CN114191389A - Preparation method and application of mesalazine enema - Google Patents

Preparation method and application of mesalazine enema Download PDF

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CN114191389A
CN114191389A CN202210004948.9A CN202210004948A CN114191389A CN 114191389 A CN114191389 A CN 114191389A CN 202210004948 A CN202210004948 A CN 202210004948A CN 114191389 A CN114191389 A CN 114191389A
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mesalazine
parts
enema
stirring
enema liquid
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叶世春
王腾飞
王祖焕
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SICHUAN JEWELLAND PHARMACEUTICAL CO Ltd
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SICHUAN JEWELLAND PHARMACEUTICAL CO Ltd
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/08Solutions
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/60Salicylic acid; Derivatives thereof
    • A61K31/606Salicylic acid; Derivatives thereof having amino groups
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0031Rectum, anus
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

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  • Pharmacology & Pharmacy (AREA)
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  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention discloses a mesalazine-containing enema which is prepared from the following raw material medicines and auxiliary materials in parts by weight: 3.0-8.0 parts of mesalazine, 1.0-2.0 parts of xanthan gum, 20.0-44.0 parts of edetate disodium, 10.0-15.0 parts of sodium benzoate, 0.5-1.0 part of carbomer, 9.0-28.0 parts of pH regulator and 1.0-4.0 parts of antioxidant. The enema containing mesalazine can be conveniently applied to patients who are not suitable for swallowing, the dosage form directly acts on rectum, the medicine is quickly released, and the bioavailability is improved.

Description

Preparation method and application of mesalazine enema
The technical field is as follows: the invention relates to a medicinal preparation, in particular to an enema containing mesalazine.
Background art:
mesalazine is white-like crystalline powder, odorless, tasteless, and gradually darkened with light, and is dissolved in water slightly and insoluble in ethanol, acetone or chloroform. Slightly dissolved in dilute sodium hydroxide (2%) solution or dilute hydrochloric acid (9.5% -10.5%) solution.
Mesalazine was developed by the company cenoft, and since then the united states area was licensed to the company Meda and the japanese area was licensed to apricot forest for pharmaceutical use, there are a number of dosage forms on the market. Mesalazine enema was first marketed in the United states in 1987 and later approved in Germany 5 months in 2009, the dosage form was not marketed in Japan. The trade name is Rowasa in the United states and salofack in the Germany. Mesalazine is a protease phosphatase (PP-2A) inhibitor and is used for treating ulcerative colitis.
Mesalazine is influenced by the first-pass effect of the liver, and has low bioavailability, however, the clinical conventional oral dosage forms such as capsules, tablets and the like have the problems of frequent administration and poor patient compliance. Therefore, the development of a novel mesalazine administration form is urgently needed.
The enema has the advantages of simple preparation method, no need of taking and chewing, direct action on target spot, and quick action, and is especially suitable for bedridden patients and the old who have dysphagia. Avoids the first pass effect of the liver and improves the bioavailability of the medicine.
The invention content is as follows: aiming at the prior art, the invention provides the enema containing mesalazine, which can be conveniently applied to patients with dysphagia, and has the advantages of rapid drug release and improved bioavailability.
The invention is realized by the following technical scheme:
an enema containing mesalazine is prepared from the following raw material medicines and auxiliary materials in parts by weight: 3.0-8.0 parts of mesalazine, 1.0-2.0 parts of xanthan gum, 20.0-44.0 parts of edetate disodium, 10.0-15.0 parts of sodium benzoate, 0.5-1.0 part of carbomer, 9.0-28.0 parts of pH regulator and 1.0-4.0 parts of antioxidant.
Preferably, the traditional Chinese medicine is prepared from the following raw material medicines and auxiliary materials in parts by weight: 4.0 parts of mesalazine, 1.0 part of xanthan gum, 40.0 parts of edetate disodium, 13 parts of sodium benzoate, 1.0 part of carbomer, 13.0 parts of pH regulator, 1.0 part of antioxidant and the balance of purified water.
The xanthan gum is selected from 75, 180, preferably 75. The xanthan gum is used as a suspending agent, and the stability and the release of the medicine are improved.
The pH regulator is selected from sodium acetate and potassium acetate, preferably potassium acetate.
Preferably, the specification of each bottle of the enema containing mesalazine is 4g, and the weight content of the mesalazine is as follows: 4 g/bottle.
The preparation method of the enema containing mesalazine comprises the following steps:
(1) preparing liquid: adding metal chelating agent, pH regulator and antiseptic into appropriate amount of purified water, stirring and dissolving;
(2) preparing an auxiliary suspension: adding the suspending agent in the formula amount under stirring to fully swell;
(3) dispersing main drugs: adding antioxidant and principal drug in a formula amount, and stirring uniformly;
(4) homogenizing: homogenizing in vacuum state with homogenizer, adding water to full volume, and stirring;
(5) filling: and filling the mesalazine solution into a bottle to obtain the enema containing mesalazine.
Experiments prove that after the enema containing mesalazine and the mesalazine tablet are applied to a single rat dosage form, the relevant parameters are shown in the following table 1.
TABLE 1 summary of pharmacokinetic relevant parameters
Preparation Cmax(ng.ml-1.mg-1) AUCmax(ng.ml-1.mg-1) CL/F(L/min/kg)
Enema liquid 381 619 5.87
Tablet formulation 265 187 25.6
The beneficial technical effects of the invention are as follows: the enema containing mesalazine can be conveniently applied to patients with dysphagia, the drug is quickly released, and the bioavailability is improved.
Description of the drawings:
FIG. 1: the enema, mesalazine enema (imitation drug) prepared according to the patent is compared with the dissolution curve of mesalazine oral tablets.
FIG. 2: the pharmacokinetics of the enema liquid containing mesalazine and the common tablet in rats are compared.
Detailed Description
The present invention will be further described with reference to the following examples.
Example 1: preparing 100 bottles of enema containing mesalazine, wherein each bottle contains 4g of mesalazine, and the dosage of the raw materials and the auxiliary materials is as follows: 400g of mesalazine, 1.8g of xanthan gum, 4.0g of edetate disodium, 1.3g of sodium benzoate, 0.1g of carbomer, potassium acetate: 1.9g and antioxidant 0.1 g.
The preparation method comprises the following steps:
(1) preparing liquid: adding metal chelating agent, pH regulator and antiseptic into appropriate amount of purified water, stirring and dissolving;
(2) preparing an auxiliary suspension: adding the suspending agent in the formula amount under stirring to fully swell;
(3) dispersing main drugs: adding antioxidant and principal drug in a formula amount, and stirring uniformly;
(4) homogenizing: homogenizing in vacuum state with homogenizer, adding water to full volume, and stirring;
(5) filling: and filling the mesalazine solution into a bottle to obtain the enema containing mesalazine.
Comparative example 1: mesalazine enema (imitation drug): mesalazine enema sold in China
Comparative example 2: mesalazine oral tablet: dissolution test of domestic marketed mesalazine oral tablet (one):
the experimental method comprises the following steps: the in vitro dissolution curve of the mesalazine preparation is measured according to the general rules of the four parts of the China pharmacopoeia 2020 edition. Ultrasonic degassed PBS (Ph7.2) was used as release medium at 37. + -. 0.5 ℃. 5ml of release liquid is taken at the rotating speed of 50r/min for 5min,10min,15min,20min,30min,45min and 60min, a blank release medium with the same temperature and quantity is supplemented, after filtration through a microporous membrane, the subsequent filtrate is taken for ultraviolet determination.
As a result: from fig. 1 it can be seen that the enema of mesalazine prepared as described in this patent has a better dissolution profile than the other products.
(II) in vivo pharmacokinetic experiment:
the experimental method comprises the following steps:
12 SD rats with weight of 250 + -20 g were fasted for 1 day before the test and were randomly divided into enema and tablet groups.
The mesalazine enema group rats were administered rectal enema (prepared in example 1) and the tablet group was administered 1 tablet of the commercially available product. Collecting blood samples from rat venous sinus 10min,15min,30min,1h,1.5h,2h,4h,8h,12h,24h,36h and 48h after administration, placing the blood samples into heparinized anticoagulation tubes, centrifuging the blood sample at 6000rpm for 5min, and separating plasma to determine the mesalazine content in the plasma.
The experimental results are as follows: see figure 2 and table 1 for details. The enema containing mesalazine of the invention provides 374ng.ml per mg of mesalazine in a single dosage form after administration to rats-1.mg-1Mean maximum blood concentration (C)max). While mesalazine tablet is used for single dosage to ratsAfter administration, the dosage form provides 277ng per mg of mesalazine-1.mg-1(Cmax)。
The enema containing mesalazine of the invention provides 725.8ng per mg of mesalazine in a single dosage form after administration to rats-1.mg-1Average bioavailability (AUC) ofmax). And the mesalazine tablet provides 469.6ng per mg of mesalazine in the dosage form after a single dose administration to rats-1.
mg-1(AUCmax)。
The enema containing mesalazine of the present invention provided clearance (CL/F) of mesalazine of 6.92L/min/kg after single dosage administration to rats. While the mesalazine tablet provided 10.41L/min/kg (CL/F) per mg of mesalazine in the dosage form after single dose administration to rats.
TABLE 2 measurement of plasma concentration in rats
Figure BDA0003455168050000031
Figure BDA0003455168050000041
(3) Investigation of stability test
The accelerated stability of the experimental samples (example 1) was examined according to pharmacopoeia stability test guidelines 2020 (examination conditions: 40 ℃. + -. 2 ℃ C., RH 75%. + -. 5%), and the main examination results were as follows:
Figure BDA0003455168050000042
the results show that: in the process of expecting the experimental sample for 6 months, the main quality indexes of the experimental sample accord with the regulations, and the stability of the sample prepared by the prescription process is good.

Claims (6)

1. An enema comprising mesalazine, characterized in that: is prepared from the following raw material medicaments and auxiliary materials in part by weight: 3.0-8.0 parts of mesalazine, 1.0-2.0 parts of xanthan gum, 20.0-44.0 parts of edetate disodium, 10.0-15.0 parts of sodium benzoate, 0.5-1.0 part of carbomer, 9.0-28.0 parts of pH regulator and 1.0-4.0 parts of antioxidant.
2. The enema liquid comprising mesalazine according to claim 1, characterized in that: the process comprises the following steps: adding metal chelating agent, pH regulator and antiseptic into appropriate amount of purified water, stirring and dissolving; adding the suspending agent in the formula amount under stirring to fully swell; adding antioxidant and principal drug in a formula amount, and stirring uniformly; homogenizing with homogenizer, adding water to full volume, and stirring; and (6) filling.
3. The enema liquid comprising mesalazine according to claim 1 or 2, characterized in that: the particle size d (90) of the mesalazine is in accordance with 20-40 μm.
4. The enema liquid comprising mesalazine according to claim 1 or 2, characterized in that: the xanthan gum is selected from 75.
5. The enema liquid comprising mesalazine according to claim 1 or 2, characterized in that: the carbomer type is selected from B.
6. The method for preparing a enema liquid containing mesalazine according to any one of claims 1 to 5, characterized in that: the solution is homogenized in vacuum.
CN202210004948.9A 2022-01-04 2022-01-04 Preparation method and application of mesalazine enema Pending CN114191389A (en)

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Application Number Priority Date Filing Date Title
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CN114191389A true CN114191389A (en) 2022-03-18

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