Two-layer drug structure

Abstract

Two-layer drug structure (1) comprising the following: an inner core (11) which is spherical in shape, wherein the inner core (11) contains a pharmaceutically active component; an enveloping polymer layer (12) having a thickness wherein the enveloping polymer layer (12) envelops the outer surface of the inner core (11), wherein the enveloping polymer layer (12) shrinks inwards in a gastric acid environment and swells outwards in an intestinal environment; and a multitude of hydrophilic pore-forming particles (13) embedded in the enclosing polymer layer (12), wherein the hydrophilic pore-forming particles (13) are exposed to the outside when the enclosing polymer layer (12) swells and dissolve in the intestinal fluid to form channels.

Description

Technical field

[0001] The present invention relates to a two-layer drug structure, in particular a two-layer drug structure which enables the pharmaceutically active ingredient to be released slowly only after entering the intestine. Technical background

[0002] Oral medications currently represent the primary form of drug therapy. After being swallowed by the patient, the medication passes through the esophagus into the stomach. Most medications are broken down in the stomach by gastric acid and mixed with gastric fluid before being transported to the small intestine. To prevent breakdown in the stomach, certain medications are administered with an enteric coating or in capsules containing the active pharmaceutical ingredient (i.e., enteric-coated tablets or capsule formulations). Only after the medication enters the small intestine does the enteric coating or capsule break down in the intestinal environment, at which point the release of the active pharmaceutical ingredient begins. Disclosure of the invention

[0003] With the aforementioned enteric-coated tablets or capsule formulations, the pharmaceutically active ingredient is released suddenly and completely upon entering the intestinal environment due to the disintegration of the enteric coating or capsule, thus precluding a slow and sustained release of the pharmaceutically active ingredient. Therefore, a drug structure is being sought that allows for a slow release of the pharmaceutically active ingredient only after it has entered the intestine.

[0004] The purpose of the present invention is to solve the above problem by providing a two-layer drug structure comprising: an inner core in a spherical shape, the inner core containing a pharmaceutically active ingredient; an enveloping polymer layer having a thickness, wherein the enveloping polymer layer surrounds the outer surface of the inner core, the enveloping polymer layer shrinking inwards in a gastric acid environment and swelling outwards in an intestinal environment; and a plurality of hydrophilic pore-forming particles embedded in the enveloping polymer layer, wherein, upon swelling of the enveloping polymer layer, the hydrophilic pore-forming particles are exposed to the intestinal fluid and form channels.

[0005] The two-layer drug structure described above allows for the provision of a drug structure that enables a slow release of the pharmaceutically active ingredient only after it enters the intestine. Presentation of the illustrations Fig. Figure 1 is a cross-section of the two-layer drug structure according to an embodiment of the present invention. Fig. Figure 2 is a schematic representation of the changes in state of the two-layer drug structure according to an embodiment of the present invention in the gastrointestinal tract. Specific examples of implementation

[0006] In order to fully understand the purposes, features and effects of the present invention, the present invention will be explained in detail with reference to the following specific embodiment: The two-layer drug structure 1 produced in this embodiment is in Fig.Figure 1 illustrates the two-layer drug structure 1, which comprises an inner core 11, an enveloping polymer layer 12, and hydrophilic pore-forming particles 13 dispersed therein. The inner core 11 is spherical and contains a pharmaceutically active ingredient, which can be a drug or a biologically active natural substance such as quercetin, silymarin, puerarin, and curcumin. The enveloping polymer layer 12 has a thickness of [missing information] and envelops the outer surface of the inner core 11. The enveloping polymer layer 12 shrinks inwards in the gastric acid environment (e.g., in gastric acid) and expands outwards in the intestinal environment (e.g., in the intestine).The hydrophilic pore-forming particles 13 are embedded in the enveloping polymer layer 12; when the enveloping polymer layer 12 swells outwards, the hydrophilic pore-forming particles 13 are exposed to the intestinal fluid and dissolved by the intestinal fluid, thereby forming channels.

[0007] The manufacturing process of the two-layer drug structure 1 of this embodiment is explained in more detail below.

[0008] First, a coating solution is prepared to produce the enclosing polymer layer 12. The composition of the coating solution is given in Table 1 below. Table 1 - Components of the coating solution Spray coating solution volume Carrageenan 200 g Polyethylene glycol 50 g titanium dioxide 15 g Hydroxypropylcellulose 50 g Lactose 50 g Strength 25 g Microcrystalline cellulose 50 g Magnesium stearate 20 g Pure water Fill to 1000 ml

[0009] Among the components of the foregoing coating solution, carrageenan is an anionic polysaccharide colloid that is gastric acid-resistant and enterosolubilous. Carrageenan causes the coating polymer layer 12 to shrink inwards and resist gastric acid in the acidic environment of the stomach, and to dissolve in the weakly acidic to neutral environment of the intestine. In other embodiments, other anionic polysaccharide colloids may be used instead of carrageenan, including xanthangum, gellangum, guar gum, carboxymethyl guar gum (CMG), curdlan, arabic gum, algin, pectin, sodium carboxymethylcellulose (CMC), sodium carboxymethyl starch (CMS), cellulose acetate phthalate, levan, sorbitol, xylitol, erythritol, methylcellulose, ethylcellulose, maltodextrin, glucomannan, lignin, or combinations thereof.

[0010] Among the components of the aforementioned coating solution, whole milk powder serves as the necessary protein component. Proteins denature and coagulate upon contact with acidic components, thereby preventing rupture and dissolution of the encapsulating polymer layer 12. In other embodiments, other proteins may be used instead of whole milk powder, including basic amino acid polymers, skimmed milk powder, whey protein powder, casein powder, soy protein isolate powder, pea protein powder, corn protein powder, yeast powder, or combinations thereof. The aforementioned basic amino acid polymers refer to proteins or peptides whose isoelectric point is at a pH greater than 7 and which consist mainly of lysine and arginine, including protamine, clupein, sturin, lysozyme, polylysine, polyarginine, or soy-based basic peptides.

[0011] Among the components of the aforementioned coating solution, microcrystalline cellulose serves as a binder. In other embodiments, other binders may also be used, including polyacrylic acid, polyacrylamide, polyvinyl alcohol, polyvinylpyrrolidone, or combinations thereof.

[0012] Among the components of the aforementioned coating solution, titanium dioxide serves as a solid dispersant. In other embodiments, other solid dispersants may also be used. In some embodiments, the solid dispersant is freely selected from the group consisting of: polyvinylpyrrolidone (PVP), polyvinylpyrrolidone-vinyl acetate copolymer (PVP-VA), cross-linked polyvinylpyrrolidone (PVP-CL), polyvinyl alcohol (PVA), polyethylene glycol (PEG), hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose phthalate (HPMCP), hypromellose acetate succinate (HPMC-AS), corn starch, potato starch, silicon dioxide, trehalose, sucrose, and inulin, or combinations thereof. Among the components of the aforementioned coating solution, hydroxypropyl cellulose serves as an adhesion agent for intestinal fluid. In other embodiments, other adhesive agents for intestinal fluid can also be used.In some embodiments, the mucosal adhesion aid polymer is freely selected from the group consisting of: natural polymeric adhesion materials, semi-synthetic polymeric adhesion materials, synthetic polymeric adhesion materials, or combinations thereof.

[0013] In some embodiments, the natural polymeric adhesion material is freely selected from the group consisting of: gelatin, starch, hyaluronic acid, chitosan, deacetylated chitin, plant lectins or combinations thereof.

[0014] In some embodiments, the semi-synthetic polymeric adhesion material is freely selected from the group consisting of the following: Hydroxypropylmethylcellulose (HPMC), hydroxyethylcellulose (HEC), chitin derivatives, chitosan cysteine, chitosan thiobutylamidine or combinations thereof.

[0015] In some embodiments, the synthetic polymeric adhesion material is freely selected from the group consisting of: carbomer, glycerol monoesters, polyvinyl alcohol, polyacrylic acid, polyethylene glycol or combinations thereof.

[0016] Among the components of the aforementioned coating solution, starch serves as a coating agent; in other embodiments, other types of coating agents may also be used, for example, lactose. Among the components of the aforementioned coating solution, magnesium stearate serves as a lubricant; in other embodiments, other lubricants may also be used as excipients.

[0017] Among the components of the foregoing coating solution, polyethylene glycol serves as a hydrophilic pore-forming agent and is embedded in the coating layer in the form of powdered particles, thereby forming the dispersed hydrophilic pore-forming particles 13. In other embodiments, polyethylene glycol can be replaced by other proteins that are readily degraded by intestinal proteases or by conventional organic water-soluble pore-forming agents, including polyvinyl alcohol, povidone, urea, and hydroxypropyl methylcellulose, or combinations thereof.

[0018] After preparation of the coating solution for the encapsulating polymer layer 12, the aforementioned coating solution is sprayed onto the surface of the inner core 11 (produced in a quantity of 250 g) using a fluidized bed reactor. The spraying conditions of the fluidized bed reactor are as follows: sterile environment, atmospheric pressure of 2.5–5 kg / cm². 2 The hot air temperature is 40-50 °C, air flow rate: 0.8-1.5 m³ / h 3 / min for fluidized bed, 0.1-0.25 m 3 The nozzle speed is / min, the coating solution flow rate is 50-100 ml / h, and the coating spraying process lasts approximately 1.5-3 hours. Finally, a two-layer drug structure 1 with a particle size of 40-80 mesh is produced.

[0019] The shape changes of the aforementioned two-layer drug structure 1 in the gastrointestinal tract are in Fig.Figure 2 shows the process from state (a) to state (c). The initial structure size of the two-layer drug structure 1 is as shown in state (a). Upon entry of the two-layer drug structure 1 into the stomach, the structure size of the two-layer drug structure 1 is as shown in state (b); the enveloping polymer layer 12 shrinks inward, thereby reducing the overall structure size of the two-layer drug structure 1. The enveloping polymer layer 12 resists erosion by gastric acid, with the hydrophilic pore-forming particles 13 remaining embedded within the enveloping polymer layer 12.Upon entering the weakly acidic to neutral environment of the intestine, the structure size of the two-layer drug structure 1 is as shown in state (c); the enveloping polymer layer 12 slowly expands outwards, thereby increasing the overall structure size of the two-layer drug structure 1. The intestinal fluid penetrates the enveloping polymer layer 12, causing the hydrophilic pore-forming particles 13 to come into contact with the intestinal fluid and slowly dissolve. After the hydrophilic pore-forming particles 13 dissolve, pores form at the sites previously occupied by these hydrophilic pore-forming particles 13 in the enveloping polymer layer 12, thus giving the enveloping polymer layer 12 a porous structure.This allows the intestinal fluid to penetrate the two-layer drug structure 1 and come into contact with the inner core 11 (which contains the pharmaceutically active ingredient), thereby dissolving the pharmaceutically active ingredient. This dissolution process occurs slowly within the two-layer drug structure 1. The intestinal fluid forms an intestinal fluid-pharmaceutical-active ingredient complex with the pharmaceutically active ingredient in the inner core 11, which is subsequently released through the pores formed in the encapsulating polymer layer 12. The more hydrophilic pore-forming particles 13 dissolve, the more pores are created in the encapsulating polymer layer 12, thus increasing the release rate of the intestinal fluid-pharmaceutical-active ingredient complex through these pores in the encapsulating polymer layer 12.The two-layer drug structure 1 remains in the intestine for 2 to 3 hours before slowly disintegrating and breaking down. During this slow disintegration, the intestinal fluid-pharmaceutical active ingredient complex is slowly released and absorbed from the intestinal surface, thus achieving the goal of slow release of the pharmaceutical active ingredient in the intestine.

[0020] In the two-layer drug structure described above, the shrinking of the outer enveloping polymer layer in the stomach environment and its swelling in the intestinal environment, as well as the design of the hydrophilic pore-forming particles in the enveloping polymer layer, enables a slow release of the pharmaceutically active ingredient in the intestine.

[0021] The present invention has been disclosed above with reference to a preferred embodiment. However, those skilled in the art will understand that this embodiment serves only to illustrate the invention and must not be interpreted as limiting its scope. It should be noted that all equivalent modifications and substitutions of this embodiment are to be included within the scope of protection of the present invention. The scope of protection of the present invention is therefore defined by the scope of the claims. Reference symbol list 1. Two-layer drug structure 11 Inner core 12 Enveloping polymer layer 13 Hydrophilic pore-forming particles

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