CN212067227U

CN212067227U - Long-acting preparation retained in stomach

Info

Publication number: CN212067227U
Application number: CN201922214686.5U
Authority: CN
Inventors: 胡连栋
Original assignee: Heibei University
Current assignee: Heibei University; Hebei University
Priority date: 2019-12-12
Filing date: 2019-12-12
Publication date: 2020-12-04
Anticipated expiration: 2029-12-12

Abstract

The utility model provides a long-acting preparation retained in the stomach, which comprises a gastric soluble capsule shell and a medicine release unit, wherein the medicine release unit is folded into a geometric shape and is arranged in the gastric soluble capsule shell, the medicine release unit comprises a long and thin component and a biodegradable connecting piece, two ends of the long and thin component are sealed, at least one medicine release hole is arranged on the pipe wall, and the medicine is arranged in the long and thin component; the biodegradable connector is used to connect two ends of the elongated member. The preparation method of the utility model is simple, the long-acting preparation detained in the stomach releases the drug at a steady rate, adjusts the release rate and the release time of the drug by arranging the drug release holes with different quantities and diameters on the slender component, and controls the detention time of the preparation in the stomach through the degradation time of the biodegradable connecting piece.

Description

Long-acting preparation retained in stomach

Technical Field

The utility model relates to an oral sustained and controlled release preparation, in particular to a long-acting preparation detained in the stomach.

Background

The oral sustained and controlled release preparation can maintain effective blood concentration within 12-24 h, overcomes the defects of strong first pass effect, inaccurate positioning, high blood concentration fluctuation, poor tolerance of patients and the like of the traditional oral preparation to a certain extent, and improves the bioavailability of the medicine. However, most oral formulations are not completely absorbed in the gastrointestinal tract and have low bioavailability due to interference from factors such as gastric emptying, gastric motility, and gastric contents.

The research and development of the gastric retention drug delivery preparation provides a more effective drug delivery way for the treatment of gastrointestinal diseases, and provides a brand new treatment mode for the gastrointestinal diseases. The gastric retention drug delivery system is a drug delivery system which can be retained in gastric juice after oral administration, prolongs the release time of a drug in a digestive tract and improves the drug absorption, and the system can promote the absorption of a weakly acidic drug at a specific part of the gastrointestinal tract, a drug actively transported in a duodenum section, a drug unstable in an intestinal environment and a drug with a narrow treatment window, and makes up for the defect of short biological half-life of the drug.

Currently, commercially available long-acting preparations for gastric retention mainly include preparations for gastric floating, preparations for gastric sinking, preparations for gastric adhesion, preparations for gastric retention and expansion, and the like. The floating preparation in the stomach enters the stomach through oral administration, and the density of the floating preparation in the stomach is less than that of gastric juice and contents (1.004-1.010 g as much as cm)^-3) But is in a floating state and is not influenced by gastric emptying, thereby prolonging the detention time of the drug in the stomach to achieve long-acting effect. The high-density pharmaceutic adjuvant is added into the stomach sedimentation preparation medicine to ensure that the total density of the medicine is greater than that of the stomach contents, the medicine will quickly sink to the bottom of the stomach after being taken orally, and the folds in the stomach firmly wrap the medicine and are not discharged, so that the release time of the medicine in the stomach is prolonged, but the medicine cannot resist the physiological movement of the stomach. After the high molecular adhesive material carrying the medicine in the gastric adhesive preparation is contacted with gastric mucosa, the high molecular adhesive material is tightly combined together under the comprehensive actions of mechanical binding force, hydrogen bonds, van der waals force, electrostatic attraction, covalent bonds, hydrophobic bonds and the like, so that the release time is prolonged, but the gastric adhesive preparation, particularly the biological adhesive preparation, can be influenced by gastric acid and mucus due to the characteristics of the gastric adhesive preparation. The gastric retention swelling preparation has small volume when being taken orally, immediately swells after being swallowed into the stomach, and has large volume enough to resist the discharge of the gastric retention swelling preparation into duodenum through pylorus, and mainly uses some water absorptionThe preparation can be gradually eroded after the medicine is released and safely discharged out of the body, but the complete expansion of the preparation can not be completely finished before the stomach is emptied.

In conclusion, the long-acting drug delivery preparation for gastric retention also has the limitations, is still greatly influenced by food and gastric emptying, has complex production process and low drug encapsulation efficiency, easily remains toxic organic solvent, and is difficult to achieve the requirements of stability and reliability in large-scale batch production; part of the medicine can not release medicine uniformly, and the sustained and controlled release effect can not be achieved; meanwhile, the preparation can be generally retained in the stomach for only 5 to 6 hours, and the time is short. Therefore, there is a need to develop novel gastroretentive long-acting formulations.

SUMMERY OF THE UTILITY MODEL

The utility model aims to provide a long-acting preparation retained in the stomach to solve the problems of short retention time, non-uniform drug release, complex production process and the like of the existing long-acting drug delivery preparation retained in the stomach.

The purpose of the utility model is realized like this:

the long-acting preparation retained in the stomach comprises a gastric soluble capsule shell and a medicine release unit, wherein the medicine release unit is folded into a geometric shape and is arranged in the gastric soluble capsule shell, the medicine release unit comprises a long and thin component and a biodegradable connecting piece, two ends of the long and thin component are closed, at least one medicine release hole is formed in the pipe wall of the long and thin component, and medicines are arranged in the long and thin component; the biodegradable connector is used for connecting two ends of the elongated member.

Optionally, the elongated member is a silicone rubber tube, preferably a medical sterile silicone tube; preferably, the inner diameter of the silicone tube is 1-5 mm; preferably, the outer diameter of the silicone tube is 1.5-8 mm; preferably, the length of the silicone tube is 5.0-20.0 cm.

Preferably, the aperture and the number of the drug release holes formed in the tube wall of the elongated member can be determined according to the time and the rate of drug release; preferably, one side of the pipe wall of the slender component is provided with a drug release hole, and two ends of the slender component are provided with a section of pipe wall without holes so as to seal the two ends of the slender component and be connected with the biodegradable connecting piece; preferably, the aperture of the drug release hole is 0.2 mm-0.8 mm; preferably, the number of the medicine releasing holes is 1-10.

Specifically, the silicone tube longitudinal section internal diameter is 2mm, and the external diameter is 3mm, and length is 9cm, the both ends of silicone tube adopt silicon rubber special adhesive (for example nontoxic, can be to silicon rubber effective adhesion and seal effectual glue) to seal, one side trompil of silicone tube wall, the aperture is 0.4mm ~0.8mm, and the trompil position is selected between 0.5cm to 8.5cm section, confirms that the trompil figure is 7~10 according to fixed hole interval.

The biodegradable connector is a degradable suture, the degradation time of the biodegradable connector can be determined according to the drug release time, and the optimal degradation time is 3-14 days.

Preferably, the medicament is a slow-release medicament, and is prepared from medicament-carrying and slow-release auxiliary materials and the like.

The drug loading is not particularly limited in terms of the drug effect and the like, as long as it is an orally administrable active ingredient; the effective components can be gastrointestinal drug, chemotherapeutic drug, bronchodilator, cardiotonic, hypotensive drug, vasodilator, vasoconstrictor, vasoenhancer, antipyretic, analgesic, anti-inflammatory drug, hyperlipidemia drug, antipsychotic drug, antibiotic, antiepileptic drug, anti-Parkinson drug, antihistaminic drug, anxiolytic drug, osteoporosis drug, skeletal muscle relaxant, hypnotic and sedative drug, antidiarrheal drug, peptic ulcer drug, autonomic nerve drug, psychogenic drug, antacid drug, intestine regulating drug, antitussive and expectorant drug, spasmolytic drug, gout therapeutic drug, diabetes drug, arrhythmia drug, hormone drug, diuretic drug, etc. Supplements (supplements) such as vitamins and amino acids, or nutritional ingredients can also be used as the active ingredient. These drugs may be used alone or in combination of two or more.

The slow release adjuvant can be hydrophilic gel skeleton material such as K100M, hydroxyethyl cellulose, hypromellose, carbomer, sodium alginate, methylcellulose, carboxymethylcellulose sodium, etc.

A method for preparing a long-acting preparation retained in the stomach comprises the following steps:

(a) at least one drug release hole is arranged on the tube wall of the slender component;

(b) filling the interior of the elongated member with a drug and closing both ends of the elongated member;

(c) connecting the biodegradable connecting piece with two ends of the slender member, folding into geometric shape, and filling into gastric soluble capsule shell.

Optionally, the drug is a sustained-release drug micro-tablet, which is prepared by adding a drug carrier and sustained-release excipients into a suitable solvent (water or ethanol with different concentrations), and then pressing into a micro-tablet adapted to the inner diameter of the tube of the elongated member by using a special mold, so as to fill the sustained-release drug micro-tablet into the elongated member.

The utility model discloses the unit setting that releases medicine that will fold for geometric shape dissolves in the stomach capsule shell, dissolve in the stomach when the capsule shell, the long and thin component in the unit that releases medicine is expanded and is formed cyclic annularly, can not pass through the stomach pylorus, thereby realize the gastric retention, release rate and the time of releasing medicine of medicine are adjusted through the medicine hole of releasing that sets up different quantity and diameter on long and thin component simultaneously, biodegradable connector can degrade gradually in the stomach along with the time lapse, long and thin component can discharge smoothly after forming linear pipe in vitro, the time of delay of degradation time control preparation in the stomach through biodegradable connector.

The utility model discloses long-acting preparation medicine release rate of being detained in the stomach is steady, clinical administration is convenient, avoided once or several times of dosing daily, especially be suitable for like old person, children, have swallowing difficulty or to the patient of taking medicine resistance, can improve patient and use the compliance of medicine, and take effect soon, the bioavailability is high, the not enough in the aspect of clinical application of ordinary tablet on the market at present has been solved, and its preparation method is simple, the production process is easy to control, stable in quality is reliable, the medicine entrapment rate is high, do not contain poisonous and harmful substance, be suitable for large-scale batch production.

Drawings

Figure 1 is a schematic diagram of the structure of a drug release unit in a gastric retention depot.

Figure 2 is a schematic diagram of the structure of the extended release unit in the gastric retention depot.

In the figure, 1, a medical sterile silicone tube, 2, a medicine filling section, 3, a medicine releasing hole, 4, a sealing section, 5 and a biodegradable connecting piece.

Fig. 3 is a graph showing the daily release profile (a) and the cumulative release profile (b) of the huperzine A gastric retentive long acting formulation prepared in example 2.

Fig. 4 is a graph (a) showing the daily release profile and the cumulative release profile (b) of the huperzine A gastric retentive long acting formulation prepared in example 5.

Fig. 5 is an endoscopic photograph of the gastro-retentive depot prepared in example 6 in the stomach of a dog.

Fig. 6 is an X-ray of the gastro-retentive, depot prepared in example 6 in the stomach of a dog.

Detailed Description

The present invention is further illustrated by the following examples, which are given by way of illustration only and are not intended to limit the scope of the present invention in any way.

Procedures and methods not described in detail in the following examples are conventional methods well known in the art, and the reagents used in the examples are either analytically or chemically pure and are either commercially available or prepared by methods well known to those of ordinary skill in the art. The following embodiments all achieve the object of the present invention.

Example 1

Weighing 4mg of huperzine A and 1.5g of hydroxypropyl methylcellulose K100M, dissolving huperzine A in 0.5ml of 75% ethanol, uniformly pouring into K100M, and sufficiently mixing to obtain a soft material; pressing into sustained release drug micro-tablets with diameter of 1.9mm by using a special mould, and drying for later use.

Taking a medical sterile silicone tube (the inner diameter of a longitudinal section is 2mm, the outer diameter is 3 mm) with the length of 9cm, opening a hole on one side of the tube wall, wherein the hole diameter is 0.5mm, and uniformly opening 7 holes between sections of 0.5cm to 8.5cm of the silicone tube; filling the sections of 0.5cm to 8.5cm of the perforated silicone tube with the slow-release drug micro-tablets, and sealing the empty sections which are 0.5cm away from the two ends of the perforated silicone tube by filling a special adhesive for silicone rubber; and (3) sewing the sealed silica gel section by using a degradable suture to form a closed medicament-containing silica gel ring, folding the silica gel ring, and filling the folded silica gel ring into a shell of the gastric-soluble capsule to obtain the long-acting preparation retained in the stomach.

Example 2

A long-acting preparation for gastric retention containing 4mg of huperzine A was prepared as in example 1, and the long-acting preparation for gastric retention thus obtained was put in a glass bottle, 10ml of water was added thereto, and the stopper was sealed, and the 6 groups were paralleled. Placing into shaking table, rotating at shaking table speed of 75r/min, measuring light absorption value by ultraviolet every day, then changing water by 10ml, continuously placing into shaking table, and measuring for 15 days. Daily measurements were recorded, averaged, and daily and cumulative release profiles were plotted, with the results shown in figure 3.

Example 3

Taking a medical sterile silicone tube with the length of 9cm (the inner diameter of a longitudinal section is 2mm, the outer diameter is 3 mm), opening a hole at one side of the tube wall, wherein the hole diameter is 0.5mm, and uniformly opening 9 holes between sections of 0.5cm to 8.5cm of the silicone tube; filling the sections of 0.5cm to 8.5cm of the perforated silicone tube with the slow-release drug micro-tablets, and sealing the empty sections which are 0.5cm away from the two ends of the perforated silicone tube by filling a special adhesive for silicone rubber; and (3) sewing the sealed silica gel section by using a degradable suture to form a closed medicament-containing silica gel ring, folding the silica gel ring, and filling the folded silica gel ring into a shell of the gastric-soluble capsule to obtain the long-acting preparation retained in the stomach.

Example 4

Weighing 60mg of tamsulosin hydrochloride and 1.5g of hydroxypropyl methylcellulose K100M, dissolving tamsulosin hydrochloride by 0.5ml of 75% ethanol, uniformly pouring into K100M, and sufficiently and uniformly mixing to obtain a soft material; pressing into sustained release drug micro-tablets with diameter of 1.9mm by using a special mould, and drying for later use.

Example 5

The long-acting preparation for gastric retention containing tamsulosin hydrochloride 3mg was prepared by the method of example 4, and the obtained long-acting preparation for gastric retention was put in a glass bottle, 10ml of water was added, and the stopper was sealed, and the 6 groups were paralleled. Placing into shaking table, rotating at shaking table speed of 75r/min, measuring light absorption value by ultraviolet every day, then changing water by 10ml, continuously placing into shaking table, and measuring for 15 days. Daily measurements were recorded, averaged, and daily and cumulative release profiles were plotted, with the results shown in fig. 4.

Example 6

To confirm that the formulation achieved gastric retention, barium sulfate (20 wt%) was used in place of the drug in the gastric retention dosage form and they were administered to dogs that fasted for one day. The dog was placed in a prone position for the imaging procedure, and the intragastric state of the formulation was photographed using an endoscope to further confirm the intragastric retention effect of the formulation. The resulting gastro-retentive depot formulation was shown in figures 5 and 6 as an endoscopic and X-ray photograph of the stomach of a dog.

Claims

1. The long-acting preparation is characterized by comprising a gastric soluble capsule shell and a medicine release unit, wherein the medicine release unit is folded into a geometric shape and is arranged in the gastric soluble capsule shell, the medicine release unit comprises a long and thin member and a biodegradable connecting piece, two ends of the long and thin member are closed, at least one medicine release hole is formed in the wall of the tube, and medicines are arranged in the long and thin member; the biodegradable connector is used for connecting two ends of the elongated member.

2. The gastro-retentive, long-acting formulation of claim 1, wherein the elongate member is a medical sterile silicone tube.

3. The long-acting preparation retained in the stomach according to claim 2, wherein the silicone tube has an inner diameter of 1 to 5mm, an outer diameter of 1.5 to 8mm, and a length of 5.0 to 20.0 cm.

4. The gastro-retentive, long-acting formulation of claim 1, wherein the elongated member has a drug release hole formed in one side of the wall of the elongated member and a non-perforated wall is left at each end of the elongated member to close the ends of the elongated member and to connect to the biodegradable connector.

5. The long-acting preparation retained in the stomach according to claim 1, wherein the diameter of the drug release hole is 0.2mm to 0.8mm, and the number of the drug release holes is 1 to 10.

6. The long-acting preparation retained in the stomach according to claim 2, wherein the inner diameter of the longitudinal section of the silicone tube is 2mm, the outer diameter is 3mm, the length is 9cm, the two ends of the silicone tube are closed, one side of the wall of the silicone tube is provided with an opening, the diameter of the opening is 0.4 mm-0.8 mm, the position of the opening is 0.5 cm-8.5 cm, and the number of the drug release holes is 7-10.

7. The gastro-retentive, depot formulation of claim 1, wherein the biodegradable connector is a degradable suture.

8. The gastro-retentive, long-acting formulation of claim 7, wherein the degradable suture has a degradation time of 3 to 14 days.