CN102106838A - Sulfasalazine enteric-coated preparation and preparation method thereof - Google Patents

Abstract

The invention provides high-release sulfasalazine enteric-coated preparation which is tablet comprising sulfasalazine as active component and pre-gelatinized starch, starch, magnesium stearate and sodium carboxymethyl starch as pharmaceutic adjuvants and a gastric soluble coat and an enteric coat are sequentially coated. The release of the preparation reaches over 85 percent, and the absorption of a human body on the medicine is improved, thereby reducing adverse reactions of the sulfasalazine in the process of being absorbed by the human body and improving the compliance of patients during administration and further facilitating the treatment of the sulfasalazine on rheumatoid arthritis and inflammatory bowel disease.

Description

A kind of sulfasalazine enteric coated preparation and preparation method thereof

Technical field

The present invention relates to pharmaceutical preparation, be specifically related to sulfasalazine intestinal controlled release preparation of a kind of high release and preparation method thereof.

Background technology

Sulfasalazine (SASP) passes through the azo bond be combined into by sulfapyridine (SP) and 5-aminosalicylic acid (5-ASA) two parts, and enteritis and rheumatoid arthritis are had good efficacy.But the individual variation when this medicine is absorbed is bigger, and the oral about 10%～30%SASP in back is from little intestinal absorption, and unabsorbed SASP is cracked into SP and 5-ASA by the antibacterial azo reductase after arriving large intestine.About 90%SP is from big intestinal absorption. and 5-ASA only has 20%～30% to be absorbed, and absorption portion is not discharged through stool.The SASP part that absorbs is SP and 5-ASA at liver metabolism, and residue SASP discharges from urine with prototype.SP is that acetylsulfapyridine (AcSP) is its main metabolic pathway at liver through N-acetyltransferase 2 (NAT2) metabolism; wherein a part of AcSP directly discharges through urine; remaining AcSP and SP carry out hydroxylating and glucoside acidify metabolism; the glucosiduronic acid conjugate is discharged through urine; hydroxylated metabolite may also be discharged by urine, and the 5-ASA acetyl of absorption turns to acetylation 5-aminosalicylic acid (Ac-5-ASA) after urine is discharged.Though SASP has been used for the treatment of rheumatic arthritis (RA) for many years, its mechanism of action is still not fully aware of.Research at present think SASP and (or) its metabolite may be mainly brings into play anti rheumatism action by mechanism such as antibiotic, antiinflammatory and immunomodulating.

(1) antibacterial action: the sulfanilamide that will have an antibacterial action is treated this antibacterial action of RA. with 5-AsA be combined into SASP and is confirmed in the relevant SpA of treatment intestinal infection.

(2) the same methotrexate of the antiinflammatory action of antiinflammatory action: SASP (MTX) is similar; 5-aminooimidazole-4-formoxyl nucleotide transformylase (AICAR Tfase) causes that the interior AICAR of cell assembles and adenosine release increases in the purine building-up process by suppressing; adenosine combines with the A2 type adenosine receptor on inflammatory cell surface, thus the inflammation-inhibiting cytoactive.The effect of sticking as neutrophil cell is subjected to press down.SASP also can suppress the neutrophil cell activity of myeloperoxidase, reduces oxygen-derived free radicals and generates, and quickens the apoptosis of neutrophil cell, suppresses the inductive lymphocyte transformation of mitogen.

(3) immunoregulation effect: SASP can suppress the release of the various kinds of cell factor, as interleukin (IL-2, IL-1, IL-6, IL-12) and tumor necrosis factor (TNF). these cytokines are to cause RA that the key factor of development takes place as the proinflammatory factor.SASP also can suppress nuclear factor (NF-KB) activation, and NF-KB is a kind of important nuclear factor, regulates and control the expression of multiple important immune factor.In addition, SASP and major metabolite thereof have demonstrated the effect that suppresses the B cell at external clinical concentration, and be synthetic as reducing immunoglobulin, suppresses rheumatoid factor (RF) and produce

(4) other effects: SASP and SP can reduce endotheliocyte chemotactic and propagation. reduce blood vessel hyperplasia, and outgrowth blood capillary is the basis that development takes place inflammation.SASP also can reduce the expression of NF-KB part and increase the expression of osteoprotegerin (OPG).Generate protection joint sclerotin thereby suppress osteoclast.

Controlled trial before and after 90 years 20th century proves, to improving tenderness and swollen joint number, pain scores.Erythrocyte sedimentation rate index S ASP such as (ESR) organizes the placebo group that is better than evident in efficacy.Alleviate the moist medicine of wind resistance (DMARDs) of disease and the contrast of biological preparation with other, a large amount of clinical trials show, close aspect joint number, the swollen joint number improving stiff time of Ritchie joint index (RAI), grip, morning, ESR, pain scores, tenderness, SASP and leflunomide, oxychloroquine (HCQ), penicillamine, MTX, the golden curative effect of injection are similar.The overall state of an illness assessment of other indexs such as clinical response rate (ACR20), doctor and patient, the assessment of patient's functional status, iconography index (as the Larsen scoring), meta-analysis shows that the same MTX of SASP, penicillamine, injection gold curative effect are similar, is more effective traditional DMARDs.SASP shows that with 6 months by a definite date double-blind trials of leflunomide the two curative effect is similar, and SASP has the more remarkable ESR of falling effect than leflunomide.Studies show that SASP wants early than other traditional DMARDs onsets.

The clinical in recent years treatment that is used for enteritis and rheumatoid arthritis.But sulfasalazine is the sulphonamides of conventional oral difficult absorption, and the medicine of absorption resolves into 5-aminosalicylic acid and sulfapyridine under the intestinal microbial action, if using dosage is excessive, easily causes increasing of untoward reaction rate.

Summary of the invention

Technical problem to be solved by this invention is to overcome above-mentioned weak point, and research design makes medicine in intestinal absorption, and the performance curative effect reduces the preparation that adverse effect takes place.

The invention provides a kind of sulfasalazine enteric coated preparation.

Sulfasalazine enteric coated preparation of the present invention is made up of following components by weight ratio:

The main material of described stomach dissolution type Opadry is hydroxypropyl methylcellulose and polyvinyl alcohol.

Described stomach dissolution type Opadry is preferably Opadry ZY type 29F68956.

The refined gram of described enteric solubility is preferably the aqueous enteric material, and its main material is the metering system copolymer.

The refined gram of described enteric solubility should be preferably 93062693.

Above-mentioned stomach dissolution type Opadry and the refined gram of enteric solubility should be available from the happy Kanggong of card departments.

The present invention is by changing the coating mode of preparation, common enteric sugar-coat is changed into enteric film coat, doing after changing, significantly improved the release of medicine, requirement by Chinese Pharmacopoeia 2005 editions is tested, its release can reach more than 85%, requirement far above state-promulgated pharmacopoeia 60%, it is a kind of enteric coated preparation of sulfasalazine efficiently, use under the same dose, preparation of the present invention is compared with common oral preparation, and human body is improved to bioavailability of medicament, improve the compliance the when patient takes medicine, be beneficial to use sulfasalazine to be used for the treatment of rheumatoid arthritis and inflammatory bowel.

Another object of the present invention has provided the preparation method of above-mentioned sulfasalazine enteric coated preparation.

The inventive method comprises the following steps:

One, label preparation:

(1) with the starch water (6～12g) damping, (60～75g) make starch slurry with the purified water of boiling;

(2) sulfasalazine is dropped into granulator, behind the mix homogeneously, the starch slurry of step preparation in the adding continues to stir, and makes wet granular;

(3) wet granular is laid on the drip pan, enters baking railway carriage or compartment inner drying (75～90 ℃), make dried granule;

(4) dried granule adds magnesium stearate, carboxymethyl starch sodium mixing behind granulate;

(5) mixture is pressed into label;

Two, label coating:

(1) coating solution preparation

Gastric solubleness coating solution: get purified water and add in the stainless steel burden drum, Opadry (stomach dissolution type) coating powder is added, continue to stir 20 minutes, make the solution that concentration is 15～25% (W/W), before coating, coating solution is crossed 60 eye mesh screens;

Enteric coating liquid: get purified water and add in the stainless steel burden drum, suitable (enteric solubility) coating powder of refined gram is added, continue to stir 20 minutes, make the solution that concentration is 20～30% (W/W), before coating, coating solution is crossed 60 eye mesh screens;

(2) label with preparation drops in the efficient film coating machine, is preheated to 35～45 ℃, by the order coating of enteric solubility clothing layer behind the first gastric solubility clothing layer.

During in the JIUYUE, 2009, the sulfasalazine enteric coatel tablets that we make with this prescription and preparation process thereof amount to 12 batches, test by the requirement of Chinese Pharmacopoeia 2005, and its release sees the following form respectively.The result shows: its release of sulfasalazine enteric coatel tablets of film-coat is a kind of enteric coated preparation of sulfasalazine efficiently far above the requirement of state-promulgated pharmacopoeia 60%.

The specific embodiment

Embodiment 1

Preparation method:

One, sheet heart preparation:

(1) with starch water 9g damping, makes starch slurry 192g with the purified water of boiling;

(2) raw material is dropped into granulator, behind the mix homogeneously, add starch slurry, continue to stir, make wet granular;

(3) wet granular is laid on the drip pan, enters 82 ℃ of baking railway carriage or compartment inner dryings 8.5 hours, make dried granule;

(4) dried granule adds magnesium stearate, carboxymethyl starch sodium mixing behind granulate;

(5) mixture is pressed into label;

Two, label coating:

(1) coating solution preparation

Gastric solubleness coating solution: get purified water (56g) and add in the stainless steel burden drum, Opadry (stomach dissolution type) coating powder is added.Continue to stir 20 minutes.Before coating, coating solution is crossed 60 eye mesh screens.

Enteric coating liquid: get purified water (192g) and add in the stainless steel burden drum, suitable (enteric solubility) coating powder of refined gram is added.Continue to stir 20 minutes.Before coating, coating solution is crossed 60 eye mesh screens.

(2) label with preparation drops in the efficient film coating machine, is preheated to 35～45 ℃, by the order coating of enteric solubility clothing layer behind the first gastric solubility clothing layer.

In the coating process, guarantee the continuous stirring of coating solution, the disintegrate that draw samples carries out enteric coatel tablets detects (pressing Chinese Pharmacopoeia version appendix in 2005 XA inspection technique disintegration).Disintegrate testing result as enteric coatel tablets is defective, then appends the coating enteric coating liquid, and is qualified until the disintegrate detection of enteric coatel tablets.

This batch sulfasalazine enteric coatel tablets release is 92%.

Embodiment 2

Preparation method is with embodiment 1.

This batch sulfasalazine enteric coatel tablets release is 93%.

Embodiment 3

Preparation method is with embodiment 1.

This batch sulfasalazine enteric coatel tablets release is 94%.

Claims (7)

1. sulfasalazine enteric coated preparation is characterized in that described enteric coated preparation is made up of following components by weight ratio:

Per 1000 tablet recipes: unit: g

Raw material weight

Sulfasalazine 250.0

Pregelatinized Starch 50.0-58.0

Starch 20.0-30.0

Magnesium stearate 2.0-5.0

Carboxymethyl starch sodium 5.0-20.0

Opadry stomach dissolution type 10.0-15.0

The suitable enteric solubility 35.0-65.0 of refined gram

2. enteric coated preparation according to claim 1, the content that it is characterized in that every sulfasalazine of described enteric coated preparation is 150-300mg.

3. enteric coated preparation according to claim 1, the main material that it is characterized in that described stomach dissolution type Opadry is hydroxypropyl methylcellulose and polyvinyl alcohol.

4. enteric coated preparation according to claim 3 is characterized in that described stomach dissolution type Opadry is Opadry ZY type 29F68956.

5. enteric coated preparation according to claim 1 is characterized in that the refined gram of described enteric solubility is preferably the aqueous enteric material, and its main material is the metering system copolymer.

6. enteric coated preparation according to claim 5 is characterized in that the refined gram of described enteric solubility is preferably 93062693.

7. the preparation method of sulfasalazine enteric coated preparation according to claim 1 is characterized in that this method comprises the following steps:

One, label preparation:

(1), makes starch slurry with the purified water 60～75g that boils with starch water 6～12g damping;

(2) sulfasalazine is dropped into granulator, behind the mix homogeneously, the starch slurry of step preparation in the adding continues to stir, and makes wet granular;

(3) wet granular is laid on the drip pan, enters 75～90 ℃ of baking railway carriage or compartment inner dryings, make dried granule;

(4) dried granule adds magnesium stearate, carboxymethyl starch sodium mixing behind granulate;

(5) mixture is pressed into label;

Two, label coating:

(1) coating solution preparation

Gastric solubleness coating solution: get purified water and add in the stainless steel burden drum, stomach dissolution type Opadry coating powder is added, continue to stir 20 minutes, make the solution that concentration is 15～25%W/W, before coating, coating solution is crossed 60 eye mesh screens;

Enteric coating liquid: get purified water and add in the stainless steel burden drum, the suitable coating powder of the refined gram of enteric solubility is added, continue to stir 20 minutes, make the solution that concentration is 20～30%W/W, before coating, coating solution is crossed 60 eye mesh screens;

(2) label with preparation drops in the efficient film coating machine, is preheated to 35～45 ℃, by the order coating of enteric solubility clothing layer behind the first gastric solubility clothing layer.