WO2014035219A1 - Dosage form for oral administration capable of being adhered to flowing gastric mucosa - Google Patents

Abstract

The present invention relates to a dosage form for oral administration capable of being adhered to the flowing gastric mucosa, comprising mucosa-adhesive needles between a corrosive polymer layer and a swellable polymer layer, and independently identical or different pharmacologically active substances. According to the present invention, the dosage form for oral administration capable of being adhered to the flowing gastric mucosa can effectively control the in vivo release and absorptivity of pharmacologically active substances through the combination of desired corrosive and swellable polymers thereby facilitating the control of a blood drug concentration, comprises pharmacologically active substances in each of a corrosive layer and a swellable layer thereby showing a pharmacological synergistic effect, and exhibits superior mucosa adhesion and sustained efficacy of a drug compared with conventional a Geomatrix system dosage form and a mucosa-adhesive dosage form, by the adhesion of the mucosa-adhesive needles exposed by the corrosion of the corrosive layer to the gastric mucosa, and thus can be useful as an extended release drug delivery system for oral administration.

Description

Fluid Gastrointestinal Mucoadhesive Oral Formulations

The present invention relates to a fluid gastrointestinal mucosa adhesive oral dosage form.

Oral drug delivery agents are the most commonly used drug dosage forms for ease of taking and the benefits of manufacturing.The drug is released from the body immediately, increasing the drug concentration in the blood within a short time, and thus rapidly increasing the level of drug in the blood. It can be reached above the minimum drug expression concentration. However, in general oral preparations, it is difficult to arbitrarily control the time until administration of the drug after administration, and each pharmacologically active substance has a unique absorption window in the body, and according to the half-life of the pharmacologically active substance. Since the degree of drug efficacy is also different, the characteristics of the pharmacologically active substance should be considered when designing the formulation.

Representatively, oral sustained-release preparations have been developed, which include pharmacologically active substances with long half-life in the body, persistent drug expression, and time acting as control factors.

Oral sustained release preparations have been developed to maintain optimal blood levels in vivo by controlling the release of pharmacologically active substances to a pre-designed level. The purpose of these oral sustained release formulations is to effectively measure the blood concentration of pharmacologically active substances. By continuously maintaining in the blood concentration range, the number of administration of the pharmacologically active substance is reduced, the patient's medication compliance is increased, and the side effects such as toxicity of the pharmacologically active substance are prevented.

A drug delivery system (DDS), designed to reduce the side effects of drugs and maximize the efficacy and effectiveness of drugs, is called drug delivery system (DDS). Type DDS ”,“ drug sustained DDS ”,“ target site-focused DDS ”, and“ artificial intelligence DDS ”. Among them, the "drug sustained-type DDS" is a DDS for maintaining the effective blood concentration and drug effect in the blood of a large drug that is lost from the body after taking the drug by using sustained release.

Drug sustained DDS includes osmotic pressure control system, pulse release system, geomatrix system, colon target preparation, ion resin release control system, SODAS, especially for diffusion of pharmacologically active substances or erosion of polymers. The matrix formulation in which the release of the pharmacologically active substance is controlled is the most widely used because of its simple composition and easy manufacturing method. In preparing the matrix formulation, various water-soluble high molecular materials such as HPMC, PEO, sodium alginate are used, and the degree of release of the pharmacologically active substance can be controlled according to their molecular weight (viscosity). However, even if the degree of release of the pharmacologically active substance can be controlled to some extent, the formulation containing the water-soluble polymer will follow the law of diffusion of the pharmacologically active substance release, resulting in an initial burst at the beginning of administration. Even in sustained DDS, since the drug is metabolized in about 24 hours in the body, the release time of the pharmacologically active substance is also limited to about 24 hours.

Conventional mucoadhesive formulations are used to adhere to the gastrointestinal mucosa using mucoadhesive polymers attached to the gastrointestinal tract mucosa, thereby prolonging the gastric retention time, allowing continuous release of drugs. The factors affecting adhesion to mucous membranes such as mucin turns over, initial contact time, etc. are so diverse that it is not possible to ensure effective prolongation of residence time and drug delivery. There is a need for development.

Accordingly, the present inventors can effectively control the release of the pharmacologically active substance in the body as an oral drug-sustaining agent, and develop a drug-sustaining agent that can last for more than 24 hours, while adhering to the mucosa between the erosive polymer layer and the swellable polymer layer. Formulations for fluid gastrointestinal mucoadhesive oral administration including adult acupuncture were completed.

It is an object of the present invention to provide a formulation for fluid oral gastrointestinal mucoadhesive adhesion.

In order to achieve the above object, the present invention provides a fluid gastrointestinal mucosa adhesive oral dosage form.

The fluid gastrointestinal mucoadhesive oral dosage form according to the present invention can effectively control the release and absorption of the pharmacologically active substance through the combination of the desired erosive and swellable polymers, thereby easily controlling the blood concentration of the drug, the erosive layer and the swelling property. Including the pharmacologically active substance in each layer can not only have a pharmacological synergistic effect, but also the mucoadhesive saliva exposed by the erosion of the erosive layer adheres to the gastrointestinal mucosa, thereby reducing the conventional Since mucoadhesiveness and drug efficacy are excellent, it can be usefully used as an oral drug sustained drug delivery system.

1 is a view showing a schematic structure of the gastrointestinal mucosa adhesive oral dosage form of the present invention.

Hereinafter, the present invention will be described in detail.

The present invention may include the same or different pharmacologically active substances independently of each other,

Erosive polymer layers;

Swellable polymer layer; And

A mucoadhesive needle positioned between the two layers, the sharp side of the needle facing the erosive layer, the opposite side of the sharp side being bonded to the swellable polymer layer; It provides a fluid gastrointestinal mucosa adhesive oral dosage form comprising a.

The fluid gastrointestinal mucoadhesive oral dosage form according to the present invention includes a mucoadhesive saliva between an erosive polymer layer and a swellable polymer layer, and when the formulation is exposed to an aqueous medium, the erosive polymer layer is eroded to prevent mucosal adhesion. The mucoadhesive saliva exposed to an aqueous medium is attached to the gastrointestinal mucosa, and the swellable polymer layer swells to encapsulate the mucoadhesive saliva, thereby removing it from the gastrointestinal mucosa.

In addition, when the flexible gastrointestinal mucoadhesive oral dosage form of the present invention is exposed to an aqueous medium, the erosive polymer layer is eroded while releasing pharmacologically active substances contained therein, thereby exposing the mucoadhesive saliva. It can be attached in contact with the mucous membranes of the gastrointestinal tract. The mucoadhesive needles have excellent mucoadhesive strength compared to conventional drug-sustaining DDS using conventional mucoadhesive polymers, and thus the drug can be released for a long time, and thus has excellent sustaining effect. In addition, since the release of the pharmacologically active substance is completed, the swellable polymer layer swells to surround the mucoadhesive saliva, thereby dropping the formulation from the mucosa, thereby controlling the duration of the drug.

The fluid gastrointestinal mucoadhesive oral dosage form of the present invention should be prepared so that the sharp part of the mucoadhesive needle is directed toward the erosive polymer layer, and when the erosive polymer is eroded due to contact with an aqueous medium, the exposed mucoadhesive Sharp parts of the saliva may be exposed to the aqueous medium and the gastrointestinal mucosa and adhere to the gastrointestinal mucosa. In addition, the mucoadhesive needle is sufficient to be easily attached to the gastrointestinal mucosa, it may be preferably jagged. The mucoadhesive saliva is made of stainless steel, gold, platinum, titanium, and the like, which are harmless to oral administration to the human body; Or pharmaceutically acceptable excipients (e.g., polyethylene glycol (PEG), lactose, dextrose, sucrose, dextrate, mannitol, sorbitol, xylitol, sodium chloride, magnesium chloride, calcium hydrogen phosphate, citric acid, microcrystalline cellulose, etc.) , Binders (e.g. copovidone, polyvinylpyrrolidone, hydroxypropyl cellulose, etc.), disintegrants (e.g. sodium starch glycolate, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl Cellulose), a lubricant (for example, magnesium stearate, stearic acid, stearyl fumarate, hard silicic acid, etc.), or the like, or may be plated or coated with a material having a needle shape. It is not limited to this.

The present invention is a fluid gastrointestinal mucoadhesive oral dosage form comprising mucoadhesive saliva between an erosive polymer layer and a swellable polymer layer, which may include the same or different pharmacologically active substances independently of each other, each in a matrix structure. Since the pharmacologically active substance of the physiologically stable substance is present as a separate tablet until it is exposed to the aqueous medium, the physicochemical stability is maintained, so the preservation is excellent. Therefore, the use of the liquid gastrointestinal mucoadhesive oral dosage form of the present invention is economical because it does not have to take each pharmacologically active substance separately, there is an advantage that the medication compliance of the patient is increased.

On the other hand, the present formulation by controlling the degree of gelation (swelling), erosion of the polymer layer through a combination of the polymer and excipient type, mixing ratio, thickness, etc. of the erosive and swellable polymer layer, blood concentration and It is possible to control the duration of the drug more finely and to control the exposure time of adherent saliva, so that the drug absorption window (absorption window) of the drug can be applied to the desired amount of drug for a long time effectively.

In the present invention, the erosive polymer is a polymer exhibiting the property of being eroded upon contact with a water-soluble medium. The erosive polymer is not divided by the reference value of absolute erosion, but is divided by the difference in relative erosion. In the polymer, a polymer having a relatively high erosion property is defined as an erosive polymer.

In addition, in the present invention, a swellable polymer is a polymer exhibiting a property of swelling upon contact with a water-soluble medium, and a conventional swellable polymer known in the pharmaceutical art may be used.

The erosive polymer and swellable polymer include polyethylene glycol (PEG), polyethylene oxide (PEO), hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose, carboxymethyl cellulose, polyvinyl alcohol, carbomer, microcrystalline cellulose (MCC , microcrystalline celluose, lactose, etc. may be used, but is not limited thereto. In addition, the polyethylene oxide may be commercially available POLYOX Water-Soluble Resins (POLYOX WSR N-10, N-80, N-750, POLYOX WSR-205, WSR-1105, WSR-301, WSR-303 may be used, and as the hydroxypropylmethylcellulose, commercially available Methocel K4M CR Premium (Methocel K4M CRPremium, Dow Chemical, USA) may be used. In general, the lower molecular weight, the stronger the erosion, and when the erosive polymer and the swellable polymer are the same type of polymer, for example, polyethylene glycol (PEG), the lower molecular weight polymer (PEG 1000) becomes the erosive polymer. The higher molecular weight polymer (PEG 20000) becomes the swellable polymer.

The content of the swellable polymer may vary depending on the type of polymer, but is preferably 40 to 99% by weight relative to the total weight of the formulation.

The swellable polymer layer of the present invention includes pharmaceutically acceptable excipients (e.g. polyethylene glycol (PEG), lactose, dextrose, sucrose, dextrate, mannitol, sorbitol, xylitol, sodium chloride, magnesium chloride, calcium hydrogen phosphate, Citric acid, microcrystalline cellulose and the like), binders (e.g. copovidone, polyvinylpyrrolidone, hydroxypropyl cellulose, etc.), disintegrants (e.g. sodium starch glycolate, croscarmellose sodium, crospovidone, Low-substituted hydroxypropyl cellulose), glidants (eg, magnesium stearate, stearic acid, sodium stearyl fumarate, light silicic anhydride, etc.) and the like may further be included.

The pharmacologically active substance may be sufficient as oral pharmacologically active substance, and all known oral pharmacologically active substances may be used. Such pharmacologically active substances include, for example, antifungal agents, antihyperlipidemic agents, circulatory organ agents, antitumor agents, antipyretics, analgesics, anti-inflammatory agents, eukaryotic expectorants, sedatives, anti-allergic agents, vasodilators, hypertensive diuretics, diabetes treatments, hormones, blood vessels Anti-inhibitors and the like, and specifically include hyperoxia doxazosin, terrazosin, prostate hypertrophy drug tamsulosin, hyperlipidemia drug simvastatin, lovastatin, fluvastatin, nonsteroidal anti-inflammatory drugs acetaminophen, zaltoprofen and analgesics It may be a pharmacologically active substance which is selected from the group consisting of intramadol, but is not limited thereto.

In addition, the flowable gastrointestinal mucoadhesive oral dosage form of the present invention may be used directly in the form of a tablet or in a form filled into a capsule. The capsule is a gelatin and / or white sugar as a raw material, a plasticizer such as glycerin, gum arabic, agar, and other capsules composed of colorants, light-shielding agents and preservatives, prepared by methods well known in the art using the raw materials Alternatively, a commercially available capsule may be used.

Hereinafter, preferred examples are provided to aid in understanding the present invention. However, the following examples are merely provided to more easily understand the present invention, and the contents of the present invention are not limited by the examples.

Example 1. Measurement of the degree of gelation (swelling) of the swellable polymer layer of the present invention

In order to test the gelation degree (swellability) of the swellable polymer layer of the present invention, the following experiment was performed.

1-1. Preparation of swellable polymer tablets (Preparation of test tablet)

Before preparation, all raw materials including excipients were prevented from agglomeration between powders using the sieve of No. 20. After accurately weighing the polymer and the lubricant shown in Table 1, the mixture was evenly mixed for 5 minutes. The mixed powder was compressed into tablets using a single-punch hydraulic laboratory press at a pressure of 15 MPa using a flat-shaped round-shaped punch with a diameter of 9.0 mm and used as a test sample.

Table 1

No.		Input factors
	St-mg	X1	X2	X3	X4	X5	X6	X7	X8
		PEG 6000	PEO N-10	PEO301	PEO Coagulant	PEO 303	HPMC 100SR	HPMC 4000SR	HPMC 10 5 SR
One	2.5	25							210
2	2.5	50							185
3	2.5	25	210
4	2.5	25		210
5	2.5	25			210
6	2.5	25				210
7	2.5	25					210
8	2.5	25						210
9	2.5	50	185
10	2.5	50		185
11	2.5	50			185
12	2.5	50				185
13	2.5	50					185
14	2.5	50						185

PEG: polyethyleneglycol

PEO: polyethylene oxide

HPMC: hydroxypropy methylcellulose

St-Mg: Stearate Magnesium

1-2. Evaluation of tablet gelation

First, the test sample prepared in 1-1 was placed between two polyacrylic plates (5cm × 5cm) and fixed using a rubber band. Then, the sample was placed in 900 mL, pH 6.8, 37 ° C. eluent at 300 rpm / min. It was stirred using a magnetic stir bar. Each sample was taken out at a predetermined time and the gelation index was measured according to Equation 1 by measuring the total diameter of the experimental tablet, the diameter of the gelled portion and the diameter of the non-gelled portion using a caliper (Sako et. al., 1996).

Equation 1

The results are shown in Table 2.

TABLE 2

No.	Gelation degree (swellability) (%)
	Y1	Y2	Y3	Y4	Y5	Y6	Y7	Y8
	0.5h	1h	1.5h	2h	2.5h	3h	4h	5h
One	34.19	50.48	66.28	67.29	72.76	80.72	88.62	90.21
2	35.19	56.43	67.00	69.94	70.88	83.72	92.47	94.48
3	-	-	-	-	-	-	-	-
4	38.60	62.98	72.08	79.83	83.13	87.88	92.11	95.36
5	28.04	38.00	48.22	54.68	59.89	67.82	70.81	74.92
6	30.77	55.46	68.21	73.72	84.32	87.79	92.65	95.81
7	-	-	-	-	-	-	-	-
8	21.99	44.67	55.65	63.27	75.59	79.17	82.38	84.79
9	-	-	-	-	-	-	-	-
10	19.06	41.27	59.35	64.71	71.66	78.86	82.63	85.16
11	21.81	49.68	65.02	68.20	73.41	80.46	83.00	86.08
12	20.29	47.28	55.63	61.10	67.97	72.57	77.96	82.05
13	41.93	57.96	74.22	83.66	89.59	92.16	94.08	94.99
14	53.52	75.17	80.87	87.69	92.06	91.75	97.33	96.41

As shown in Table 2, it can be seen that the polymer swells at various speeds according to time by varying the combination of the lubricant and the type and weight ratio of the polymer. Therefore, the swellable polymer layer of the present invention, as shown in Figure 1, after the erosion polymer layer is eroded, the gelation proceeds over time and swelling occurs, so that the mucoadhesive saliva is wrapped around the needle attached to the gastrointestinal mucosa It can be confirmed that can be eliminated.

Claims (8)

1. Which may comprise the same or different pharmacologically active substances independently of one another,

   Erosive polymer layers;

   Swellable polymer layer; And

   A mucoadhesive needle positioned between the two layers, the sharp side of the needle facing the erosive layer, the opposite side of the sharp side being bonded to the swellable polymer layer; Fluid gastrointestinal mucosa adhesion oral dosage form comprising a.
2. The swellable polymer layer of claim 1, wherein when the formulation is exposed to an aqueous medium, the eroding polymer layer is eroded to expose the mucoadhesive saliva, wherein the mucoadhesive saliva exposed to the aqueous medium is attached to the gastrointestinal mucosa and the swellable polymer layer. Is swelled to surround the mucoadhesive saliva, thereby dropping it from the gastrointestinal mucosa, the flowable gastrointestinal mucoadhesive formulation for oral administration.
3. The method of claim 1, wherein the erosive polymer and the swellable polymer are polyethylene glycol (PEG), polyethylene oxide (PEO), hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose, carboxymethyl cellulose, polyvinyl alcohol, carbomer, Microcrystalline cellulose (MCC), lactose (lactose), characterized in that at least one selected from the group consisting of, fluid gastrointestinal mucosa adhesion oral dosage form.
4. The fluid gastrointestinal mucoadhesive oral dosage form of claim 1, wherein the erosive polymer layer and the swellable polymer layer further comprise a pharmaceutically acceptable excipient, binder, disintegrant, or glidant.
5. The method of claim 1, wherein the mucoadhesive needle is one or more materials selected from the group consisting of stainless steel, gold, platinum, and titanium; Or pharmaceutically acceptable excipients, binders, disintegrants, and glidants; at least one material selected from the group consisting of; or a material having the shape of a needle or plated or coated with the material, Gastrointestinal mucoadhesive oral dosage form.
6. The fluid gastrointestinal mucoadhesive oral dosage form of claim 1, wherein the mucoadhesive saliva is serrated.
7. The method of claim 1, wherein the pharmacologically active substance is an antifungal agent, antihyperlipidemic agent, circulatory agent, antitumor agent, antipyretic agent, analgesic agent, anti-inflammatory agent, antitussive expectorant agent, sedative agent, antiallergic agent, vasodilator, hypotensive agent, diabetes treatment agent, At least one selected from the group consisting of hormonal agents and angiogenesis inhibitors, the fluid gastrointestinal mucosa adhesion oral dosage form.
8. The method of claim 7, wherein the pharmacologically active substance is at least one member selected from the group consisting of doxazosin, terrazosin, tamsulosin, simvastatin, lovastatin, fluvastatin, acetaminophen, zaltoprofen and tramadol. , Fluid gastrointestinal mucoadhesive oral dosage forms.

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