Drug delivery vehicles, methods of making drug delivery vehicles, and methods of using drug delivery vehicles

Abstract

The present disclosure relates to a method of making a capsule, the method including providing a mold, depositing parylene onto the mold to form a parylene layer, scoring the parylene layer, and coating the parylene layer with a polymer to produce a capsule.

Description

[Technical field]

[0001] Technical Field

[0001] The present disclosure relates generally to drug delivery vehicles, methods of making drug delivery vehicles, and methods of using drug delivery vehicles to deliver drugs or other payloads to the body of a subject. More specifically, the present disclosure relates to ingestible drug delivery vehicles (e.g., capsules) for delivering a payload to a subject (e.g., to the inner wall of the subject's digestive tract). [Background technology]

[0002] 2. Background of the Invention

[0002] Drug delivery vehicles (e.g., capsules) are designed to deliver a payload (e.g., an active pharmaceutical ingredient (API) or a mechanical actuator) to a desired area of ​​the body. During delivery, the payload must remain stable to ensure efficacy and patient safety. Degradation of the payload can occur due to thermal degradation, oxidation, ultraviolet light, microorganisms, or hydrolysis. For example, the physical and chemical properties of pharmaceutical solid dosage forms can be affected by moisture.

[0003]

[0003] Moisture can affect the glass transition temperature of active pharmaceutical ingredients, thus affecting their stability. Many APIs and excipients are hygroscopic in nature and need to be protected from moisture. Specifically, moisture can significantly affect a wide range of chemical, physical and microbial properties of the final formulation, leading to degradation of the API and a concomitant loss of efficacy. Therefore, drug delivery vehicles containing such ingredients need to be designed to prevent degradation, as moisture affects the performance of some drugs.

[0004]

[0004] Despite the low moisture content of conventional hydroxypropyl methylcellulose capsules, there are still APIs that are highly hygroscopic and moisture sensitive. Such hygroscopic and moisture sensitive compounds can be challenging for compounders and can involve extra investments, as they need to apply different measures to protect the API, namely, galenic formulations such as pellet or capsule-in-capsule technology, a final additional drying process after filling, or the use of moisture-proof packaging materials. The possibility of drying the filled capsules to reduce the moisture content as much as possible exposes the entire filling to harsh drying conditions. Furthermore, adding an extra step to the post-filling process requires extra resources in terms of capacity and timing (due to dedicated equipment, rooms, manpower and conditions), extends the process, and therefore reduces the overall yield. Summary of the Invention [Problem to be solved by the invention]

[0005]

[0005] Therefore, there is a need for improved drug delivery vehicles that prevent the ingress of moisture and vapor. [Means for solving the problem]

[0006] Summary of the Invention

[0006] The present disclosure relates to capsules, enteric coatings for capsules, methods of making capsules, and methods of coating capsules. The capsules described herein prevent moisture and vapor ingress into the capsule during delivery of a payload. For example, the capsules can include a moisture barrier layer that prevents moisture from entering the capsule's internal volume until delivery in the digestive tract. The capsules described herein include an enteric coating that dissolves leaving little or no residue. The friability of the capsule's enteric coating advantageously allows a mechanical actuator to be effectively deployed from the capsule's internal volume.

[0007]

[0007] An embodiment of the present disclosure includes a method of producing a capsule. The method includes providing a mold, depositing parylene onto the mold to form a parylene layer, scoring the parylene layer, and coating the parylene layer with a polymer to produce a capsule. In some embodiments, the method includes polishing a surface of the mold to facilitate demolding of the capsule. In some embodiments, the method includes applying a release agent onto the mold prior to depositing the parylene layer. In some embodiments, the release agent is Micro90. In some embodiments, scoring the parylene layer includes scoring the parylene layer to form a pattern on both sides of the capsule. In some embodiments, the method includes treating an exterior surface of the parylene layer with oxygen plasma prior to coating with the polymer. In some embodiments, the parylene layer has a thickness in the range of 0.5 μm to 30 μm. In some embodiments, the parylene layer has a thickness in the range of 5 μm to 10 μm. In some embodiments, depositing the parylene layer includes chemical vapor deposition of parylene onto the mold. In some embodiments, depositing the parylene layer includes depositing parylene on the mold in a first deposition step to produce a primer layer, treating the primer layer with a release agent, and depositing parylene on the primer layer in a second deposition process to produce the parylene layer. In some embodiments, the polymer is polyvinyl alcohol. In some embodiments, coating the parylene layer with a polymer includes multiple coating processes. In some embodiments, the thickness of the polymer layer ranges from 100 μm to 250 μm. In some embodiments, the method further includes applying an enteric coating on the polymer layer. In some embodiments, the enteric coating includes an anionic methacrylic acid copolymer, talc, and a plasticizer. In some embodiments, the method further includes encapsulating the needle delivery system in a capsule.

[0008]

[0008] An embodiment of the present disclosure includes a capsule. The capsule includes a first layer comprising parylene. The capsule includes a second layer adjacent to the first layer. The second layer comprises a polymer. The coating includes a third layer adjacent to the second layer. The third layer comprises an enteric coating. In some embodiments, the first layer is scored. In some embodiments, the first layer is scored to form a bi-fold pattern on both sides of the capsule. In some embodiments, the parylene layer has a thickness ranging from 0.5 μm to 30 μm. In some embodiments, the second layer includes multiple layers, at least one of the multiple layers comprises polyvinyl alcohol. In some embodiments, the polymer comprises one or more of hydroxypropyl methylcellulose, pullulan, polyvinyl alcohol, or polyvinylpyrrolidone. In some embodiments, the second layer has a thickness of 100 μm to 250 μm. In some embodiments, the enteric coating includes an anionic methacrylic acid copolymer, talc, and a plasticizer. In some embodiments, the talc comprises 40% to 80% by weight of the enteric coating, based on the total weight of the enteric coating. In some embodiments, the anionic methacrylic acid copolymer comprises 20% to 60% by weight of the enteric coating, based on the total weight of the enteric coating. In some embodiments, the first layer is surface treated with oxygen plasma. In some embodiments, the capsule does not comprise pullulan or hydroxypropyl methylcellulose. In some embodiments, the capsule comprises a fourth layer comprising an anionic methacrylic acid copolymer and a plasticizer. In some embodiments, the polymer of the second layer comprises polyvinyl alcohol, the enteric coating comprises an anionic methacrylic acid copolymer, talc, and a plasticizer, and the fourth layer comprises an anionic methacrylic acid copolymer and a plasticizer.

[0009]

[0009] An embodiment of the present disclosure includes an enteric coating composition. The enteric coating composition can include an anionic methacrylic acid copolymer, talc, and a plasticizer. In some embodiments, the enteric coating composition includes 20% to 60% by weight of the anionic methacrylic acid copolymer, based on the total weight of the composition. In some embodiments, the enteric coating composition includes 40% to 80% by weight of the talc, based on the total weight of the composition. In some embodiments, the weight ratio of the talc to the anionic methacrylic acid copolymer ranges from 0.5:1 to 10:1. In some embodiments, the weight ratio of the talc to the anionic methacrylic acid copolymer ranges from 1:1 to 3:1. In some embodiments, the plasticizer is present in an amount of 5% to 25% by weight, based on the total weight of the anionic methacrylic acid copolymer. In some embodiments, the plasticizer is hydrophobic. In some embodiments, the plasticizer includes dibutyl sebacate. In some embodiments, a capsule includes the enteric coating composition described herein.

[0010]

[0010] An embodiment of the present disclosure includes a method of making a coating composition. The method includes providing a solvent including a plasticizer, adding an anionic methacrylic acid copolymer to the solvent, adding talc to the solvent, and mixing the anionic methacrylic acid copolymer and the talc in the solvent to make the coating composition. In some embodiments, the plasticizer is hydrophobic. In some embodiments, the plasticizer includes dibutyl sebacate. In some embodiments, the solvent includes one or more of acetone, isopropyl alcohol, and water. In some embodiments, the plasticizer is present in an amount of 5% to 25% by weight based on the weight of the anionic methacrylic acid copolymer. In some embodiments, the weight ratio of the talc to the anionic methacrylic acid copolymer ranges from 0.5:1 to 10:1. In some embodiments, the weight ratio of the talc to the anionic methacrylic acid copolymer ranges from 1:1 to 3:1. In some embodiments, providing the solvent includes mixing the plasticizer in the solvent before adding the enteric composition.

[0011]

[0011] An embodiment of the present disclosure includes a method of coating a capsule. The method includes providing an enteric solution including a solvent, a plasticizer, an anionic methacrylic acid copolymer, and talc, coating a capsule with the enteric solution, and drying the enteric solution on the capsule to provide an enteric coating. In some embodiments, coating the capsule includes dip-coating the capsule with the enteric solution. In some embodiments, the enteric coating includes 20% to 60% by weight of the anionic methacrylic acid copolymer based on the total weight of the enteric coating. In some embodiments, the enteric coating includes 40% to 80% by weight of the talc based on the total weight of the enteric coating. In some embodiments, the method includes overcoating the capsule with a second enteric solution including an anionic methacrylic acid copolymer and a plasticizer. In some embodiments, the method includes coating one or more additional polymer layers on the capsule. In some embodiments, drying the enteric solution on the capsule includes a first drying process comprising rotating the capsule in a rotisserie at ambient conditions, a second drying process comprising rotating the capsule in a rotisserie at ambient conditions using forced air, and a third drying process comprising drying the enteric solution in an oven.

[0012]

[0012] Further aspects, objects, and advantages will become apparent from consideration of the detailed description. [Brief description of the drawings]

[0013] BRIEF DESCRIPTION OF THE DRAWINGS [Figure 1]

[0013] A flow diagram of a method for producing a capsule according to some embodiments of the present disclosure is provided. [Figure 2A]

[0014] 1 illustrates a capsule according to some embodiments of the present disclosure. [Figure 2B]

[0015] 1 illustrates a capsule including a needle delivery system according to some embodiments of the present disclosure. [Figure 3A]

[0016] 1 illustrates an embodiment of an encapsulated scored parylene layer according to some embodiments of the present disclosure. [Figure 3B] 1 illustrates one embodiment of an encapsulated, scored parylene layer according to some embodiments of the present disclosure. [Figure 4]

[0017] 1 illustrates a cut pattern on a parylene layer of an capsule according to some embodiments of the present disclosure. [Diagram 5]

[0018] 1 provides a graph of polymer thickness of a capsule according to some embodiments of the present disclosure. [Figure 6A]

[0019] 1 illustrates the deployment of a microneedle system from a capsule according to some embodiments of the present disclosure. [Figure 6B]

[0019] Figure 1 illustrates the deployment of a microneedle system from a capsule according to some embodiments of the present disclosure. [Figure 6C]

[0019] Figure 1 illustrates the deployment of a microneedle system from a capsule according to some embodiments of the present disclosure. [Figure 7]

[0020] 1 provides a flow diagram of a method for coating a capsule with an enteric solution according to some embodiments of the present disclosure. [Figure 8A]

[0021] 1 illustrates a manufacturing process for producing capsules according to some embodiments of the present disclosure. [Figure 8B]

[0021] A manufacturing process for producing capsules according to some embodiments of the present disclosure is shown. [Figure 8C]

[0021] A manufacturing process for producing capsules according to some embodiments of the present disclosure is shown. [Figure 8D]

[0021] A manufacturing process for producing capsules according to some embodiments of the present disclosure is shown. [Figure 9]

[0022] Qualitative graphs of dissolution rate and gastroprotection of various HPMC capsules are provided. [Figure 10A]

[0023] 1 provides an image showing the remains of a capsule after dissolution according to some embodiments of the present disclosure. [Figure 10B]

[0023] Provides images showing capsule residue after dissolution according to some embodiments of the present disclosure. [Figure 10C]

[0023] Provides images showing capsule residue after dissolution according to some embodiments of the present disclosure. [Figure 10D]

[0023] Provides images showing capsule residue after dissolution according to some embodiments of the present disclosure. [Figure 10E]

[0023] Provides images showing capsule residue after dissolution according to some embodiments of the present disclosure. [Figure 10F]

[0023] Provides images showing capsule residue after dissolution according to some embodiments of the present disclosure. [Figure 10G]

[0023] Provides images showing capsule residue after dissolution according to some embodiments of the present disclosure. [Figure 10H]

[0023] Provides images showing capsule residue after dissolution according to some embodiments of the present disclosure. [Figure 11A]

[0024] 1 provides a visibility test showing moisture ingress into a capsule in simulated gastric fluid according to some embodiments of the present disclosure. [Figure 11B]

[0024] A visibility test showing moisture ingress into a capsule in artificial gastric fluid according to some embodiments of the present disclosure is provided. [Figure 11C]

[0024] A visibility test showing moisture ingress into a capsule in artificial gastric fluid according to some embodiments of the present disclosure is provided. [Figure 11D]

[0024] A visibility test showing moisture ingress into a capsule in artificial gastric fluid according to some embodiments of the present disclosure is provided. [Figure 11E]

[0024] A visibility test showing moisture ingress into a capsule in artificial gastric fluid according to some embodiments of the present disclosure is provided. [Figure 11F]

[0024] A visibility test showing moisture ingress into a capsule in artificial gastric fluid according to some embodiments of the present disclosure is provided. [Figure 12A]

[0025] 1 illustrates a process for making capsules by melting and reflowing a polymer according to some embodiments of the present disclosure. [Figure 12B]

[0025] A process for producing a capsule by melting and reflowing a polymer according to some embodiments of the present disclosure is shown. [Figure 12C]

[0025] A process for producing a capsule by melting and reflowing a polymer according to some embodiments of the present disclosure is shown. [Figure 12D]

[0025] A process for producing a capsule by melting and reflowing a polymer according to some embodiments of the present disclosure is shown. [Figure 12E]

[0025] A process for producing a capsule by melting and reflowing a polymer according to some embodiments of the present disclosure is shown. [Figure 12F]

[0025] A process for producing a capsule by melting and reflowing a polymer according to some embodiments of the present disclosure is shown. [Figure 13]

[0026] 1 provides a graph of coating thickness for capsules made from Kollicoat® IR and polyvinyl alcohol (PVA) according to some embodiments of the present disclosure. [Figure 14A]

[0027] 1 shows images of capsules made from Kollicoat® IR deposited on a parylene layer, according to some embodiments of the present disclosure. [Figure 14B]

[0027] Figure 1 shows images of capsules made from Kollicoat® IR without a parylene layer, according to some embodiments of the present disclosure. [Figure 15A]

[0028] 1 shows an image of a capsule including a Kollicoat® IR layer and a parylene layer prior to in vivo dissolution testing, according to some embodiments of the present disclosure. [Figure 15B]

[0028] Figure 1 shows images of capsules including a Kollicoat® IR layer and a parylene layer after in vivo dissolution testing according to some embodiments of the present disclosure. [Figure 15C]

[0028] Figure 1 shows images of capsules including a Kollicoat® IR layer and a parylene layer prior to in vivo dissolution testing according to some embodiments of the present disclosure. [Figure 15D]

[0028] Figure 1 shows images of capsules including a Kollicoat® IR layer and a parylene layer after in vivo dissolution testing according to some embodiments of the present disclosure. [Figure 16A]

[0029] 1 shows an image of a capsule including a pullulan layer prior to in vivo dissolution testing according to some embodiments of the present disclosure. [Figure 16B]

[0029] Figure 1 shows images of capsules including a pullulan layer after in vivo dissolution testing according to some embodiments of the present disclosure. [Figure 16C]

[0029] Figure 1 shows an image of a capsule including a pullulan layer prior to in vivo dissolution testing according to some embodiments of the present disclosure. [Figure 16D]

[0029] Figure 1 shows images of capsules including a pullulan layer after in vivo dissolution testing according to some embodiments of the present disclosure. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] Detailed Description of Specific Embodiments

[0030] Examples are described herein in the context of drug delivery vehicles as tablets or capsules. Those skilled in the art will appreciate that the following description is merely exemplary and is not intended to be limiting in any way. Reference will now be made in detail to example embodiments as illustrated in the accompanying drawings. Throughout the drawings and the following description, the same reference labels are used to refer to the same or similar items.

[0015]

[0031] For clarity, not all of the routine features of the examples described herein are shown and described, and it will, of course, be understood that in the development of any such actual implementation, numerous implementation-specific decisions must be made to achieve the developer's specific goals, such as compliance with application and business related constraints, and that these specific goals will vary from implementation to implementation or developer to developer.

[0016] I. Introduction

[0032] The present disclosure describes numerous embodiments related to capsules, coatings for capsules, methods of making capsules, and methods of coating capsules. In some embodiments, the present disclosure relates to ingestible capsules for delivering a payload to any portion of the inner wall of a subject's digestive tract. The capsules described herein prevent ingress of moisture and vapor into the capsule during delivery of the payload. For example, the capsules can include a moisture barrier layer (e.g., a parylene layer) that prevents moisture and vapor from entering the interior volume of the capsule until the payload is delivered in the digestive tract. The capsules described herein can also include an enteric coating that leaves little or no residue when it dissolves. The friability of the enteric coating of the capsule advantageously allows a mechanical actuator to be effectively deployed from the interior volume of the capsule.

[0017]

[0033] In some embodiments, the capsules described herein encapsulate a needle delivery system comprising microneedles. Microneedles are very small protrusions with micrometer dimensions and have the ability to deliver drugs, vaccines and other biomolecules to the skin. For example, the microneedles may be dissolving microneedles containing active pharmaceutical ingredients (APIs). This transdermal delivery platform has many advantages compared to traditional subcutaneous and intramuscular injections with needles and syringes. First, there is no or minimal pain, cross-infection and needlestick injury. Second, microneedles can be designed to target a certain layer of the skin. Third, there is the possibility of self-administration. Last but not least, it can be used in cases where there is a significant hepatic first-pass effect that may cause drugs to be metabolized prematurely. Microneedle arrays are usually made of silicon, metal and polymer. Among them, polymeric microneedle arrays are becoming increasingly attractive because they are expected to be less costly to mass-produce and safer during application than silicon or metal arrays. When soluble polymers are used, drugs and biomolecules can be incorporated within the microneedle itself. During application, the polymer structure dissolves rapidly within the skin, thereby releasing the drugs and biomolecules, thus eliminating sharps waste.

[0018]

[0034] Capsules are designed to deliver a payload to a certain area of ​​a subject. For example, the payload must maintain stability during delivery to the gastrointestinal tract to ensure efficacy and patient safety. The payload may be affected by moisture, which may adversely affect the physical and chemical properties of the payload. For example, a soluble microneedle containing an API must be protected from moisture during stomach passage in order to be deployed in the gastrointestinal tract.

[0019]

[0035] Commercially available capsules made from materials such as gelatin, hydroxypropyl methylcellulose (HPMC) and pullulan do not provide sufficient moisture barrier effect. Although these commercially available capsules may provide some moisture barrier effect, they are not effective in preventing vapor intrusion. Furthermore, commercially available capsules may gradually swell and disintegrate, which may impede the deployment of the payload (e.g., mechanical actuator) from the capsule. Therefore, improving the mechanical properties of the delivery vehicle (e.g., capsule) may be beneficial in terms of efficacy and design flexibility. Furthermore, commercially available enteric coatings provide some moisture barrier effect, but are insufficient for highly moisture-sensitive payloads. Also, commercially available enteric coatings gradually swell and disintegrate, which impedes the deployment of the payload in the capsule. In fact, these coatings leave residues, which may affect the delivery of the payload. For example, capsules containing needle delivery systems may require the capsule to be ruptured and penetrated to deploy the needle delivery system, which may be affected by the residues of the enteric coating.

[0020]

[0036] Various examples of the present disclosure relate to capsules that prevent moisture ingress and dissolve quickly with little or no residue. The capsules described herein prevent moisture and steam ingress into the capsule during delivery of the payload. For example, the capsules can include a parylene layer coated with a polymer (e.g., polyvinyl alcohol), which prevents moisture from entering the capsule's internal volume until delivery in the digestive tract. The capsules described herein can also include an enteric coating that leaves little or no residue when it dissolves. The friability of the capsule's enteric coating advantageously allows the payload (e.g., mechanical actuator) to be effectively deployed from the capsule's internal volume. In some embodiments, the capsules include a miniature needle delivery system that utilizes an outwardly expanding mechanical actuation to engage the needle with the inner wall of the digestive tract or other body lumen, for example, to facilitate delivery of a therapeutic agent or other payload through such engagement within the subject's body.

[0021] II. Method of Making Capsules

[0037] FIG. 1 provides a flow diagram of a method for manufacturing a capsule according to some embodiments. The method 100 can include providing a mold (110). The shape of the mold determines the size and shape of the capsule. The size and shape of the mold can be selected to provide a desired shape and volume for the capsule. For example, the mold can include a cylinder with hemispherical ends. In this embodiment, two cylinders with hemispherical ends are manufactured and bonded to form the capsule. In some embodiments, the mold is a finger mold that defines the dimensions of the capsule. In some embodiments, the mold includes a metal mold (e.g., a stainless steel mold) or a 3D printed mold. The mold can be coated with a release agent. The release agent prevents the capsule from sticking to the mold.

[0022]

[0038] In some embodiments, the mold can be a 3D printed mold. 3D printed molds have a higher surface roughness than metal molds (e.g., stainless steel), which can lead to problems with releasing the capsule from the mold. Due to the surface characteristics of the 3D printed mold, it may be necessary to polish the mold surface for uniform coating. In some embodiments, the method can include smoothing the 3D printed mold to reduce roughness. For example, the mold surface can be polished and cleaned to improve the release of the capsule from the mold. In some embodiments, the mold can be polished and coated with a release agent.

[0023]

[0039] The method 100 includes depositing 120 a parylene layer on the mold. The parylene layer can be coated or deposited on the mold. For example, the parylene layer can be deposited on the mold using chemical vapor deposition. The parylene layer can form an inner layer of the capsule that prevents moisture ingress into the capsule. In some embodiments, the mold is treated with a release agent prior to depositing the parylene layer. The release agent facilitates demolding after the capsule is fabricated on the mold. In some embodiments, the release agent can be Micro90. The parylene layer can be deposited on the mold one or more times to adjust the thickness of the parylene layer.

[0024]

[0040] In some embodiments, multiple parylene layers can be deposited on the mold. For example, the deposition step can include a first step including depositing a first parylene layer on the mold and a second step including depositing a second parylene layer on the first parylene layer. The outer surface of the first parylene layer (e.g., a primer layer) can be coated with a release agent before depositing the second parylene layer. In this embodiment, the first parylene layer serves as a release layer from the mold. The two-step deposition of parylene is particularly beneficial for 3D printing molds that may have rough surfaces. The rough surface of the 3D printing mold promotes adhesion of the first parylene layer. In some embodiments, the first parylene serves as a release layer and the second parylene layer serves as a moisture barrier layer. In some embodiments, metal molds may not utilize a two-step deposition step.

[0025]

[0041] The method 100 optionally includes scoring the parylene layer (130). After depositing the parylene layer on the mold, the parylene layer can be pre-scored in a desired pattern. The scored parylene layer allows the parylene layer to be more efficiently broken to release the payload (e.g., needle delivery system). In some embodiments, the parylene layer can be scored with a razor or laser cut into the score pattern. For example, the parylene layer can be scored on both sides of the capsule. The score lines in the parylene layer are beneficial for breaking the parylene layer when a mechanical actuator is delivered to the gastrointestinal tract. The parylene layer is mechanically strong, so without the score lines, the parylene layer may not break due to actuation forces.

[0026]

[0042] The method 100 includes treating (140) the outer surface of the parylene layer. For example, the parylene layer can be treated with an etching solution. In some embodiments, the surface of the parylene layer is treated with oxygen for plasma activation. Treating the surface of the parylene layer with oxygen plasma reverses the polarity of the plastic material (e.g., parylene), increasing the surface tension and allowing the polymer to receive new surface functionality by forming a very small contact angle on the surface of the treated material. This promotes adhesion with any coating on top of the parylene layer, resulting in good moisture barrier properties. Oxygen plasma activation can be performed on the surface of the parylene layer to promote good adhesion with a polymer coating (e.g., polyvinyl alcohol). The adhesion between the parylene layer and the polymer layer affects the moisture barrier properties of the capsule.

[0027]

[0043] The method 100 includes coating 150 the parylene layer with a polymer. For example, the parylene surface can be etched with a plasma and the etched surface of the parylene layer can be coated with a polymer. In some embodiments, the parylene layer is dip coated with a polymer solution. For example, the parylene layer can be dip coated with a solution including polyvinyl alcohol. In some embodiments, the mold is baked to dry the polymer coating on the parylene layer. The parylene layer can be coated multiple times with the polymer solution to adjust the coating thickness of the polymer layer. In some embodiments, the mold is dip coated at an elevated temperature to facilitate drying. The thickness of the polymer layer can be adjusted by the speed, viscosity and number of dips into the polymer solution.

[0028]

[0044] In some embodiments, the method can include coating the parylene layer with a first polymer solution (e.g., a polyvinyl alcohol solution) one or more times for a desired thickness of the first polymer layer. The mold can be baked after each coating of the first polymer solution to form a first polymer layer on the parylene layer. The method can include coating the first polymer layer with a second polymer solution (e.g., a polyvinylpyrrolidone solution) one or more times for a desired thickness of the second polymer layer. The mold can be baked after each coating of the second polymer solution to form a second polymer layer on the first polymer layer. In some embodiments, the capsule can include a parylene layer and a polyvinyl alcohol layer disposed on the parylene layer. In some embodiments, the capsule can include a parylene layer, a polyvinyl alcohol layer disposed on the parylene layer, and a polyvinylpyrrolidone layer disposed on the polyvinyl alcohol layer.

[0029]

[0045] In some embodiments, the polymer solution can include biodegradable and bioabsorbable polymers. In some embodiments, the polymer solution includes natural polymers such as arginine, chitosan, dextrin, polysaccharides, poly(glycolic acid), poly(lactic acid), and hyaluronic acid. In some embodiments, the polymer solution includes synthetic polymers such as poly(2-hydroxyethyl methacrylic acid), poly(N-isopropylacrylamide), poly(ethyleneimine), dendritic polymers, polyvinyl alcohol, or polyvinylpyrrolidone. In some embodiments, the polymer solution includes copolymers of polyvinyl alcohol and polyethylene glycol, such as Kollicoat IR®.

[0030]

[0046] To prevent the capsules from becoming over-dried and brittle from the multiple coating and baking processes, the method can include a rehydration step. In some embodiments, the mold can be rehydrated after multiple coating and baking steps to form the polymer layer. The rehydration step prevents the capsules from becoming over-dried and brittle. The rehydration step can include hydrating the capsules in a high humidity environment. In some embodiments, the capsules are rehydrated at a temperature of 10° C. to 40° C. with a relative humidity ranging from 50% to 95%. In some embodiments, the capsules are rehydrated at a temperature of about 25° C. with a relative humidity of about 80%. Rehydrating the capsules at high humidity can also soften the capsules for improved demolding. If the capsules become overly wet from the rehydration steps, they will lose their rigidity and become taut. Thus, the method can include baking the capsules to restore their structural integrity. For example, the baking step can allow the capsules to restore their mechanical structure. After the final baking step, the capsules can be removed from the mold. For example, a polymer layer is coated onto the parylene layer, and then the molded portion of the capsule is removed from the mold. In some embodiments, the capsule is coated with an additional polymer before demolding. For example, the capsule can be coated with one or more enteric coatings.

[0031]

[0047] In some embodiments, a method of making a capsule is provided. The method includes providing a mold. The method includes depositing parylene onto the mold to produce a parylene layer. The method includes scoring the parylene layer. The method includes activating a surface of the parylene layer with oxygen plasma. The method includes dip-coating the mold with a polymer solution and baking the dip-coated capsule to produce a polymer layer. In some embodiments, the polymer solution includes polyvinyl alcohol. In some embodiments, the method includes coating the parylene layer with a plurality of polymer coatings. The method may include coating the capsule with one or more enteric coatings.

[0032]

[0048] It should be understood that the specific steps shown in FIG. 1 provide a particular method of manufacturing a capsule according to some embodiments. Other sequences of steps may be performed according to alternative embodiments. For example, alternative embodiments of the present invention may perform the steps outlined above in a different order. Furthermore, each step shown in FIG. 1 may include multiple sub-steps that may be performed in various orders as appropriate for that individual step. Furthermore, additional steps may be added or removed depending on the particular application. Those skilled in the art will recognize many variations, modifications, and alternatives.

[0033]

[0049] In some embodiments, the method of making capsules can include melting and reflowing a polymer to produce one or more layers of the capsule. The melting and reflowing process can be used in combination with dip coating or can be used instead of dip coating. For example, a first layer of the capsule can be produced by dip coating into a polymer solution, and a second layer of the capsule can be produced by melting and reflowing the polymer (e.g., over the dip coated layer). The method can include melting and reflowing one or more polymers to produce one or more layers of the capsule. In some embodiments, melting and reflowing a polymer to produce a layer of the capsule is particularly suitable for producing thermoplastic capsule materials that are difficult to dissolve in water or solvents for dip coat applications. Furthermore, the method including melting and reflowing is a faster and more scalable process for high throughput production of capsules compared to dip coat capsules, since it can avoid the time-consuming drying process. In some embodiments, the material for producing capsules can include any thermoplastic polymer, blend of thermoplastic polymers, or blend of thermoplastic polymers with thermosetting materials suitable for capsules.

[0034]

[0050] In some embodiments, a method of making a capsule includes wrapping a polymer around a mandrel or mold to produce an assembly, inserting a portion of the assembly into heat shrink tubing, sealing ends of the assembly with fixtures to define an outer portion of the polymer layer, applying heat to the assembly to cause the polymer to melt and reflow to conform to the shape of the capsule and fixtures, withdrawing the mandrel and fixtures from each end of the molded capsule, removing the heat shrink wrap, and optionally trimming the capsule to a length. In some embodiments, the mandrel or mold is coated with a layer of parylene prior to wrapping the polymer around the mandrel or mold.

[0035]

[0051] 12A-12F illustrate an exemplary process for making a capsule including melting and reflowing a polymer to produce one or more layers according to some embodiments of the present disclosure. FIG. 12A illustrates a polymer film 1210 disposed on a mandrel 1220. The mandrel 1220 can include a parylene layer 1205. In some embodiments, the mandrel 1220 is coated with parylene to form the parylene layer 1205, for example, by chemical vapor deposition. The polymer film 1210 can be wrapped around the parylene layer 1205 and the mandrel 1220 to produce an assembly. The dimensions of the mandrel 1220 correspond to the internal volume of the resulting capsule. The shape of the mandrel 1220 determines the size and shape of the capsule. The size and shape of the mandrel 1220 can be selected to provide a desired shape and volume for the capsule. For example, the mandrel 1220 can include a cylinder with hemispherical ends. In this embodiment, two cylinders with hemispherical ends are produced and glued together to form a capsule.

[0036]

[0052] FIG. 12B shows a heat shrink tube 1230 disposed around the polymer film 1210. The heat shrink tube 1230 can be disposed around the outer surface of the polymer film 1210. A fixture 1240 can be inserted into one end of the assembly. The fixture 1240 can define the outer dimensions of the capsule (e.g., the hemispherical top of the capsule). The fixture 1240 closes the end of the assembly and defines a portion of the capsule's outer shape. For example, FIG. 12B shows a fixture 1240 with a concave end. The concave end can correspond to the dome-shaped end of the capsule. Heat can then be applied to the assembly to melt and reflow the polymer film 1210. The polymer film 1210 melts and fills the space between the mandrel 1220 and the fixture 1240. As shown in FIG. 12C, the polymer film 1210 conforms to the dimensions of the mandrel 1220 and the fixture 1240 to provide the shape of the capsule. For example, heat can be applied to the polymer film 1210 to melt the polymer, causing it to flow into the space between the mandrel 1220 and the fixture 1240. In this manner, the polymer conforms to the size and shape of the mandrel 1220 and fixture 1240.

[0037]

[0053] As shown in Figure 12D, the mandrel 1220 and fixtures 1240 can be removed from each end of the assembly after the polymer film 1210 has dried, resulting in a molded capsule 1250 with heat shrink tubing 1230. Figure 12E shows that the heat shrink tubing 1230 is removed from the polymer layer, resulting in the final capsule 1250 including the polymer layer 1210 and the parylene layer 1205. In some embodiments, the length of the capsule 1250 can be trimmed to provide the final length, as shown in Figure 12F.

[0038] III. Capsule Design

[0054] 2A and 2B show a capsule according to some embodiments of the present disclosure. In some embodiments, the capsule 200 can be manufactured by the methods described herein. The capsule 200 can include a first layer 210, a second layer 220, and a third layer 230. The capsule 200 can be shaped to accommodate a payload in an interior volume 240. For example, the capsule 200 can be cylindrical with hemispherical ends, as shown in FIG. 2A. The capsule 200 can also be spherical, rectangular, cylindrical, spherocylindrical, elliptical, or any combination thereof.

[0039]

[0055] The first layer 210 may be the innermost layer of the capsule 200. The first layer 210 may act as a moisture barrier layer to protect the contents within the interior volume 240 from the ingress of moisture and vapor. In some embodiments, the moisture barrier layer may include a polymer. For example, the first layer 210 may include a parylene layer. The first layer 210 may have a thickness that provides adequate moisture barrier while being thin enough to break during delivery of the payload. In some embodiments, the thickness of the first layer 210 may range from 0.5 microns to 30 microns, e.g., 1 micron to 25 microns, 2 microns to 20 microns, 3 microns to 15 microns, 4 microns to 12 microns, 5 microns to 10 microns, or 6 microns to 8 microns. In some embodiments, the thickness of the first layer 210 may range from 5 microns to 10 microns. It has been found that parylene layers having a thickness greater than 30 microns are too thick to break and parylene layers having a thickness less than 0.5 microns do not provide sufficient moisture barrier.

[0040]

[0056] In some embodiments, the first layer 210 is scored or pre-cut to form a break line. For example, the first layer 210 can be cut with a razor or laser cut. The first layer 210 can be pre-cut in a pattern that facilitates breakage by the payload within the capsule 200. As shown in FIGS. 3A and 3B, the parylene layer of the capsule is scored to form a break line. FIG. 3A shows a cut pattern including a first cut line 320A and a second cut line 330A on the parylene layer 310A of the capsule 300A. In this embodiment, the first cut line 320A and the second cut line 330A intersect at a tip of the parylene layer 310A of the capsule 300A (e.g., at a hemispherical end of the capsule). FIG. 3B shows an alternative cut pattern of the parylene layer 310B of the capsule 300B. The parylene layer 310B can include a first score line 320B along the longitudinal axis of the capsule 300B and a plurality of second score lines 330B that intersect the first score line 320B. FIG. 4 shows the parylene layer 410 of the capsule 400 scored in a lattice pattern 420. The parylene layer 410 can include a lattice pattern that is scored in multiple portions of the parylene layer 410. For example, the parylene layer 410 can include a lattice pattern 420 on both sides of the capsule 400. The score lines on the parylene layer can be selected to facilitate fracture based on the size, function, and properties of the payload.

[0041]

[0057] In some embodiments, the second layer 220 is disposed on the first layer 210. For example, the second layer 220 can be deposited or coated on the first layer 210. In some embodiments, the capsule 200 including the first layer 210 can be dip coated with a polymer solution to form the second layer 220. In some embodiments, the second layer 220 can include a polymer, collagen, a fatty acid, starch, gelatin, pullulan, or hydroxypropyl methylcellulose. In some embodiments, the polymer can be a biodegradable and bioabsorbable polymer. In some embodiments, the polymer includes natural polymers such as arginine, chitosan, dextrin, polysaccharides, poly(glycolic acid), poly(lactic acid), and hyaluronic acid. In some embodiments, the polymer includes synthetic polymers such as poly(2-hydroxyethyl methacrylic acid), poly(N-isopropylacrylamide), poly(ethyleneimine), dendritic polymers, polyvinyl alcohol, or polyvinylpyrrolidone.

[0042]

[0058] In some embodiments, the second layer 220 includes polyvinyl alcohol. The surface of the parylene layer that contacts the second layer 220 is treated prior to coating with polyvinyl alcohol. For example, the surface of the parylene layer can be treated with oxygen plasma to roughen the surface of the parylene layer and promote adhesion with polyvinyl alcohol.

[0043]

[0059] In embodiments in which the first layer 210 comprises parylene, the second layer 220 comprising polyvinyl alcohol was found to synergistically combine with the parylene to form a moisture barrier. Additionally, capsules comprising a first layer comprising parylene and a second layer comprising polyvinyl alcohol were found to have improved demolding characteristics. In particular, the mechanical toughness and ductility of the polyvinyl alcohol coated parylene was superior for removing the capsules from the mold without any breakage.

[0044]

[0060] 5 shows a graph of the thickness of the second layer 220 according to some embodiments. The graph shows a range of thicknesses for the polyvinyl alcohol layer. The thickness of the second layer 220 can range from 100 microns to 250 microns, e.g., 220 microns to 240 microns, 240 microns to 230 microns, 125 microns to 220 microns, 130 microns to 210 microns, 140 microns to 200 microns, 150 microns to 190 microns, or 160 microns to 180 microns. In some embodiments, the thickness of the second layer 220 can range from 150 microns to 190 microns.

[0045]

[0061] In some embodiments, the capsule 200 can include a third layer 230. The third layer can include an enteric coating. The enteric coating can include a polymer that prevents dissolution or disintegration in the stomach (e.g., in the gastric environment). The enteric coating can protect the payload in the internal volume 240 of the capsule 200 from the acid in the stomach. In some embodiments, the enteric coating can include an anionic methacrylic acid copolymer (e.g., EUDRAGIT® L 100-55) and a plasticizer. The plasticizer can be one or more of alkyl citrates, glycerin esters, alkyl phthalates, alkyl sebacates, sucrose esters, sorbitan esters, diethyl sebacate, dibutyl sebacate, propylene glycol and polyethylene glycol, triethyl citrate, acetyl triethyl citrate, diethyl sebacate, or dibutyl sebacate. In some embodiments, the plasticizer can be dibutyl sebacate.

[0046]

[0062] In some embodiments, the third layer 230 can include a first sublayer and a second sublayer. For example, the third layer can include a first sublayer including a polymer, talc, and a plasticizer, and a second sublayer including a polymer and a plasticizer. In some embodiments, the first sublayer includes an anionic methacrylic acid copolymer (e.g., EUDRAGIT® L 100-55), talc, and a plasticizer (e.g., dibutyl sebacate). In some embodiments, the second sublayer includes an anionic methacrylic acid copolymer (e.g., EUDRAGIT® L 100-55) and a plasticizer (e.g., dibutyl sebacate). The second sublayer can be coated over the first sublayer.

[0047]

[0063] The capsule 200 can include an internal volume 240 that receives a payload. In some embodiments, the payload can include an API, a mechanical actuator, a biomedical device (e.g., an implantable pulse generator), or a combination thereof. For example, FIG. 2B illustrates a capsule 200 that includes a mechanical actuator 250 as a payload. The mechanical actuator 250 can include a needle delivery system according to some embodiments of the present disclosure. In an illustrative example, a subject may wish to take a dose of an API or other compound without the need for injection with a syringe, the use of intravenous infusion, and the potential discomfort or other concerns associated therewith. To this end, the person can take a capsule according to the present disclosure to deliver a dose of the API or a needle system that includes the API. For example, the drug delivery vehicle can be in the form of a tablet or capsule that the subject can swallow. In some embodiments, the drug delivery vehicle can include components that can be deployed within the body to effectively provide an internal injection, which causes much less tissue damage and has less systemic impact compared to an external injection or infusion. When the drug delivery vehicle reaches the target portion of the gastrointestinal tract (such as the duodenum), the special coating on the tablet or capsule dissolves or breaks apart sufficiently to allow a mechanical actuator within the tablet to expand outward.

[0048]

[0064] In use, capsule 200 can travel to a target portion of the GI tract (such as the duodenum) where the capsule coating dissolves or degrades sufficiently to break apart and allow a mechanical actuator within the capsule to expand outward. The outwardly expanding mechanical actuator can employ a variety of options, such as a stent-like tube that expands vertically or radially, an uncoiling coil, a set of curved arms that unfold, a set of double-hinged arms that splay out against a central hub and then splay out again against a portion connected to the hub, or a scissor-lift-like arrangement with centrally hinged side posts that lift vertically from a compressed state to an expanded state, with portions of the posts hinged to each other.

[0049]

[0065] FIG. 2B shows a plurality of arrays of microneedles arranged around a mechanical actuator. The plurality of arrays of microneedles can be actuated by expanding outward to engage with surrounding tissue (e.g., tissue of the mucosal lining of the duodenum). A drug dose can be delivered to the tissue through the engaged microneedles, by flowing through the microneedles if they are hollow, or by direct absorption if the drug is embedded in the soluble composition of the microneedles (FIG. 6C). After delivery of the dose, the components of the device can biodegrade, avoiding potential complications from trying to expel the remains of the device from the body. Thus, a subject can use the device to administer an internal injection that may ultimately be less invasive, less difficult, and / or less bothersome to the subject than alternatives that use external syringes or intravenous infusions.

[0050] IV. Methods of Delivering the Capsules to the Gastrointestinal Tract

[0066] 6A-6C illustrate a method of using a capsule to deliver a payload to a target area of ​​a subject, according to some embodiments of the present disclosure. In this embodiment, a mechanical actuator is deployed from the capsule, however, the capsule is effective to deliver any payload described herein. FIG. 6A illustrates a capsule 610 moving through a portion of the GI tract 650. The capsule 610 can include multiple layers. In some embodiments, the capsule includes an innermost layer including parylene, a polymeric layer disposed on the innermost layer, and an enteric coating disposed on the polymeric layer. The polymeric layer can include polyvinyl alcohol, and the enteric coating can include an anionic methacrylic acid copolymer (e.g., EUDRAGIT® L 100-55), talc, and a plasticizer. In some embodiments, an overcoat can be applied to the enteric coating layer including the anionic methacrylic acid copolymer (e.g., EUDRAGIT® L 100-55) and a plasticizer. The polymeric layer and the enteric coating can be tailored to a predetermined thickness for deployment in a predetermined region of the GI tract.

[0051]

[0067] In some embodiments, the capsule 610 can include a parylene layer, one or more polymer layers, and optionally one or more enteric coatings. For example, the capsule can include an inner layer including parylene, a second layer including polyvinyl alcohol, a third layer including polyvinylpyrrolidone, and an enteric coating. Polyvinyl alcohol is water soluble, but polyvinylpyrrolidone dissolves faster than polyvinyl alcohol. However, combining a parylene layer with a polyvinyl alcohol layer provides the best release from the mold. This is because polyvinyl alcohol is mechanically tough and flexible, so it does not break when lifted from the mold. The parylene layer is very brittle with other materials, so the selection of the base capsule material is important for good release from the mold. As mentioned above, the capsules described herein include a housing including an inner layer including parylene and an outer layer including a polymer. The parylene inner layer provides a moisture barrier, thereby protecting the contents of the drug delivery vehicle.

[0052]

[0068] 6B shows the payload 620 deployed from the capsule 610. The capsule 610 releases the payload 620 after being transported to the intestine without releasing the payload in the highly acidic environment of the stomach. The capsule 610 protects the payload from stomach acid or gastric enzymes or releases the payload 620 with use during the period the capsule is transported from the stomach to the small intestine. In some embodiments, the payload 620 can include a mechanical actuator 625 within the interior volume of the capsule 610. The mechanical actuator 625 can include a needle delivery system including a plurality of microneedles 630. The microneedles 630 can include an active pharmaceutical ingredient.

[0053]

[0069] As shown in FIG. 6C, the mechanical actuator 625 can deploy microneedles 630 into the gastrointestinal lining. The microneedles 630 penetrate the gastrointestinal lining 640 to deliver the active pharmaceutical ingredient into the digestive tract. In some embodiments, the microneedles 630 are dissolving microneedles that contain a biological agent. The microneedles 630 can dissolve and release the biological agent after penetrating the digestive tract, as shown in FIG. 6C.

[0054] V. Enteric Coating

[0070] The present disclosure provides an enteric coating composition comprising a polymer, talc and a plasticizer. For example, the enteric coating can comprise EUDRAGIT® L 100-55 (polymer), talc and dibutyl sebacate (plasticizer). The enteric coatings described herein are designed to remain intact in the stomach and dissolve in the digestive tract (e.g., intestine). The enteric coatings can be applied to solid dosage forms such as granules, pellets, capsules or tablets. The enteric coatings improve the bioavailability of drugs by protecting the payload in the capsule from gastric acid in the stomach and preventing the degradation of drugs that are unstable to acid or gastric enzymes. The enteric coatings described herein resist disintegration or dissolution in the stomach, dissolve or disintegrate rapidly in the small intestine, remain physically and chemically stable during storage, and are easily applied as coatings.

[0055]

[0071] Additionally, the enteric coatings described herein beneficially prevent moisture and vapor ingress into the drug delivery vehicle (e.g., capsule). The talc in the enteric coating results in an enteric coating layer that is easy to friable. Due to the friability of the enteric coating, the enteric coating dissolves quickly and surprisingly leaves no residue after dissolution. This is particularly advantageous for payloads that include mechanical actuators, since the enteric coating does not impede the deployment of the mechanical actuator.

[0056]

[0072] In some embodiments, the enteric coating comprises a copolymer. The copolymer can be an anionic methacrylic acid copolymer polymerized from 40-60% by weight methacrylic acid and 60-40% by weight methyl methacrylate or 60-40% by weight ethyl acrylate. For example, the copolymer can be polymerized from 50% by weight ethyl acrylate and 50% by weight methacrylic acid. Commercially available anionic methacrylic acid copolymers that can be used in the enteric coating compositions described herein can include EUDRAGIT® L 100-55 or EUDRAGIT® L (available from Evonik Industries, Essen, Germany).

[0057]

[0073] In some embodiments, the anionic methacrylic acid copolymer can be present in the enteric coating in an amount ranging from 20% to 60% by weight, based on the total weight of the enteric coating. For example, the anionic methacrylic acid copolymer can be present in the enteric coating in an amount ranging from 25% to 55%, 30% to 55%, 30% to 40%, 35% to 55%, 35% to 50%, 35% to 45%, or 40% to 50% by weight, based on the total weight of the enteric coating.

[0058]

[0074] In some embodiments, talc can be present in the enteric coating in an amount ranging from 40% to 80% by weight, based on the total weight of the enteric coating. For example, talc can be present in the enteric coating in an amount ranging from 45% to 80% by weight, 45% to 75% by weight, 50% to 75% by weight, 50% to 70% by weight, 55% to 65% by weight, or 60% to 70% by weight, based on the total weight of the enteric coating. It has been found that the addition of talc improves the friability of the enteric coating. However, talc is insoluble in water, making the enteric coating more brittle. If talc is included in the enteric composition in an amount greater than 80% by weight, the enteric coating becomes very brittle. If talc is included in the enteric coating in an amount less than 40% by weight, the enteric coating does not achieve sufficient friability. An enteric coating containing talc in an amount ranging from 40% to 80% by weight, based on the total weight of the enteric coating, provides a balance of friability and ductility of the enteric coating.

[0059]

[0075] The ratio of talc to anionic methacrylic acid copolymer in the enteric coating can be in the range of 0.5:1 to 10:1, for example, 1:1 to 8:1, 1.25:1 to 6:1, 1.5:1 to 4:1, 1:1 to 3:1, 1:1 to 2:1, or 1.25:1 to 1.75:1. In some embodiments, the ratio of talc to anionic methacrylic acid copolymer is 1.5:1. Combining talc with anionic methacrylic acid copolymer results in a layer that is easy to friable. Advantageously, enteric coatings comprising anionic methacrylic acid copolymer and talc dissolve quickly and leave little or no residue. The dissolution characteristics and minimal amount of residue advantageously do not impede the deployment of the payload in the capsule.

[0060]

[0076] In some embodiments, the plasticizer can be present in the enteric coating in an amount ranging from 5% to 25% by weight based on the total weight of the polymer (e.g., anionic methacrylic acid copolymer). For example, the plasticizer can be present in the enteric coating in an amount ranging from 5% to 20% by weight, 5% to 15% by weight, 5% to 10% by weight, 10% to 20% by weight, or 10% to 15% by weight based on the total weight of the polymer. The plasticizer can be hydrophobic. In some embodiments, the plasticizer comprises dibutyl sebacate.

[0061]

[0077] The enteric coating composition (e.g., polymer, talc, and plasticizer) can be provided in a solvent mixture to produce an enteric coating solution. The drug delivery vehicle can be coated with the enteric coating solution and dried to produce an enteric coating layer. The solvent can include one or more of acetone, isopropyl alcohol, and water. The solvent mixture can include a solids (e.g., polymer) content of 20% to 50% by weight, for example, 20% to 45% by weight, 20% to 40% by weight, 25% to 40% by weight, 30% to 40% by weight, or 30% to 35% by weight. For example, the solids in the solvent mixture can include a polymer, talc, and a plasticizer.

[0062]

[0078] In some embodiments, the present disclosure provides a method of making an enteric coating composition. The method of making a coating composition can include providing a solvent. The solvent can include water, acetone, and isopropyl alcohol. In some embodiments, the solvent can include a plasticizer. The plasticizer can be added to the solvent. For example, the plasticizer can be mixed into the solvent mixture. The method includes adding an anionic methacrylic acid copolymer and talc to the solvent to produce a coating composition. In some examples, the anionic methacrylic acid copolymer and talc can be mixed together before adding these components to the solvent. For example, the anionic methacrylic acid copolymer and talc can be mixed in a solvent (e.g., water, acetone, and / or isopropyl alcohol) and then added to a solvent containing a plasticizer. The enteric coating composition described herein can be coated onto a drug delivery vehicle (e.g., a capsule).

[0063] VI. Methods of Coating Capsules with Enteric Coatings

[0079] According to some embodiments, the present disclosure provides a method of coating a capsule with an enteric coating. The method includes coating a capsule with an enteric solution to produce a first enteric coating layer. The first enteric coating layer can include an anionic methacrylic acid copolymer (e.g., EUDRAGIT® L 100-55), talc, and a plasticizer. In some embodiments, the method can also include coating the first enteric coating layer with a second enteric coating layer. For example, the second enteric coating layer can include an anionic methacrylic acid copolymer (e.g., EUDRAGIT® L 100-55) and a plasticizer. The second enteric coating layer can be disposed on top of the first enteric coating layer to keep the first enteric coating intact. In particular, the first enteric coating layer is prone to fracturing due to the presence of talc, and the second enteric coating layer can provide rigidity to the first enteric coating layer. In some embodiments, the enteric coated capsule can contain a payload (eg, a needle delivery system containing a therapeutic agent).

[0064]

[0080] FIG. 7 provides a flow diagram of a method of coating a capsule with an enteric coating according to some embodiments of the present disclosure. The method 700 includes providing (710) a capsule. The capsule can be any capsule for delivering a payload. For example, the capsule can include a polymer, collagen, a fatty acid, starch, gelatin, pullulan, or hydroxypropyl methylcellulose. In some embodiments, the capsule can include a first layer including parylene and a second layer including a polymer as described herein. For example, the capsule can include a polyvinyl alcohol layer coated over a parylene layer. The parylene layer can include a score pattern that provides a break line for the payload. For example, the payload can include a mechanical actuator. The mechanical actuator can be deployed from the capsule by breaking the score line in the parylene layer.

[0065]

[0081] The method 700 can include coating the capsule with an enteric solution (720). In some embodiments, coating the capsule with the enteric solution can include dip-coating the capsule with the enteric solution. The enteric solution includes a solvent, an anionic methacrylic acid copolymer, talc, and a plasticizer. In some embodiments, the anionic methacrylic acid copolymer can be EUDRAGIT® L 100-55. The enteric composition can include talc and an anionic methacrylic acid copolymer in a ratio of 0.5:1 to 10:1. The enteric composition can be provided in a solvent to form the enteric solution. For example, an enteric composition including talc and an anionic methacrylic acid copolymer can be mixed in a ratio described herein and then added to a solvent to form the enteric solution.

[0066]

[0082] The method 700 includes drying the enteric solution to produce a first enteric coating (730). Drying conditions for the first enteric coating are controlled to provide a uniform enteric coating without air bubbles. The drying conditions are important to suppress air bubbles in the enteric coating layer to provide a high quality enteric coating. The capsules coated with the enteric solution can be partially dried in a rotisserie and then dried in an oven to form the enteric coating. The rotisserie is configured to rotate the capsules to homogenize the enteric solution and provide a uniform thickness to the enteric coating.

[0067]

[0083] In some embodiments, drying the enteric solution to produce the first enteric coating comprises multiple steps. For example, the drying steps can include a first drying step including drying the enteric coating in a rotisserie at ambient conditions without forced air, a second drying step including drying the enteric coating in a rotisserie at ambient conditions with forced air, and a third drying step including drying the enteric coating at elevated temperatures in an oven. The first drying step can be ambient drying of the enteric coating without forced air (e.g., without a fan). The second drying process can be ambient drying of the enteric coating with forced air (e.g., with a fan). The first and second drying processes can be partial drying processes. It has been found that insufficient partial drying prior to thermal drying (e.g., heated forced air) and / or sudden exposure to high drying temperatures in an oven can result in the enteric coating having air bubbles and reduced quality.

[0068]

[0084] In some embodiments, the drying step can include rotating the capsules in a rotisserie at ambient conditions for a period of time (e.g., 30 seconds to 5 minutes), followed by rotating the capsules in a rotisserie at ambient conditions with forced air for a period of time (e.g., 30 seconds to 5 minutes). The capsules can then be heated in an oven to thoroughly dry the enteric coating on the capsules. In some embodiments, the forced air can be heated air or ambient air supplied by a fan. The enteric coating and drying process can be repeated multiple times to adjust the thickness of the enteric coating. For example, the capsules can be coated with an enteric solution and heated in a rotisserie to provide multiple coats of enteric coating.

[0069]

[0085] The method 700 includes coating the enteric coated capsule with a polymer solution (740). The polymer solution can be a second enteric solution. For example, the second enteric solution can include an anionic methacrylic acid copolymer (e.g., EUDRAGIT® L 100-55) and a plasticizer. In some embodiments, the plasticizer can be one or more of alkyl citrates, glycerin esters, alkyl phthalates, alkyl sebacates, sucrose esters, sorbitan esters, diethyl sebacate, dibutyl sebacate, propylene glycol and polyethylene glycol, triethyl citrate, acetyl triethyl citrate, diethyl sebacate and dibutyl sebacate. The plasticizer can be present in an amount ranging from 10-60% (e.g., 10-60%, 20-60%, 25-55%, 30-50%, 30-60%, or 40-60%) by weight based on the total weight of the polymer. For example, the plasticizer can be present in a concentration of about 10%, 20%, 30%, 40%, 50%, or 60% by weight based on the total weight of the polymer. The method 700 includes drying (750) the polymer solution to form a second enteric coating.

[0070]

[0086] 8A-8D show a manufacturing process for producing an enteric coated capsule according to some embodiments. FIG. 8A shows a capsule including a polyvinyl alcohol layer coated over a parylene layer. The parylene layer includes a score pattern that provides a break line for a payload. For example, the capsule can include a mechanical actuator as a payload. The mechanical actuator can be deployed from the capsule by breaking the score lines in the parylene layer.

[0071]

[0087] 8B illustrates a process of coating a capsule with an enteric solution. The enteric solution can include a solvent, a polymer, talc, a plasticizer, and water. In some embodiments, the polymer includes an anionic methacrylic acid copolymer (e.g., EUDRAGIT® L 100-55). The anionic methacrylic acid copolymer and the talc can be mixed in a ratio described herein and then added to the solvent. In some embodiments, coating the capsule with the enteric solution can include dip coating the capsule with the enteric solution.

[0072]

[0088] The capsules coated with the enteric solution can be dried in a rotisserie, as shown in FIG. 8. The rotisserie is configured to rotate the capsules to homogenize the enteric solution and provide a uniform thickness to the enteric coating. In some embodiments, forming the enteric coated capsules can include dip coating the capsules with the enteric solution, partially drying the enteric solution in the rotisserie at ambient conditions for a period of time (e.g., 30 seconds to 5 minutes), partially drying the enteric solution in the rotisserie at ambient conditions for a period of time (e.g., 30 seconds to 5 minutes) using forced air, and final drying the enteric solution at elevated temperature in an oven. In some embodiments, the forced air can be provided by a fan. The enteric coating and drying processes can be repeated multiple times to adjust the thickness of the enteric coating.

[0073]

[0089] The drying process advantageously prevents air bubble formation in the enteric coating layer. In conventional processes, the evaporation of the solvent in the enteric solution is faster than the evaporation of the water, which results in air bubbles being trapped in the enteric coating layer. Beneficially, the rotisserie homogenizes the enteric coating, providing a coating of uniform thickness without any air bubbles. In some embodiments, the drying process in the rotisserie includes partially drying the enteric solution, including a first step of rotating the capsule at ambient conditions, followed by a second step of rotating the capsule while applying forced air. In some embodiments, the process can include overcoating the enteric coating with another polymer. For example, the enteric coating can be coated with another enteric coating that includes an anionic methacrylic acid copolymer (e.g., EUDRAGIT® L 100-55) and a plasticizer.

[0074]

[0090] FIG. 8C illustrates the process of applying a belt to a capsule. The capsule may include two different molded components that form the capsule. A belt portion may be provided at the open end of the capsule to ensure proper joining of the two molded components that form the capsule. For example, FIG. 8C illustrates a polyvinyl alcohol belt attached (e.g., glued) to the open end of the capsule. This belt assists in butt jointing and tying. As shown in FIG. 8D, the butt joint may be sealed with an enteric coating that includes an anionic methacrylic acid copolymer and talc. In some embodiments, an enteric overcoat may be applied to the butt joint. The overcoat may include an anionic methacrylic acid copolymer and a plasticizer. The final capsule may include a scored parylene layer, a polyvinyl alcohol layer, a first enteric coating that includes an anionic methacrylic acid copolymer, talc, and a plasticizer, and a second enteric coating that includes an anionic methacrylic acid copolymer and a plasticizer. In some embodiments, the anionic methacrylic acid copolymer is EUDRAGIT® L 100-55. The joint between the two portions of the capsule can be adhered using any of the enteric coating combinations described above.

[0075]

[0091] In some embodiments, the method of coating a capsule includes providing a base capsule and coating the base capsule with an enteric solution. In some embodiments, the base capsule is dip coated with the enteric solution. The method includes drying the enteric solution on the base capsule as described herein. In some embodiments, the capsule is partially dried in a rotisserie and then dried in an oven. For example, the base capsule coated with the enteric solution is rotated while applying heat or forced air to the capsule. In some embodiments, forced air is provided to the rotisserie to facilitate drying. In some embodiments, the method includes multiple coating and drying steps to build and control the thickness of the enteric coating. The method includes overcoating the enteric coating of the capsule with a second enteric coating. For example, the base capsule can be coated with a second enteric coating comprising an anionic methacrylic acid copolymer (e.g., EUDRAGIT® L 100-55) and a plasticizer.

[0076]

[0092] In some embodiments, the enteric composition comprises talc and an anionic methacrylic acid copolymer (e.g., EUDRAGIT® L 100-55) in a 60:40 ratio. The enteric composition can be a dry powder that is added to a solvent to provide an enteric solution. Adding more talc to the enteric composition improves friability, but talc is insoluble in water, making the enteric coating more brittle. The dry enteric coating comprises talc embedded in an anionic methacrylic acid copolymer and a plasticizer. In some embodiments, an additional enteric layer (e.g., an overcoat) comprising an anionic methacrylic acid copolymer is coated over the enteric coating. EXAMPLES

[0077] VII. Examples Dissolution rate and gastroprotection of HPMC capsules

[0093] Sample capsules were tested to determine the moisture ingress and dissolution characteristics of the HPMC capsules. Specifically, immersion tests in simulated gastric fluid (SGF) were performed to understand moisture ingress (the enteric layer must protect the base capsule from dissolution in an acidic environment so that the enteric coating remains intact), and dissolution tests in simulated intestinal fluid (SIF) or phosphate buffered saline (PBS) were performed to understand the dissolution rate of the enteric coated capsules and the residue from the dissolved capsules. Table 1 provides the sample capsule compositions of Comparative Examples 1-5. Each of the sample capsules contained HPMC as the base capsule material.

[0078] [Table 1]

[0079]

[0094] FIG. 9 provides a qualitative analysis of capsule designs with respect to moisture barrier effect and dissolution rate. For example, FIG. 9 shows the effect of enteric coating layer thickness, plasticizer, and parylene on moisture barrier effect and dissolution rate. As shown in FIG. 9, Comparative Examples 1-5 did not achieve a good combination of rapid dissolution without excessive residue and gastric protection. For example, Comparative Examples 1, 2, and 4 did not achieve rapid dissolution and left substantial residue. In fact, Comparative Example 4 left enough residue to prevent the mechanical actuator in the HPMC capsule from deploying. The modified capsules of Comparative Examples 3 and 5 provided good dissolution rates but did not provide sufficient gastric protection (e.g., moisture intrusion). Thus, capsules with HPMC as the base capsule material did not provide good properties for delivering payloads to the gastrointestinal tract.

[0080] Capsule dissolution rate and residue testing

[0095] Figures 10A-10H provide dissolution tests of different base capsule materials in simulated intestinal fluid at fixed time points. Specifically, Figures 10A-10D show the dissolution rate of polyvinyl alcohol capsules, and Figures 10E-10H show the dissolution rate of HPMC capsules. The dissolution rates of the capsules are shown with timestamps of before dissolution (Figures 10A and 10E), 3.67 minutes (Figures 10B and 10F), 4.5 minutes (Figures 10C and 10G), and 8.0 minutes (Figures 10D and 10H). The tests show how long it takes each base capsule to dissolve and how much residue remains. As shown in Figures 10A-10D, the polyvinyl alcohol capsule dissolved in approximately 4 minutes and 30 seconds, and the mechanical actuator could be deployed from the capsule. There was minimal residue from the polyvinyl alcohol capsule. In contrast, Figures 10E-10H show that the HPMC capsule took approximately twice as long to dissolve (i.e., 8 minutes) and left a substantial residue. The HPMC capsule swells and remains on the mechanical actuator, thus affecting deployment. The residue may block or impede deployment of the payload from the HPMC capsule. For example, the residue may impede deployment of a needle delivery system in the intestine. The needle may become embedded in the capsule residue and not be able to penetrate deep enough into the intestinal tissue (e.g., to the submucosa) to deliver the therapeutic agent.

[0081] Moisture-proof properties of capsules

[0096] The moisture barrier properties of capsules containing different materials were tested in an immersion test to determine the amount of moisture that entered the capsule. Figures 11A and 11B provide capsules made from pullulan, Figures 11C and 11D provide capsules made from HPMC, and Figures 11E and 11F provide capsules made from HPMC with an inner layer containing parylene. The inner layer of Example 3 included a 1.3 micron membrane of parylene. Examples 1-3 each included a moisture indicator in the capsule, as shown in Figures 11A-11F. Figures 11A-11F provide images of capsules before immersion, including Example 1 (pullulan, Figure 11A), Example 2 (HPMC, Figure 11C), and Example 3 (HPMC with an inner layer containing parylene, Figure 11C). The inner layer of Example 3 includes a 1.3 micron membrane of parylene. Each of the capsules includes an outer layer containing Eudragit. Each moisture indicator square is marked with a corresponding relative humidity value (20, 40, 60, 80% RH). Below the marked relative humidity the square remains blue and above the marked relative humidity it fades to pink.

[0082]

[0097] The capsules were immersed in artificial gastric juice for 1 hour. Visibility tests are shown in Figure 11B, Figure 11D, and Figure 11F. As shown in Figure 11B, Figure 11D, and Figure 11F, the inner layer containing parylene substantially reduced moisture and vapor intrusion compared to the commercial capsules containing only pullulan or HPMC. In Figure 11E (before immersion) and Figure 11F (after immersion), after 1 hour of gastric immersion, the humidity inside the capsule reached 40-60% (the 60% square remains blue). In other words, if the capsule had a parylene coating as a moisture barrier, the humidity inside the capsule remained below 60% RH after 1 hour of gastric immersion.

[0083] Capsules containing Kollicoat® IR

[0098] Sample capsules were produced to determine the properties of Kollicoat® IR for producing one or more layers of capsules. FIG. 13 shows the thickness of Kollicoat® IR capsules compared to PVA capsules. Capsules produced from Kollicoat® IR showed a more uniform coating thickness than PVA capsules. Specifically, Kollicoat® IR had a narrower thickness window than capsules produced from PVA. Kollicoat® IR has a lower viscosity than PVA, which allows for a more uniform coating thickness due to less overflow during the curing process. This results in capsules with a precise and controlled coating thickness. For capsules containing a layer of Kollicoat® IR, an additional coating process (e.g., dipping into a polymer solution) was required to reach a similar thickness to the PVA capsules. As shown in FIG. 13, the thickness of the body and cap of the capsules produced from Kollicoat® IR was less than that of the capsules produced from PVA with the same number of coatings, but showed improved uniformity.

[0084]

[0099] FIG. 14A shows an image of a Kollicoat® IR capsule coated on a parylene layer, and FIG. 14B shows an image of a Kollicoat® IR capsule without a parylene layer. Each of the capsules shown in FIG. 14A and FIG. 14B was manufactured to produce a Kollicoat® layer by dip coating and had a thickness of 0.14-0.17 mm. Each of the capsules was scored for release. The Kollicoat® IR capsules showed adequate wetting and adhesion on the micro-90 treated rods. The Kollicoat® IR capsule without parylene (FIG. 14B) showed cracks and wrinkles along the score line. For example, FIG. 14B shows that wrinkles were observed in the Kollicoat® IR capsule manufactured without a parylene layer. FIG. 14A shows that no wrinkles were observed in the Kollicoat® IR coated on a parylene layer. The Kollicoat® IR polymer showed good adhesion to the parylene layer and also had good mechanical robustness.

[0085]

[0100] Sample capsules were tested to determine the dissolution characteristics of Kollicoat® IR capsules. Specifically, in vivo dissolution tests were performed in pig intestines to examine the dissolution rate of capsules containing a Kollicoat® IR layer compared to conventional pullulan capsules. Table 2 provides capsule sample capsule compositions for Examples 4 and 5 and Comparative Examples 6 and 7. Each of Comparative Examples 6 and 7 contained pullulan as the base capsule material.

[0086]

[0101] 15A-15D and 16A-16D show images of capsules subjected to in vivo dissolution testing of capsules including a Kollicoat® IR layer (FIGS. 15A-15D) and a pullulan layer (FIGS. 16A-16D) according to some embodiments of the present disclosure.

[0087] [Table 2]

[0088]

[0102] Table 3 provides the dissolution results of Comparative Examples 6 and 7 and Examples 4 and 5. Figures 15A and 15C show the capsules of Examples 4 and 5 before immersion test at T0, and Figures 16A and 16C show the capsules of Comparative Examples 6 and 7 before immersion test at T0. After 47 minutes of immersion test, Examples 4 and 5 had slight enteric removal. After 50 minutes of immersion test, Comparative Examples 6 and 7 showed capsule deformation. At T2, Examples 4 and 5 and Comparative Examples 6 and 7 had significant deformation. Surprisingly, Examples 6 and 7 showed faster dissolution rates with minimal residue. Specifically, Examples 6 and 7 were much more dissolved than Comparative Examples 6 and 7 at T3 (pullulan remained as a mechanically intact membrane rather than actually being able to resist some stretching). The capsules of Examples 6 and 7 have improved dissolution properties (e.g., faster properties) for releasing payload in the digestive tract than Comparative Examples 6 and 7.

[0089] [Table 3]

[0090]

[0103] The foregoing description, for purposes of explanation, used specific nomenclature to provide a thorough understanding of the described embodiments. However, it will be apparent to one skilled in the art that specific details are not required to practice the described embodiments. Thus, the foregoing descriptions of specific embodiments have been presented for purposes of illustration and description. They are not intended to be exhaustive or to limit the described embodiments to the precise forms disclosed. It will be apparent to one skilled in the art that many modifications and variations are possible in light of the above teachings.

Claims

1. 1. A method for producing a capsule, comprising: Preparing the mold, depositing parylene onto the mold to form a parylene layer; scoring the parylene layer; coating the parylene layer with a polymer to produce a capsule; The method includes:

2. The method of claim 1 further comprising polishing a surface of the mold to facilitate demolding of the capsule.

3. 10. The method of claim 1, further comprising applying a release agent onto the mold prior to depositing the parylene layer, the release agent being Micro90.

4. The method of claim 1 , wherein scoring the parylene layer comprises cutting the parylene layer to form a pattern on both sides of the capsule.

5. The method of claim 1 , further comprising treating an outer surface of the parylene layer with an oxygen plasma prior to coating with the polymer.

6. 2. The method of claim 1, wherein the parylene layer has a thickness in the range of 0.5 μm to 30 μm and the polymer layer has a thickness in the range of 100 μm to 250 μm.

7. The method of claim 1 , wherein depositing the parylene layer comprises chemical vapor deposition of parylene onto the mold.

8. depositing said parylene layer depositing parylene onto the mold in a first deposition step to form a primer layer; treating the primer layer with a release agent; depositing parylene over the primer layer in a second deposition process to form the parylene layer; The method of claim 1 , comprising:

9. The method of claim 1 , wherein the polymer is polyvinyl alcohol.

10. 10. The method of claim 1, further comprising applying an enteric coating over the polymer layer, the enteric coating comprising an anionic methacrylic acid copolymer, talc and a plasticizer, the weight ratio of talc to anionic methacrylic acid copolymer being in the range of 0.5:1 to 10:

1.

11. The method of claim 1 , further comprising enclosing a needle delivery system within the capsule.

12. a first layer comprising parylene; a second layer adjacent to the first layer, the second layer comprising a polymer; a third layer adjacent to the second layer, the third layer comprising an enteric coating; A capsule comprising:

13. 13. The capsule of claim 12, wherein the first layer is scored to form a bi-fold pattern on both sides of the capsule.

14. The capsule of claim 12, wherein the thickness of the parylene layer ranges from 0.5 μm to 30 μm.

15. 13. The capsule of claim 12, wherein the second layer comprises a plurality of layers, at least one of the plurality of layers comprising polyvinyl alcohol, and the second layer has a thickness of 100 μm to 250 μm.

16. 13. The capsule of claim 12, wherein the polymer comprises one or more of hydroxypropyl methylcellulose, pullulan, polyvinyl alcohol, or polyvinylpyrrolidone.

17. 13. The capsule of claim 12, wherein the enteric coating comprises an anionic methacrylic acid copolymer, talc and a plasticizer, wherein the talc constitutes 40% to 80% by weight of the enteric coating, based on the total weight of the enteric coating, and the anionic methacrylic acid copolymer constitutes 20% to 60% by weight of the enteric coating, based on the total weight of the enteric coating.

18. 13. The capsule of claim 12, wherein the capsule does not contain pullulan or hydroxypropyl methylcellulose.

19. 13. The capsule of claim 12, further comprising a fourth layer comprising an anionic methacrylic acid copolymer and a plasticizer.

20. the polymer of the second layer comprises polyvinyl alcohol; the enteric coating comprises an anionic methacrylic acid copolymer, talc and a plasticizer; the fourth layer comprises an anionic methacrylic acid copolymer and a plasticizer; The capsule of claim 12.

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