WO2017114228A1 - Ipragliflozin oral solid preparation and preparation method thereof - Google Patents

Abstract

An ipragliflozin oral solid preparation can be in the dosage form of tablets, powders, or capsules and comprises an anti-adhesion agent, filler, and an optional disintegrant, binder, lubricant, and coating material. Correspondingly, also provided is a preparation method of the oral solid preparation. When the oral solid preparation is in the dosage form of tablets, the method comprises the steps of forming a premix, forming a medicated mixture, tableting, and coating. When the oral solid preparation is in the dosage form of capsules, the medicated mixture is filled into capsule shells. When the oral solid preparation is in the dosage form of powders, the medicated mixture is packaged in packaging containers.

Description

Iglipide oral solid preparation and preparation method thereof Technical field

The invention relates to the field of pharmaceutical preparations. Specifically, the present invention provides an ezetide oral solid preparation and a preparation method thereof.

Background technique

Glucose cotransporter (SLGT) is a class of membrane proteins that transport glucose into cells. SLGT has two subtypes, SLGT1 and SLGT2, which are distributed in the small intestine mucosa and renal tubules, respectively. SLGT2 plays a key role in proximal tubular glucose reabsorption.

Iglitazone is a net-type SLGT2 inhibitor that selectively neutralizes SLGT2 so that glucose in the renal tubules cannot be reabsorbed into the blood, but is excreted in the urine, thereby lowering blood glucose levels. Iglister purifying name is (1S)-1,5-anhydro-1-{3-[(1-benzothiophen-2-yl)methyl]-4-fluorophenyl}-D-glucitol, The structure of the eutectic formed by ezepetide and L-valine is as shown in the formula (I).

Chinese patent CN 104382859A dissolves or disperses SLGT2 inhibitor, crystal inhibitor, filler in a certain amount of aqueous organic solvent, and prepares particles containing SLGT2 inhibitor, crystal inhibitor and filler by spray drying method. Further prepared into tablets, capsules, granules and the like; the preparation method solves the problem that the SLGT2 inhibitor has poor water solubility, resulting in low dissolution and bioavailability.

Chinese patent CN 102596206B discloses a solid pharmaceutical composition comprising (1S)-1,5-anhydro-1-{3-[(1-benzothiophen-2-yl)methyl]-4 a cocrystal of -fluorophenyl}-D-glucitol and L-valine and crystalline cellulose. In the preparation of a capsule preparation containing a co-crystal of ezepex and L-valine, it was found that the disintegration property was poor due to the strong aggregability of the co-crystals of ezepet and L-valine, resulting in a drug The problem of slower dissolution rate. If the disintegration property of the preparation is poor and the dissolution rate of the drug is slow, there is a possibility that the bioavailability is lowered and the pharmacologically sufficient therapeutic effect cannot be obtained. The production method disclosed in this patent is a step of mixing a mixture of ezepetide and L-valine with crystalline cellulose and subjecting the resulting mixture to wet granulation.

It can be seen that the net-type SLGT2 inhibitors generally have a problem of poor solubility or poor disintegration, resulting in low bioavailability of such drugs. In order to solve the above technical problems, the present invention provides a simpler oral solid preparation comprising L-proline-epigluten eutectic and a simpler preparation process thereof, which is different from the prior art. The disintegration and in vitro dissolution of the L-proline iriaglip eutectic are improved.

Summary of the invention

The present invention provides an ezetide oral solid preparation comprising L-valine iriaglip eutectic, an anti-adherent, a filler, and optionally a disintegrant, a binder, a lubricant, Coating material and capsule shell.

The ezetigide oral solid preparation of the present invention is a tablet, a powder or a capsule.

Accordingly, the present invention also provides a process for the preparation of the ezetigide oral solid preparation of the present invention.

DRAWINGS

Figure 1 is a graph showing the drug elution amount-time of the tablets of Examples 2-4.

Figure 2 is a graph showing the drug elution amount-time of the capsules of Examples 5-7.

detailed description

The present invention provides an ezetide oral solid preparation comprising an L-valine eclipide eutectic, an anti-adherent, a filler, optionally further comprising a binder, a lubricant and a disintegrant The ezepetide oral solid preparation of the present invention further comprises any one of a coating material and a capsule shell.

The ezetigide oral solid preparation of the present invention is a tablet, a powder or a capsule.

In the context of the present invention, an anti-adhesive agent refers to a substance which is commonly used in pharmaceutical preparations to reduce the viscosity of a drug substance or an auxiliary material. Since L-valine ezepide has strong agglutination, it is necessary to add an anti-adhesive agent to prevent agglomeration of the drug substance. Herein, the anti-tacking agent may be fumed silica or talc, but is not limited thereto. It is preferred to use fumed silica as an anti-tack agent.

In the context of the present invention, the filler refers to a pharmaceutical excipient which is mainly used for filling the weight or volume of the tablet, thereby facilitating tableting. Commonly used fillers are starches, sugars, celluloses and inorganic salts. Herein, the filler is, for example, starch, lactose, mannitol, xylitol, sucrose, microcrystalline cellulose, but is not limited thereto. Microcrystalline cellulose is preferably used as the filler.

In the context of the present invention, the binder refers to a viscous substance that is added to the pharmaceutical powder to cause it to stick during the formulation process. Herein, the binder may be, for example, polyvinylpyrrolidone (PVP), hypromellose (HPMC), hydroxypropylcellulose (HPC), sodium carboxymethylcellulose (CMC-Na), but Not limited to this. Preference is given to using polyvinylpyrrolidone as a binder.

In the context of the present invention, the lubricant may be, for example, magnesium stearate, calcium stearate or sodium stearyl fumarate, but is not limited thereto. Magnesium stearate is preferably used as the lubricant.

In the context of the present invention, a disintegrant refers to a substance which usually causes a tablet to be rapidly cleaved into fine particles in a gastrointestinal fluid, thereby allowing the functional ingredient to rapidly dissolve and absorb and function. Herein, the disintegrant is, for example, sodium carboxymethyl starch, crosslinked polyvinylpyrrolidone (PVPP), low-substituted hydroxypropylcellulose (L-HPC), pregelatinized starch, but is not limited thereto. Preference is given to using crosslinked polyvinylpyrrolidone as a disintegrant.

In the context of the present invention, the coating material may be a conventional gastric-soluble coating material such as hypromellose, polyvinyl alcohol or a mixture thereof, or

A gastric-soluble coating powder, but is not limited thereto. Preferred use

A series of gastric-soluble coating powders are used as coating materials.

In a preferred embodiment of the invention, the eziglipide oral solid preparation is a tablet comprising L-valine iriaglip eutectic 10-25 based on the total weight of the tablet %, disintegrant 1-4.5%, anti-adhesive agent 0.5-5%, filler 55-80%, binder 5-9%, lubricant 0.01-2%, and coating material 0.5-4%;

Preferably, it comprises L-valine iriaglip eutectic 12-22%, disintegrant 1.5-4%, anti-adherent 0.7-3%, filler 60-75%, binder 6-8%, 0.3-1.5% lubricant and 1-3% coating material;

Most preferably, it comprises 15-20% of L-valine iriagide eutectic, 2.5-3.5% of disintegrant, 1-2% of anti-adhesive agent, 65-70% of filler, and 6.5-7.5% of binder. , lubricant 0.5-1.2% and coating material 1.5-2.5%.

In a preferred embodiment of the invention, the ezetide oral solid preparation of the invention is a tablet having a coating film coated with a gastric-soluble coating material.

In a preferred embodiment of the present invention, the eziglipide oral solid preparation is a capsule or a powder, which is filled with a powder containing L-valine epigrel eutectic, based on the medicated powder The total weight, which comprises 10-25% of L-valine ignequine eutectic, 0.5-5% of anti-adhesive agent, 70-89% of filler;

Most preferably, it comprises 12-22% of L-valine epiglipide eutectic, 0.7-3% of anti-adhesive agent, and 75-85% of filler.

Accordingly, the present invention also provides a process for the preparation of the ezetigide oral solid preparation of the present invention.

In the case where the erglipide oral solid preparation of the present invention is a tablet, the preparation method comprises the following steps:

(1) mixing L-valine angaglip eutectic and anti-adhesive agent to form a premix of the drug substance;

(2) adding the filler, binder, disintegrant to the premix of the drug substance, and mixing uniformly to form a drug-containing mixture;

(3) mixing the drug-containing mixture of step (2) with a lubricant, and tableting to obtain a plain tablet;

(4) A film coat is coated with a stomach-soluble coating material.

In the case where the ezetetide oral solid preparation of the present invention is a capsule, the preparation method comprises:

(1) mixing L-valine angaglip eutectic and anti-adhesive agent to form a premix of the drug substance;

(2) adding the filler to the premix of the drug substance, mixing uniformly to form a drug-containing mixture;

(3) The drug-containing mixture of the step (2) is placed in a capsule shell.

In the case where the ezetetide oral solid preparation of the present invention is a powder, the preparation method includes:

(1) mixing L-valine angaglip eutectic and anti-adhesive agent to form a premix of the drug substance;

(2) adding the filler to the premix of the drug substance, mixing uniformly to form a drug-containing mixture;

(3) The drug-containing mixture of step (2) is packaged in a suitable packaging container.

In a preferred embodiment of the invention, the packaging container may be a vial, a sealed pouch or a foil pouch, or other sealed container that may be used.

Example

The present invention will be further described in detail below with reference to the embodiments. The following examples are not to be construed as limiting the invention. Techniques implemented in accordance with the teachings of the present invention are within the scope of the present invention.

Example 1: Preparation of L-valine ignequine

In this embodiment, the materials and reagents used are commercially available.

Preparation of the compound of formula 3:

Compound 1 (160.6 g, 0.5 mol) was added to a 3 L round bottom three-necked flask, dissolved in 400 ml of THF and 800 ml of toluene, and protected with argon. After cooling to -78 ° C, a 2.5 M solution of n-butyllithium in hexane (184 ml, 0.5 mol) was added dropwise maintaining the temperature not higher than -70 °C. Stir at -78 ° C for 30 min. The reaction solution was then slowly transferred to a 2,3,4,6-tetra-O-trimethylsilyl-D-gluconolactone (236 g, 0.5 mol) of toluene precooled to -78 ° C with a double needle ( 1.1L) solution, keeping the temperature not higher than -70 °C. After stirring at -78 ° C for 30 min, methanesulfonic acid (1 L, 0.6 N MeOH) was added and the mixture was warmed to room temperature and the mixture was stirred for 16 h. Adjust the pH to 7.5 with saturated sodium bicarbonate solution (about 200 ml). The organic phase was extracted with ethyl acetate (150 ml × 3), and the organic layer was combined, washed with saturated brine (150 ml), dried over anhydrous sodium sulfate and filtered and evaporated. The toluene was dissolved by heating and poured into 1 L of n-hexane to obtain 171 g of a white crystal of the compound of the formula 3 in a yield of 78.7%.

Preparation of ezepide (formula 4):

300 ml of dichloromethane was added to a vessel, 0.3 mol of the compound of the formula 3 was weighed, and slowly added to the dichloromethane in portions to prevent agglomeration after the addition, and while stirring until completely dissolved, 96 ml of triethyl group was added to the solution. Silane, stirred and clarified, added to the dropping funnel, and then rinsed with a small amount of dichloromethane, and then added to the dropping funnel for use.

300 ml of dichloromethane was added to the reaction vessel and stirred. Purge with nitrogen for 10 minutes. Under nitrogen protection, the temperature was lowered to below -15 ° C, and 78 ml of boron trifluoride diethyl ether was added to the reaction vessel. After the addition, the intermediate 3 solution in the dropping funnel was added dropwise, and the internal temperature was maintained at -20 to -10 °C. After completion of the dropwise addition, the cooling was turned off, and stirring was continued for 2 hours. 300 ml of a saturated sodium hydrogencarbonate solution was added dropwise to the reaction mixture, and the mixture was stirred uniformly, and then the organic solvent was evaporated under reduced pressure. It was extracted twice with methyl tert-butyl ether, and methyl tert-butyl ether was combined, and washed with purified water. After standing to thoroughly separate the layers, the lower aqueous phase was discharged, and the methyl tert-butyl ether solution was dried, and then the solvent was removed by a rotary evaporator to obtain 120 g of a syrupy solid.

0.2 mol of each of ezepide and valine was added to a 3 L reactor, and it was dissolved by adding an appropriate amount of ethanol and water. Under rapid mechanical stirring, the mixture was heated to reflux for 30 min. After cooling to room temperature, an appropriate amount of n-hexane was added dropwise, cooled to -5 ° C, stirred for 3 h, and filtered. The filter cake was washed with cold 90% aqueous ethanol and n-hexane, respectively, and dried in vacuo. Then, it was recrystallized once with 90% ethanol and n-hexane, and dried under vacuum to obtain an L-valine ezepide eutectic.

Example 2: Preparation of ezepex-coated tablets

Table 1: Composition of ezepex-coated tablets

The preparation method comprises the following steps: mixing L-valine eclipide eutectic and fumed silica in a mixer for about 5 minutes, passing through a 60 mesh sieve, and waiting for; adding microcrystalline cellulose 102, PVPP, PVP K30, mixing. About 15 minutes, spare; finally Add magnesium stearate for 3 min, compress it, and use Opadry to coat it.

Example 3: Preparation of ezepex-coated tablets

Table 2: Composition of ezepex-coated tablets

Preparation method: In the present embodiment, the present invention is prepared in the same manner as in Example 1 using talc as an anti-adhesive agent, sodium carboxymethyl starch as a disintegrant, and hydroxypropyl cellulose as a binder. Iglipide oral solid preparation.

Example 4: Preparation of ezepex-coated tablets

Table 3: Composition of ezepex-coated tablets

Preparation method: In the present example, the ezetigide oral solid preparation of the present invention was prepared in the same manner as in Example 1 using PVP K30 as a binder and microcrystalline cellulose 101 as a filler.

Example 5: Preparation of ezepex hydrochloride capsules

Table 4: Composition of egeglifloxacin capsules

effect	Component	Dosage (mg / tablet)	Weight percentage (%)
Main drug	L-valine iriggide eutectic	32.15	19.6
Anti-adhesive	Fumed silica	1.8	1.1
Filler	Microcrystalline cellulose 102	130	79.3

The preparation method comprises the following steps: mixing L-valine eclipide eutectic and fumed silica for 5 min, passing through a 60 mesh sieve, and adding microcrystalline cellulose 102 for 10 min, directly filling into a capsule shell, thereby obtaining the invention Iglipide oral solid preparation.

Example 6: Preparation of egeglifloxacin capsules

Table 5: Composition of egeglifloxacin capsules

effect	Component	Dosage (mg / tablet)	Weight percentage (%)
Main drug	L-valine iriggide eutectic	64.3	18.8
Anti-adhesive	Fumed silica	7.0	2.1
Filler	Microcrystalline cellulose 102	270	79.1

The preparation method comprises the following steps: mixing L-valine eclipide eutectic and fumed silica for 5 min, passing through a 60 mesh sieve, and adding microcrystalline cellulose 102 for 10 min, directly filling into a capsule shell, thereby obtaining the invention Iglipide oral solid preparation.

Example 7: Preparation of ezepex hydrochloride capsules

Table 6: Composition of egeglifloxacin capsules

effect	Component	Dosage (mg / tablet)	Weight percentage (%)
Main drug	L-valine iriggide eutectic	32.15	19.6
Anti-adhesive	talcum powder	1.8	1.1
Filler	Microcrystalline cellulose 102	130	79.3

The preparation method comprises the following steps: mixing the L-valine eclipide eutectic and the talc powder for 5 minutes, passing through a 60 mesh sieve, adding the microcrystalline cellulose 102 for 10 minutes, and directly filling the capsule shell, thereby obtaining the Glycine oral solid preparation.

Example 8: Preparation of ezigide granules

In the present embodiment, the composition of the granules was the same as that of the exemplified capsule of Example 5, and the components were uniformly mixed according to the method described in Example 5, and then placed in a sealed bag to obtain igril. Powder.

Example 9

The coated tablets prepared in Example 2, Example 3, and Example 4 were subjected to a disintegration test. The basket is hung on the metal bracket through the stainless steel shaft at the upper end, immersed in a 1000ml beaker, and the position of the basket is adjusted to lower the screen 25mm from the bottom of the beaker. The water in the beaker contains water at a temperature of 37 °C ± 1 °C. The height of the water level causes the screen to rise 15mm below the water surface when the basket is raised. Take 6 tablets of each of the coated tablets prepared in Example 2, Example 3 and Example 4, place the glass tube of the hanging basket, add a baffle, start the disintegration device for inspection, and record the disintegration time. The results are shown in the table. 7.

Table 7: Disintegration time record table of coated tablets (unit: second)

Numbering	1	2	3	4	5	6
Example 2	9	8	9	10	9	8
Example 3	10	11	11	10	11	10
Example 4	10	10	9	10	10	9

Example 10

The coating tablets or capsules prepared in Example 2, Example 3, Example 4, Example 5, Example 6, and Example 7 were subjected to a dissolution test. The dissolution test was carried out by paddle method, 50 rpm, using 900 mL of 0.1 N hydrochloric acid solution as the dissolution medium, and the content of ezetigin in the dissolution medium was sampled at 10, 15, 30, 45 min, respectively, and the dissolution curve was plotted as a percentage of dissolution-time. . The results are shown in Figure 1 and Figure 2.

As can be seen from the results of Figs. 1 and 2, the dissolution rate of the ezepex coated tablets or capsules prepared in Examples 2 to 7 of the present invention reached 80% or more at 30 minutes. It can be seen that the solid preparation containing the L-proline iriaglip eutectic of the invention achieves good technical effects, but the composition and preparation method of the preparation are simpler, easier to operate and more energy-saving than the prior art. .

It is apparent that various other modifications, substitutions and changes can be made in the form of the above-described embodiments of the present invention without departing from the spirit and scope of the invention. Those skilled in the art can understand that various features of the technical solutions of the present invention described in the present application can be appropriately combined as needed.

Claims (10)

1. An ezetide oral solid preparation comprising L-valine iriaglip eutectic, an anti-adherent, a filler, and optionally a disintegrant, a binder, a lubricant; The gliclazide oral solid preparation further comprises any one of a coating material or a capsule shell.
2. The oral solid preparation according to claim 1, wherein the ezepetide oral solid preparation is a tablet, a powder or a capsule.
3. The oral solid preparation according to claim 1 or 2, wherein the anti-adhesive agent is fumed silica or talc, preferably fumed silica; the filler is microcrystalline cellulose, lactose, Mannitol, xylitol, sucrose, starch, preferably microcrystalline cellulose; the disintegrant is sodium carboxymethyl starch, crosslinked polyvinylpyrrolidone, low substituted hydroxypropyl cellulose, pregelatinized starch, preferably Bipolyvinylpyrrolidone; the binder is polyvinylpyrrolidone, hypromellose, hydroxypropylcellulose, sodium carboxymethylcellulose, preferably polyvinylpyrrolidone; the lubricant is magnesium stearate, hard Calcium or stearyl fumarate, preferably magnesium stearate; the coating material is hypromellose, polyvinyl alcohol or a mixture thereof, or

   

   Gastric soluble coating powder, preferably

   

   The capsule shell is a stomach soluble capsule shell.
4. The oral solid preparation according to any one of claims 1 to 3, wherein the ezepexide oral solid preparation is a tablet comprising L-脯 based on the total weight of the tablet Isolidine eutectic eutectic 10-25%, disintegrant 1-4.5%, anti-adherent 0.5-5%, filler 55-80%, binder 5-9%, lubricant 0.01-2 %, and coating material 0.5-4%;

   Preferably, it comprises L-valine iriaglip eutectic 12-22%, disintegrant 1.5-4%, anti-adherent 0.7-3%, filler 60-75%, binder 6-8%, 0.3-1.5% lubricant and 1-3% coating material;

   Most preferably, it comprises 15-20% of L-valine iriagide eutectic, 2.5-3.5% of disintegrant, 1-2% of anti-adhesive agent, 65-70% of filler, and 6.5-7.5% of binder. , lubricant 0.5-1.2% and coating material 1.5-2.5%.
5. A method of preparing the ezepetide oral solid preparation of claim 4, comprising:

   (1) mixing L-valine angaglip eutectic and anti-adhesive agent to form a premix of the drug substance;

   (2) adding the filler, disintegrant, and binder to the premix of the drug substance, and mixing uniformly to form a drug-containing mixture;

   (3) mixing the drug-containing mixture of step (2) with a lubricant, and tableting to obtain a plain tablet;

   (4) Coating the film coat with a coating material.
6. The erglipide oral solid preparation according to any one of claims 1 to 3, wherein the ezepexide oral solid preparation is a capsule or a powder containing a total of L-valine-egliflozin a drug-containing powder of a crystal, an anti-adhesive agent, and a filler.
7. The oral solid preparation according to claim 6, wherein the anti-adhesive agent is contained in an amount of 10 to 25% based on the total weight of the medicated powder. 0.5-5%, filler 70-89%;

   Most preferably, it comprises 12-22% of L-valine epiglipide eutectic, 0.7-3% of anti-adhesive agent, and 75-85% of filler.
8. A method of preparing the capsule of claim 6 or 7, comprising:

   (1) mixing L-valine angaglip eutectic and anti-adhesive agent to form a premix of the drug substance;

   (2) adding the filler to the premix of the drug substance, mixing uniformly to form a drug-containing mixture;

   (3) The drug-containing mixture of the step (2) is filled into the capsule shell.
9. A method of preparing the powder of claim 6 or 7, comprising:

   (1) mixing L-valine angaglip eutectic and anti-adhesive agent to form a premix of the drug substance;

   (2) adding the filler to the premix of the drug substance, mixing uniformly to form a drug-containing mixture;

   (3) The drug-containing mixture of the step (2) is enclosed in a packaging container.
10. The method of claim 9 wherein said packaging container is a vial, a sealed pouch or a foil pouch.

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