Dry cefdinir suspension and preparation method thereof

A, technical field.

The invention relates to the technical field of pharmaceutical preparation, in particular to a kind of Cefdinir dry suspension agent and its preparation method.

Second, the technical background.

Cephalosporin antibiotic medicine is anti-infection drugs in a strong and effective, it has the advantages of high curative effect, small side effect, wide antibacterial spectrum, antibacterial activity is strong, and the like. Cephalosporins is to culture to obtain crown head spore fungus natural cephalosporinases C   as a raw material, the semi-synthetic transformation of a side chain obtained by a kind of antibiotic. Cephem antibiotics is cophem contains in the molecule of the semi-synthetic antibiotic, which is a β-  lactam antibiotic, β-  lactam antibiotics is the 7  -amino cephalosporanic acid derivatives. Cephalosporins, is by inhibition of bacterial cell wall synthesis, sterilization, for most stable β-lactamase.

Cefdinir on the basis of the development of pithecellobium clypearia 3rd-generation oral cephalosporin, its chemical structure is characterized in that the 7-amino cephalosporanic acid skeleton 7 is introduced to the side chain amino group is thiazolyl, OXYIMINO, 3 is the introduction of side chain vinyl, structural formula as shown in Figure 1. With Cefixime G+ than to enhance the bacteria (, including MRSA) activity. Cefdinir compensate for the original 3rd generation cephalosporin the weak action of the shortcoming of the gram-positive bacteria, to make it become the true sense of the broad-spectrum antibiotic. The 1st stage in the treatment of antibacterial capability of having sufficient to avoid the generation of drug resistant.

As cefdinir 3rd generation cephalosporin, the cefdinir G⁺, G^- bacteria with a broad-spectrum antibiotic activity, can inhibit 90%-100% of the clinical susceptibility, such as methecillin sensitive Staphylococcus aureus (MSSA), epidermal staphylococcus (MSSE), Streptococcus (including Streptococcus pneumoniae), influenza blood bacillus, Klebsiella pneumoniae, catarrh Morrah fungus , Escherichia coli, even the gonococcus, card he branham fungus , indole positive deformation baumanni also have good curative effect, but to the Pseudomonas aeruginosa, cepae pseudomonus invalid.

CHARLES Greeley Abbot Company discloses a new kind of powder for oral suspension cefdinir (application number: 200480036573.4,), the powder of the direct mixing technology, also discloses a method of preparing the suspension using the suspension and method of treatment. The current state of this Patent which belongs to the non-right.

Beijing amber Sinorama medical technology development Company limited application discloses a kind of Cefdinir dry suspension agent (application number: 200710308430. X,), adopts a wet granulation process, is mainly used for the treatment of Staphylococcus, Streptococcus, Propionibacterium, gonococcus, Escherichia coli, [...] , Proteus mirabilis, influenza baumanni, infection due to Providence, such as laryngopharyngitis, tonsillitis, bronchitis, pneumonia, pyelonephritis, Cystitis, and gynaecologic gonococcal urethritis, surgical, skin, infection, such as the organization. The present Patent is in a non-power state.

Guangdong permanent healthy pharmaceutical Company limited discloses a cephalosporinases types of suspended particles and its preparation method (application number: 201010176154.8,), wet granulation method for the preparation of cephalosporin type of suspended particles, using a fluidized bed drying method and drying. Fluidized bed drying technique, compared with the traditional oven drying, drying time is short, small influence to the active substance, and the like, not only guarantee the quality of products but also the production efficiency is greatly improved.

The preparation of cefdinir in the market have some relatively small, only a capsule, particle and dispersible tablet production. Research and development of this invention a kind of Cefdinir dry suspension agent, compared with other dosage forms, stem suspension has the following advantages: 1, than the ordinary dry suspension of large dispersion, absorbability is good, more easily absorbed by the human body, is more suitable for children; 2, easy administration, can be with water, a certain dose specifications; 3, the production process is simple, the granule production equipment and conditions are rather, the granule, tablet, capsule production workshop can be produced. Cefdinir combined with the high efficiency, safety, we developed Cefdinir dry suspension agent has filled in the blank of market, convenient for the patient, especially patients of children use, has broad market prospect.

At the same time, because cephalosporinases types of raw material in the wet, quality is not stable under thermal conditions, is apt to degrade, such products on the market at present, in general, relatively poor quality stability of, the process is suitable for adopting a wet granulation, dry granulation can be avoided the wet granulation process, the active ingredient of damp and hot condition influence to the stability of cefdinir; also can avoid direct powder mixing of the problem such as the inferior fluidity, improving the production efficiency, good taste alcaine amodicui made, rapid oral absorption, bioavailability is high, a mix of corrective and aromatic improve patient compliance of patients, especially children.

In this invention the particle size of the active ingredient of the control, is less than the 10  m. Drug micronization after insoluble drugs can be obviously improved surface area and the ratio of the dissolution rate, the easy to be degraded in the gastrointestinal drug on the transdermal, to such as the mucosa, thus improve the curative effect. The traditional method of micronization may damage the active ingredients, and on the basis of the supercritical fluid (supercriticalfluid, SCF) technical method of micronization mild conditions, suitable for preparing a heat-sensitive, ultra-fine drug particles apt to degrade, and the solvent-free residual, for the follow-up treatment and environmental protection. The basic principle is the solution in a very short time to be highly oversaturated state, so that the solute instantaneous precipitation forming ultrafine particles.

Three, the content of the invention.

The purpose of this invention is to develop a kind of Cefdinir dry suspension agent, the medicine is convenient and simple, good taste, rapid oral absorption, bioavailability is high, can improve patient compliance of patients, especially children.

The invention of a kind of Cefdinir dry suspension agent active ingredient micronized using supercritical fluid technology, so that the particle size of less than 10 the  m, slow sedimentation speed of particles, increase its dissolution. The dry granulation process to prepare Cefdinir dry suspension agent, not only can avoid the wet granulation process, the active ingredient of damp and hot condition influence to the stability of cefdinir; also can avoid direct powder mixing of the poor fluidity, the production efficiency is improved.

The object of the invention can be realized through the following technical scheme.

Cephalosporin of this invention is the novel suspension of the dry granulation process, cefdinir by the active ingredient is, thinner, suspending agent, disintegrating agent, stabilizer, corrective, glidant, wherein the active ingredient is micronized, so that the particle size of less than 10 the  m. The method is selected from the group of micronization of colloid mill, jet mill, ball mill, supercritical fluid (supercritical   fluid, SCF) technical one kind or several kinds, preferably the supercritical fluid technology. Its method of micronization mild conditions, suitable for preparing a heat-sensitive, ultra-fine drug particles apt to degrade, and the solvent-free residual, for the follow-up treatment and environmental protection.

Cephalosporin of this invention novel diluent in supensoid selected lactose, mannitol, sucrose, sorbitol, xylitol, glucose sugar , fructose in one or several kinds of.

Cephalosporin of this invention in the novel suspension suspending agent is selected from xanthan, hydroxypropylmenthyl cellulose, arabic gum, sodium alginate, polyvinyl pyrrolidone, carbomer, sodium carboxymethyl cellulose, gelatin, hydroxypropyl cellulose in one or several kinds of.

Cephalosporin of the invention in novel suspension of disintegrant is selected from low-substituted hydroxypropylmenthyl cellulose, croscarmellose sodium, crospovidone and sodium carboxymethyl starch, one or several kinds of, or joint use of effervescent disintegrant; effervescent disintegrating agent is selected from sodium bicarbonate and citric acid, sodium bicarbonate with tartaric acid, sodium bicarbonate and sodium bicarbonate and citric acid and fumaric acid in one or several kinds of.

Novel cephalosporin of this invention the stability of the suspension in the flocculating agent is selected from the, defloculant and a surfactant, preferably citrate salt, that is, acid salt, phosphate and sodium dodecyl sulphate in one or several kinds of.

Cephalosporin of this invention novel sweetener selected from the group of corrective in supensoid, aromatic, mucilage in one or several kinds of, wherein the sweetener is selected from [...] , steby xylosides, saccharin, sodium saccharin one kind or several kinds; aromatic selected from sweet orange essence, lemon essence, orange essence, mint essence, kiwifruit essence, make redbraised, spearmint one kind or several kinds; mucilage is selected from starch, arabic gum, west Huang Qijiao , sodium carboxymethyl cellulose, sodium alginate in one kind or two kinds of.

Cephalosporin of the present invention novel flow aid is selected from powder suspension of silica gel, fumed silica, magnesium stearate, talc, polyethylene glycol in one or several kinds of.

Cephalosporin of the present invention the preparation of novel suspension, comprising the following steps:

Step 1: pre-processing

The auxiliary materials are ground through 100 sieve, spare; the active ingredient micronized, so that the particle size of less than 10 the  m, spare;

Steps 2: preparation of mixed powder

The active ingredients, diluent, suspending agent, disintegrating agent, stabilizer by adopting the equivalent cumulative manner,   100 mesh sieve are evenly mixed, I shall be mixed and powder;

Steps 3: the preparation of granules

Heating step 2 I a mixed powder is prepared, using dry granulation, respectively, I make the particles;

Steps 4: total mixing

In step 3 for screening the particles, the size of the selected particle size of 18 mesh to 80 mesh particles, the weighing, the amount of flow aid and corrective prescription, mix, sub-package.

Four, specification Figures

Figure 1 the structural formula of cefdinir;

Figure 2   embodiment 1-embodiment 5 dissolution studies;

Figure 3 embodiment 1-embodiment 5 stability studies.

Five, specific embodiment.

Embodiment 1:

Cefdinir   100g

Acetyllactosyl   600g

Sucrose   600g

Hydroxypropylmenthyl cellulose   80g

Low-substituted hydroxypropylcellulose   150g

Tartaric acid   50g

Sodium bicarbonate   50g

Orange essence   10g

Saccharin sodium   10g

Micronized silica gel   5g

Magnesium stearate   8g

Made 1000 sheet

Preparation method:

The auxiliary materials are ground through 100 sieve, spare; the active ingredient micronized, so that the particle size of less than 10 the  m, spare. Cefdinir of the active ingredient and amount of lactose, sucrose, hydroxypropylmenthyl cellulose, low-substituted hydroxypropyl cellulose, tartaric acid, sodium bicarbonate, in a manner increasing the same, 100 mesh sieve mixed evenly, to be mixed and powder, using dry granulation, the choice of particle size of 18 mesh to 80 mesh, will the weighing, adding prescription amount of orange essence, saccharin sodium, micro-silica and magnesium stearate, is mixed, n, is obtained.

Embodiment 2:

Cefdinir   100g

Sucrose   1200g

Hydroxypropylmenthyl cellulose   80g

Low-substituted hydroxypropylcellulose   150g

Citr   50g

Sodium bicarbonate   50g

Orange essence   10g

Saccharin sodium   10g

Micronized silica gel   5g

Magnesium stearate   8g

Made 1000 sheet

Preparation method:

The auxiliary materials are ground through 100 sieve, spare; the active ingredient micronized, so that the particle size of less than 10 the  m, spare. Cefdinir of the active ingredient and amount of sucrose, hydroxypropylmenthyl cellulose, low-substituted hydroxypropyl cellulose, citric acid, sodium bicarbonate, in a manner increasing the same, 100 mesh sieve mixed evenly, to be mixed and powder, using dry granulation, the choice of particle size of 18 mesh and 80 mesh, will the weighing, adding prescription amount of orange essence, saccharin sodium, micro-silica and magnesium stearate, is mixed, n, is obtained.

Embodiment 3:

Cefdinir   100g

Acetyllactosyl   600g

Sucrose   600g

Sodium carboxymethyl cellulose   80g

Low-substituted hydroxypropylcellulose   150g

Tartaric acid   50g

Sodium bicarbonate   50g

Cherry essence   10g

Saccharin sodium   10g

Micronized silica gel   5g

Magnesium stearate   8g

Made 1000 sheet

Preparation method:

The auxiliary materials are ground through 100 sieve, spare; the active ingredient micronized, so that the particle size of less than 10 the  m, spare. Cefdinir of the active ingredient and amount of lactose, sucrose, sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, tartaric acid, sodium bicarbonate, in a manner increasing the same, 100 mesh sieve mixed evenly, to be mixed and powder, using dry granulation, the choice of particle size of 18 mesh and 80 mesh, will the weighing, adding prescription amount of cherry essence, saccharin sodium, micro-silica and magnesium stearate, is mixed, n, is obtained.

Embodiment 4:

Cefdinir   100g

Sucrose   1200g

Sodium carboxymethyl cellulose   80g

Low-substituted hydroxypropylcellulose   150g

Citr   50g

Sodium bicarbonate   50g

Orange essence   10g

Saccharin sodium   10g

Micronized silica gel   5g

Magnesium stearate   8g

Made 1000 sheet

Preparation method:

The auxiliary materials are ground through 100 sieve, spare; the active ingredient micronized, so that the particle size of less than 10 the  m, spare. Cefdinir of the active ingredient and amount of sucrose, sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, citric acid, sodium bicarbonate, in a manner increasing the same, 100 mesh sieve mixed evenly, to be mixed and powder, using dry granulation, the choice of particle size of 18 mesh and 80 mesh, the weighing particles thereof, adding prescription amount of orange essence, saccharin sodium, micro-silica and magnesium stearate, is mixed, n, is obtained.

Embodiment 5:

Cefdinir   100g

Acetyllactosyl   600g

Sucrose   400g

Sorbitiol   200g

Hydroxypropylmenthyl cellulose   120g

Tartaric acid   100g

Sodium bicarbonate   100g

Lemon essence   10g

Saccharin sodium   10g

Micronized silica gel   5g

Magnesium stearate   8g

Made 1000 sheet

Preparation method:

The auxiliary materials are ground through 100 sieve, spare; the active ingredient micronized, so that the particle size of less than 10 the  m, spare. Cefdinir of the active ingredient and amount of lactose, sucrose, sorbitol, hydroxypropylmenthyl cellulose, tartaric acid, sodium bicarbonate, in a manner increasing the same, 100 mesh sieve mixed evenly, to be mixed and powder, using dry granulation, the choice of particle size of 18 mesh and 80 mesh, the particle size of suitable particle weighing, adding prescription quantity of lemon essence, saccharin sodium, micro-silica and magnesium stearate, is mixed, n, is obtained.

Embodiment 6:

The embodiment 1-embodiment 5 of the 6 sheet, the inspection pH1.0 hydrochloric acid solution, Ph4.5 acetic acid buffer solution, pH6.8 phosphoric acid solution and the water dissolving the behavior, as embodiment 1-embodiment 5 each time point the mean value of the cumulative dissolution percentage (%) time (min) of the dissolution curve, results in Figure 2;

The result shows that, of the invention to prepare Cefdinir dry suspension agent in the four kinds of medium travel of the, 30 min dissolution is greater than 80%.

Embodiment 7

The embodiment 1-embodiment 5 listed packaging sample, the temperature of the 40 [...] , relative humidity 75% is placed under a condition of 6 months, respectively for 0, 1, 2, 3 and 6 month sample detection, inspection property, the related substances, sedimentation volume ratio, content, the results of the analysis in Figure 3;

Note the 40 the [...] , RH75% acceleration test 6 months, its properties, the related substances, sedimentation volume ratio, no significant change in content, annotations vigiv in the test condition (listed packaging) the quality of the product is stable.