limited to, sucrose fatty acid esters, acetic acid derivatives such as hydroxyethyl cellulose and hydroxymethyl cellulose, and chitosan, or combinations thereof. The gelling agent(s) may be present in at least one matrix in an amount of about 0.1, 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85 or 90 weight percent of the matrix. Useful ranges can be selected from any of these values (e.g., about 0.1 to about 90, about 0.1 to about 80, about 0.1 to about 50, about 0.1 to about 20, about 0.1 to about 15, about 0.1 to about 10, about 0.5 to about 90, about 0.5 to about 80, about 0.5 to about 50, about 0.5 to about 30, about 0.1 to about 5, about 5 to about 90, about 5 to about 75, about 5 to about 50, about 5 to about 25, or about 5 to about 10 weight percent of the matrix).

[0193] In some embodiments, the gelling agent may include sucrose fatty acid esters in an amount of about 5 to about 80 weight percent of the matrix.

[0194] In some embodiments, the gelling agent may include one or more poly(ethylene) oxides in an amount of about 0.1 to about 90 weight percent of the matrix.

[0195] In some embodiments, the gelling agent may include one or more polyacrylic acid polymers, such as Carbomer, in an amount of about 0.01 to about 15 weight percent of the matrix.

[0196] In some embodiments, the gelling agent may include one or more cellulose derivatives, such as hydroxyethyl cellulose and hydroxymethyl cellulose, or combinations thereof, in an amount of about 0.01 to about 90 weight percent of the matrix.

[0197] In some embodiments, the gelling agent may comprise cellulose in an amount of about 0.01 to about 30% by weight of the matrix.

[0198] In some embodiments, at least one matrix may include one or more binders. Examples of binders include, but are not limited to, cellulose derivatives such as hydroxyethyl cellulose and hydroxymethyl cellulose. The binder(s) may be present in at least one matrix in an amount from about 0, 0.1, 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3, 5, 3, 75, 4, 4.25, 4, 5, 4.75, 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50% by weight of the matrix. Useful ranges can be selected from any of these values (e.g., about 0.1 to about 50, about 0.1 to about 35, about 0.1 to about 10, about 0.1 to about 10, about 0.5 to about 50, about 0.5 to about 25, about 0.5 to about 10, about 0.5 to about 5, about 1 to about 50, about 1 to about 35, about 1 to about 20, about 1 to about 10, or about 1 to about 5% by weight of the matrix).

[0199] In some embodiments, the binder may comprise polyvinylpyrrolidone in an amount of about 0.01 to about 10% by weight of the matrix.

[0200] In some embodiments, the binder may comprise one or more cerium derivatives, such as methyl and / or ethyl cellulose, or combinations thereof, in an amount of about 0.01 to about 35% by weight of the matrix.

[0201] In some embodiments, at least one matrix may include one or more stabilizers. Examples of stabilizers that can be used in the matrix include, but are not limited to, antioxidants such as butylated hydroxytoluene, butylated hydroxyanisole, and tocopherol, and / or buffers.

[0202] The stabilizer(s) may be present in an amount from about 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.15, 0.2, 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, or 5 wt% of the matrix within at least one matrix. Useful ranges can be selected from any of these values (e.g., about 0.01 to about 5, about 0.01 to about 3, about 0.01 to about 1, about 0.01 to about 5, 0.1 to about 5%, about 0.5 to about 3.5 wt%) of the matrix.

[0203] In some embodiments, the stabilizer may include one or more chemical stabilizers. For example, in some embodiments, the stabilizer may include one or more antioxidants such as, for example, butylated hydroxytoluene, butylated hydroxyanisole, and tocopherol, or combinations thereof, in an amount from about 0.01 to about 10 wt% of the matrix.

[0204] In some embodiments, the stabilizer may include one or more buffers in an amount from 0.1 to about 5 wt% of the matrix. Suitable buffers will be known to those skilled in the art.

[0205] In some embodiments, at least one matrix may include lactose, magnesium stearate, and sucrose fatty acid ester as excipients.

[0206] In some embodiments, one or more matrices include lactose in an amount from about 0.1 to about 35%, magnesium stearate in an amount from about 0.05 to about 3.0%, and sucrose fatty acid ester in an amount from about 5 to 80%.

[0207] In some embodiments, at least one matrix may include lactose, magnesium stearate, sucrose fatty acid ester, and colloidal silicon dioxide as excipients.

[0208] In some embodiments, at least one matrix may contain lactose in an amount of about 0.1% to about 35% by weight of the matrix, magnesium stearate in an amount of about 0.05% to about 3.0% by weight of the matrix, sucrose fatty acid ester in an amount of about 5% to about 80% by weight of the matrix, and colloidal silicon dioxide in an amount of about 0.01% to about 2.0% by weight of the matrix.

[0209] 3. Manufacturing method In some embodiments, the present invention provides a method for manufacturing an intraluminal device as described herein.

[0210] In some embodiments, the method comprises · granulating a mixture comprising at least one active ingredient, at least one polymer selected from the group consisting of a nonionic polymer and a crosslinked anionic polymer, and optionally one or more excipients described herein; · drying the granules; · passing the granules through a sieve; · tableting / compressing the granules into at least one matrix; · loading at least one matrix into the body of the intraluminal device.

[0211] The granule mixture can be prepared by wet or dry granulation, and it will be apparent to those skilled in the art that several granulation processes can be used. For example, the mixture can be prepared by wet granulation using a high-shear granulator, a fluidized bed granulator, or any other suitable means known to those skilled in the art. In some embodiments, the mixture can be granulated by wet granulation in a fluidized bed dryer, including, for example, spraying a pharmaceutically acceptable solvent, such as water or a suitable alcohol or glycol ether, onto the material to be granulated.

[0212] One of ordinary skill in the art will understand that tableting / compression processes other than fluid bed granulation can be used. For example, direct mixing or other wet or dry granulation processes can be used.

[0213] In some embodiments, at least one matrix can be manufactured using a fluid bed granulation process prior to the tablet compression process. In some embodiments, a single-pass or rotary tablet press can be used.

[0214] In various embodiments, the matrix can be granulated or mixed prior to compression.

[0215] In some embodiments, granulation can include high shear mixing and / or roller compaction.

[0216] At least one matrix of the present invention can be compressed as a flat-faced compact, which means that the matrix has no or limited curvature or edge inclination. The flat-faced matrix thus formed can allow for the formation of a continuous stack of matrices when assembled in an intraluminal device.

[0217] In some embodiments, processing parameters such as air flow rate, spray air pressure, and / or spray rate can be adjusted to provide granules with desired attributes.

[0218] In some embodiments, the air flow rate used for granulation can be at least about 2, 3, 4, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, or 45 Pa or more. The useful range can be selected from any of these values (e.g., about 2 to about 24, about 2 to about 30, about 2 to about 28, about 2 to about 26, about 2 to about 24, about 2 to about 22, about 2 to about 20, about 2 to about 18, about 2 to about 16, about 2 to about 14, about 2 to about 12, about 2 to about 10, about 5 to about 45, about 5 to about 40, about 5 to about 20, about 5 to about 10 Pa).

[0219] In some embodiments, the spray air pressure can be from at least about 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, or 5.0 bar or more, and the useful range can be selected from any of these values (e.g., about 0.5 to about 5.0, about 0.5 to about 2.5, about 0.5 to about 1.0, about 1.0 to about 5.0, about 1.0 to about 4, about 1.0 to about 3.0, about 1.0 to about 2.0, about 2.0 to about 5.0, or about 2.0 to about 4.0 bar).

[0220] In some embodiments, the spraying rate is at least about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 g / min or more. The useful range can be selected from any of these values (e.g., about 5 to about 50, about 5 to about 30, about 5 to about 10, about 20 to about 50, about 20 to about 40, or about 20 to about 20 g / min).

[0221] In one embodiment, the batch is dried from about 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, or 45 °C, and the suitable range can be selected from any of these values (e.g., about 20 to about 45, about 20 to about 30, about 25 to about 45, about 25 to about 35, about 30 to about 45 or about 30 °C to about 35 °C).

[0222] In some embodiments, the batch is dried for at least about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 22, 24, 30, 36, 42, or 48 hours or more, and the suitable range can be selected from any of these values (e.g., at least about 0.5 to 48, about 0.5 to about 24, about 0.5 to about 12, about 0.5 to about 6, about 1 to about 48, about 1 to about 24, about 1 to about 12, about 1 to about 6, or about 1 to about 5 hours).

[0223] In some embodiments, the batch is dried to a defined granule moisture level, e.g., the batch can be dried until at least about 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.50, 3.75, 4, 4.25, 4.5, 4.75, or 5 weight / weight (w / w)% dry loss (LoD) value is achieved. The useful range can be selected from any of these values, e.g., about 1 to about 5, about 1 to about 3, about 1.5 to about 5, about 1.5 to about 4, about 1.5 to about 3% w / w.

[0224] In some embodiments, the dried granules are sieved, for example, passed through a 14-mesh sieve.

[0225] The above parameter ranges apply when a Glatt GPCG1 fluid bed dryer is used. Those skilled in the art will understand that several other machines can be used and that the machine used will affect the above processing parameters. It will also be apparent to those skilled in the art that the above fluid bed dryer can only be used for small-scale production. A method for scaling up the granulation process including suitable machines will be apparent to those skilled in the art.

[0226] Subsequently, the obtained granules are tableted, for example, using any suitable tablet press. In some embodiments, the granules can be tableted using a single-pass press or a rotary tablet press.

[0227] In various embodiments, the matrix is packaged for use in an intraruminal device.

[0228] In some embodiments, at least one matrix is loaded into the intraruminal device. In some embodiments, at least one matrix can be manually loaded into the intraruminal device or the loading step can be automated and performed by one or more machines.

[0229] 4. Use of the Composition When at least one matrix and an intraruminal device are used together, they can deliver a therapeutically effective amount of an active ingredient, such as an anthelmintic, to a non-human animal, preferably a ruminant. The intraruminal device can deliver the active substance to the lumen by diffusing it through at least one outlet at one end of the intraruminal device.

[0230] In various embodiments, an intraluminal device containing one or more active ingredients is used to treat animals in need of the active ingredient. The suitability of the intraluminal device of the present invention for treating a particular disease or condition depends, for example, on the active ingredient present in the composition.

[0231] In various embodiments, an intraluminal device containing one or more active ingredients is used to improve productivity, for example, by improving growth and protein yield.

[0232] In various embodiments, an intraluminal device comprising one or more active ingredients is used to minimize the impact of production animals, such as ruminants, on the environment, for example, by reducing greenhouse gas emissions and / or nitrates.

[0233] The term "treatment", and related terms such as "treating" and "treat" as used herein, generally relate to the treatment of non-human animals to achieve one or more desired therapeutic effects. The therapeutic effect can be, for example, inhibition of the progression of a disease or condition, including reduction in the rate of progression, arrest of the rate of progression, improvement, and / or cure. Treatment as a preventive measure is also contemplated. Treatment can include combination therapy and treatment, which means that two or more treatments or therapies are used in combination, for example, sequentially or simultaneously.

[0234] In various embodiments, the present invention provides a method of treating a non-human animal, preferably a ruminant, in need of treatment, the method comprising administering a therapeutically effective amount of one or more active ingredients in the form of at least one matrix within the intraluminal device described herein.

[0235] One of ordinary skill in the art will be able to readily determine the appropriate dosage required to treat an animal suffering from one or more medical conditions and / or to prevent one or more medical conditions. The dosage will depend on the active ingredient(s) present in the composition and may also depend on the frequency of administration, the sex, age, weight and general condition of the animal being treated, the nature and severity of the medical condition being treated, any complications to be treated, and any other factors that will be apparent to one of ordinary skill in the art.

[0236] In some embodiments, the intraluminal device provides for the sustained release of one or more nutritional and / or pharmaceutically active ingredients over an extended period of time. In some embodiments, the one or more active ingredients can be delivered over a delivery period of about 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, or 150 days. A useful range can be selected from among these values, for example, from about 20 days to about 150 days, or from about 40 to 100 days.

[0237] In some embodiments, the composition provides for the sustained release of one or more nutritional or pharmaceutically active ingredient(s) over an extended period of time that is not affected by pH and ionic effects.

[0238] Although the invention and its advantages have been described in detail, it should be understood that various changes, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended claims.

[0239] The invention is further illustrated in the following examples, which are given by way of example only and are not intended to limit the invention in any way.

Examples

[0240] Example 1 - Preparation of a Polymer Containing Capsules Laboratory scale batches of the sample matrix were · 42% w / w of active ingredient (monensin sodium), and · 44% w / w of sucrose fatty acid ester, and · 1.5% w / w of magnesium stearate, and · 0.5% w / w of colloidal silicon dioxide, and · the polymer described in Table 1, and lactose monohydrate, and was manufactured containing them.

Table 1

[0241] The sucrose fatty acid ester, lactose, and polymer, which are the active ingredients, were granulated by spraying water onto the material in a fluidized bed dryer (Giatt GPCG1 fluidized bed granulator). To provide granules with the required attributes, the processing parameters such as wind speed, spray air pressure, and spray rate were adjusted. The wind speed was 5 - 40 Pa. The spray air pressure was between 2.0 - 4.0 bar. The spray rate was 20 - 40 g / min. The batch was dried to 34°C and passed through a 14 - mesh sieve.

[0242] The average particle size diameter, weight range, thickness range, and hardness range of the obtained matrix were summarized in Table 2.

[0243] In each case, the tablets were within the standard expected range, indicating that the tableting method was successful.

Table 2

[0244] Example 2 - In Vitro Capsule Test A custom - made 240L stainless - steel tank was used to evaluate the formulation. This model tests the sensitivity of the formulations described herein to changes in mineral concentration and / or ionic interactions.

[0245] The closed tank is thermostatically controlled up to 39 °C and is equipped with a piston. The piston drives a brush to rub against the outlet of the capsule in order to reproduce the physical wear of the tablet stack expected to occur in vivo. The capsule is placed within a stainless-steel housing unit, and every time (every 10 minutes) the brush passes under the capsule, approximately 3 mm of bristles from the brush pass through the outlet. The piston speed is adjusted so that the total travel time of the tank is 12 - 15 seconds. The tank is equipped with a pump so that the culture medium is constantly recirculated throughout the inspection.

[0246] The dispensing of the capsules was calculated by measuring the distance from the front of the outlet to the top of the plunger using a digital caliper. In this way, the capsules were rotated 180° and each capsule was measured twice, and the dispensing rate was calculated using the average value.

[0247] The capsules were tested in the tank using N = 6 repetitions. The batches were formulations containing a secondary gel-forming excipient, and two batches were used as comparator formulations assembled into the capsules (i.e., formulations containing a conventional gel-forming agent), and one batch contained a placebo matrix. The capsules were evenly dispersed throughout the tank along the tank, taking into account any variations due to the position of the capsules. All capsules contained 12 matrices and the outlets were attached as specified.

[0248] The capsules were first tested in drinking water until a linear profile was established. Thereafter, the calcium concentration in the tank was gradually increased every 3 - 4 days and the effect on capsule dynamics was measured. Table 3 shows a summary of the test information.

Table 3

[0249] Figures 1 and 2 show the release profiles of a placebo formulation (i.e., a control formulation containing a cross-linked anionic polymer, Carbomer® 971) and a formulation containing 6% Polyox 301, respectively. When these formulations are transferred from water to 9 mmol.L -1 calcium on day 10, it can be seen that the release rates from these formulations decrease. However, a further increase in calcium concentration has only a minimal effect on the release rates from these formulations. In fact, these formulations continue to release at the highest calcium levels tested.

Table 4

[0250] The results indicate that formulations containing the claimed polymer flowed linearly over a relatively wide range of calcium concentrations. The most significant change in release rate was observed when the capsules were exposed to 9 mmol.L -1 after being placed in water. However, further increasing the calcium concentration had no significant effect on the release rate. In vivo, calcium is always present in the lumen. Therefore, the decrease in release observed when water is changed to calcium could be an artifact that does not occur in vivo.

Claims

1. An intravaginal device comprising: a body substantially impermeable to vaginal fluid, the body comprising a barrel, at least one outlet, and at least one matrix within the barrel; a compression mechanism within the body adapted to urge a column of the matrix within the barrel toward the at least one outlet; at least one variable-profile device dependent on the body for assisting in the retention of the vagina; wherein the at least one matrix within the barrel comprises at least one active ingredient, at least one polymer, and sucrose fatty acid ester, and the at least one polymer is selected from: a) i) a non-ionic polyol polymer; ii) a non-ionic polyethylene oxide homopolymer; iii) a non-ionic polyethylene oxide homopolymer having a molecular weight in the range of 0.9 to 7 million; iv) a non-ionic polyethylene oxide homopolymer having a viscosity exceeding 7,500 cP; b) v) a cross-linked anionic polymer comprising a long-chain alkyl acid ester; vi) a cross-linked anionic polymer which is a block polymer of polyethylene glycol; vii) a cross-linked anionic polymer comprising an anionic poly(acrylic acid) interpolymer (copolymer); viii) a cross-linked anionic polymer comprising an acrylic acid interpolymer cross-linked with an allyl ester of a polyalcohol; ix) a cross-linked anionic polymer comprising a water-insoluble anionic acrylic acid interpolymer; x) a cross-linked anionic polymer comprising an anionic acrylic acid interpolymer having a viscosity exceeding 45,000 cP; or c) any combination of (i) to (x); an intravaginal device.

2. The intravaginal device according to claim 1, wherein the non-ionic polymer is a homopolymer.

3. The intravaginal device according to claim 1 or 2, wherein the non-ionic polymer is a polyethylene oxide polymer.

4. The intravaginal device according to claim 3, wherein the polyethylene oxide polymer has a molecular weight in the range of 800,000 to 7,250,000 g / mol L-1.

5. The intraruminal device according to claim 1, wherein the crosslinked anionic polymer contains less than 65% of monomers having free anionic groups as compared with the total number of monomers.

6. The intraruminal device according to any one of claims 1 to 5, wherein the crosslinked anionic polymer is polyacrylic acid or a polyacrylic acid derivative.

7. The intraruminal device according to any one of claims 1, 5 or 6, wherein the crosslinked anionic polymer is crosslinked with allyl sucrose or allyl pentaerythritol.

8. The intraruminal device according to any one of claims 1 or 5 to 7, wherein the crosslinked anionic polymer has a viscosity in the range of 40,000 to 67,000 cP.

9. The intraruminal device according to any one of claims 1 or 5 to 8, wherein the crosslinked anionic polymer contains a block copolymer of polyethylene glycol and a long-chain alkyl acid ester.

10. The intraruminal device according to any one of claims 1 to 9, wherein at least one active ingredient is selected from the group consisting of an antibiotic, an antifungal agent, an antiviral agent, a steroid hormone, an antihistamine, a metabolic regulator, a productivity regulator, a corticosteroid, an antithyroid agent, an anthelmintic, a non-steroidal anti-inflammatory agent, a nutritionally active substance, a rumen fermentation regulator, or a combination thereof.

11. The intraruminal device according to claim 10, wherein the anthelmintic is an anthelmintic selected from the group consisting of benzimidazole, imidazothiazole, tetrahydropyrimidine, macrocyclic lactone, salicylanilide, substituted phenol, aromatic amide, isoquinoline, aminoacetonitrile and spiroindole, or a combination thereof.

12. The intraruminal device according to claim 10, wherein the metabolic regulator is a rumen methane inhibitor / regulator.

13. A method for treating a ruminant in need of treatment, comprising administering the intraruminal device according to any one of claims 1 to 12 to the ruminant, the method being independent of the pH and ionic effects in the rumen of the ruminant.

14. Use of the intraruminal device according to any one of claims 1 to 12 for delivering at least one active ingredient at an effective concentration to a ruminant in need thereof, wherein the effective concentration is not affected by the pH and ionic effects in the rumen of the ruminant.

15. The use according to claim 14, wherein the effective concentration is not affected by pH and ionic effects resulting from changes in the diet of the ruminant.

16. A method of assembling an intraruminal device according to any one of claims 1 to 12, comprising: granulating a mixture comprising at least one active ingredient, at least one polymer selected from the group consisting of a nonionic polymer and a crosslinked anionic polymer, and optionally one or more excipients; drying the granules; passing the granules through a sieve; tableting the granules in at least one matrix; and loading the at least one matrix into the body of the intraruminal device.

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