KR100592920B1 - Liquid suppository composition containing diclofenac sodium - Google Patents

Abstract

The present invention is a composition for rectal administration comprising a mixture of diclofenac sodium and poloxamer and containing at least one polymer selected from polyethylene oxide or polyvinylpyrrolidone, there is no foreign body or discomfort during rectal administration, easy to administer and after administration It relates to a composition for rectal administration comprising diclofenac sodium that does not escape from the anus and does not migrate to the colon end.

Rectal Compositions, Diclofenac Sodium, Poloxamer

Description

Liquid suppository composition containing diclofenac sodium}

1 is a graph showing the dissolution test results of Example 2 (●), Example 3 (▲) and conventional diclofenac sodium suppository (■).

2 is a rectal mucosal micrograph (A) before rectal administration insertion of the composition according to the present invention and a rectal mucosal micrograph (B) after 6 hours have passed after the rectal administration insertion.

The present invention relates to a composition for rectal administration comprising diclofenac sodium.

Diclofenac Sodium is one of the nonsteroidal anti-inflammatory drugs (NSAIDs) used as anti-inflammatory, analgesic and antipyretic agents. It has antipyretic effects similar to indomethacin, phenylbutazone and acetylsalicylic acid, and is effective for uterine contraction, lowering blood pressure and menstrual irregularities. It is shown. Diclofenac sodium is known to show gastrointestinal side effects such as gastric ulcer, gastrointestinal bleeding, and perforation instead of complete absorption in the gastrointestinal tract when administered orally. Diclofenac sodium suppository formulations are already known to relieve various side effects in the gastrointestinal tract during oral administration. This formulation not only has the disadvantages of general suppositories, but also results from the rapid increase in blood concentration and twice a day. It also has the disadvantage of high frequency of administration.

These shortcomings can be improved by slowing down the combination of the suppository base with the components that can delay the release rate of the drug.However, these components do not dissolve and remain dispersed even when heated with the oil base. Therefore, when developing such a formulation, it is important to prepare a suppository so that the compounding ingredients are uniformly dispersed in an oily base. Such techniques can be used to vary the amount of fatty acid esters (Japanese Patent Laid-Open Nos. 2-73010, 1-11618, 7-138149, and 64-63512) or to add hydrogen lecithin to the base of existing high melting point suppositories. There is a technique for controlling the dissolution of drugs (Japanese Patent No. 63-14716) and a technique for adding polyglycerol fatty acid esters, but these are simply to control the amount of sustained-release ingredients, so the range of drug application is not wide. In addition, there are techniques for controlling the release rate of drugs by adding water-containing polymers to existing solid suppositories ( Drug Develop. And Ind. Pharm . 16 (10) , 1675-1686, 1990). Visual mucosal irritation is a concern. In addition, formulations prepared by applying these sustained release techniques are not affected by diet due to the characteristics of the general suppository, that is, the specificity of the route of administration, and can be easily used in children, the elderly, and patients who have difficulty in drug administration. In addition, there are variations in bioavailability due to drug absorption in the large intestine rather than the rectum due to discomfort in production and handling, discomfort from the patients during the administration, discomfort and transition to the large intestine of the drug due to peristalsis to the large intestine after administration. It has the same general problems of suppositories as the big point.

On the other hand, at low temperatures such as room temperature, poloxamers have recently been selected as the basis of suppositories due to their specificity of changing to a liquid state or gel state. Among these, Tetronic, which is simply a derivative of poloxamer and poloxamer, It is the basic contents to control the gelation temperature range of the base by controlling the concentration of tergitol and the like (US Pat. No. 4,188,373 and Canadian Patent No. 1,072,413) or various types of excipients with poloxamer as a periodic agent. Attempts have been made to control the gel strength, pH, and the like (US Pat. Nos. 4,478,822, 4,474,951, 4,474,952, 4,474,752, and 4,474,753) to be added but applied to rectum, skin and other body cavities in the body. However, the above contents are basically unsuitable for application to the rectum because poloxamer is selected to control the general physical properties of the mechanism. It is also a composition that may receive.

In addition, there is a technology (European Patent No. 551626) which considers application to body cavities such as skin, eyes and rectum by controlling the gelation temperature and gel strength by adding a polymer type such as carbomer to poloxamer. When the drug is applied in one base, the elution of the drug from the base and the bioadhesion of the base itself are not considered. Therefore, this technique is not a suitable composition for the purpose of the present invention.

Subsequently, there is a technique for applying drugs such as analgesics to body cavity based on ionic polysaccharide sodium alginate or chitosan (US Pat. No. 5,346,703), but this technique is not suitable for suppositories. In addition, since the base has an irreversible property by adding counter ions such as calcium ions (Ca ⁺² ), it is inconvenient to use and handle. Also, only one poloxamer can be used to control the gelation temperature range in various ways. The amount of rectal mucosal damage that must be taken into account is also severe.

In addition, there is a technology that mainly uses chitosan as a gel forming agent (US Patent No. 4,946,870 and European Patent Publication No. 103995), but it is inconvenient because it can not accurately control the gelation temperature, even though poloxamer is used, it contains an absorption accelerator. In addition, there are limitations to the application to drugs such as peptides, and there are also technologies that use polysaccharides as main ingredients (International Patent Publications WO94 / 03157 and WO94 / 03186), but it is easy to adjust physical properties such as precise gelation temperature and gel strength. It has the disadvantage of not doing it.

Applicants have recently described a technique using poloxamer and sodium alginate or chitosan as a base for drugs that have a hepatic bypass effect or are inappropriate for oral administration due to gastrointestinal disorders or gastric acid digestion (International Patents WO97 / 30693 and WO97 / 34580). It is known but this could not be applied as a base to the diclofenac sodium of the present invention.

The inventors of the present invention as a sustained-release rectal administration composition containing a new diclofenac sodium improved the problem of the rectal administration and the patient compliance with frequent administration, firstly, gelated to maintain a liquid state at room temperature and gel state in the body The temperature is 30-36 ℃, and secondly, the lower limit of gel strength is about 15 seconds or more in the absence of load so that it is easy to administer and does not come out of the anus after dosing. In addition, it was intended to develop a composition for rectal administration in which the lower limit of the bioadhesive force exhibits a value of about 50 dyne / cm ² or more while meeting the conditions of gelation temperature and gel strength.

That is, the purpose of the present invention is a new diclofenac sodium that is easy to manufacture and economical, has excellent gel strength and bioadhesive power, no foreign body or discomfort during rectal administration, easy to administer, does not come out of the anus, and does not proceed to the colon end. To provide a composition for rectal administration comprising a.

The present invention is 1-5% by weight of diclofenac sodium; 25-40% by weight of two or more solid poloxamer mixtures; And 0.1 to 1.0% by weight of at least one polymer selected from polyethylene oxide and polyvinylpyrrolidone.

Poloxamer is a polyethylene-propylene glycol copolymer and a polymer having a characteristic of gelling when the liquid phase and temperature increase at low temperatures. Solid poloxamers usable in the present invention may be mixtures of various poloxamers of solid type, and examples of solid poloxamers include poloxamer 407, poloxamer 338, poloxamer 288, poloxamer 238, and poloxamer 188. There is this. In particular, it is preferable to use a mixture of non-toxic solid type poloxamer 407 and other types of poloxamers at a low concentration of 20% at room temperature because it is easy to control an appropriate gelation temperature range. In particular, by selecting poloxamer 407 and poloxamer 188 to prepare the poloxamer mixture while controlling the weight ratio of the two materials, the appropriate gelation temperature range of 30 to 36 ° C. can be easily adjusted. The poloxamer 407 and poloxamer 188 is preferably added in a ratio of 1: 1 to 1.5, and the amount of the poloxamer mixture is preferably 25 to 40% by weight of the total rectal composition. When the content of the poloxamer mixture is less than 25% by weight, the gel strength and the bioadhesive force are weak, and when the content of the poloxamer mixture is greater than 40% by weight, it is difficult to prepare a high viscosity.

In the preparation of suppositories, conventionally, polymers for improving gel strength and mucoadhesive properties include acrylic polymers such as carbopol and polycarbophil, cellulose-based polymers such as hydroxypropyl cellulose and hydroxypropylmethyl cellulose, or natural algae such as sodium alginate and chitosan. Although polymers have been commonly used, these polymers are not preferable in the composition of the present invention because they appear entangled in diclofenac sodium solution, which is caused by the carboxyl group (-COOH) and hydroxyl group (-OH) or the like contained in the molecular terminal. It is assumed to be.

However, hydrophilic polymers, such as polyethylene oxide and polyvinylpyrrolidone, are well mixed with poloxamer and diclofenac sodium to form a clear, transparent and viscous solution, and thus may be preferably used as the polymers included in the composition for rectal administration of the present invention. . This is because the hydrophilic polymers such as polyethylene oxide or polyvinylpyrrolidone can hydrogen bond with the hydroxyl group (-OH) in poloxamer and the carboxyl group (-COO) and amino group (-NH) of diclofenac sodium. The three-dimensional network structure of the summer is more strongly formed, and the oligosaccharide group of the rectal mucosa can be strongly hydrogen-bonded to enhance gel strength and bioadhesive power even with a small amount.

In addition, since the viscosity of the polymer varies depending on its molecular weight and the amount of addition, the composition for rectal administration having bioadhesiveness and gel strength suitable for the purpose of treatment can be obtained by appropriately adjusting the molecular weight and the amount of addition thereof. The dissolution rate can be adjusted in various ways. The amount of the at least one polymer selected from polyvinylpyrrolidone and polyethylene oxide is preferably about 0.1 to 1.0% by weight and more preferably 0.3 to 1.0% by weight of the total composition. If the addition amount is less than 0.1% by weight of the total composition can not control the gel strength and bioadhesive power, if it is more than 1.0% by weight is difficult to manufacture because of high viscosity.

Polyethylene oxide may be used having a molecular weight of about 1 × 10 ⁵ ~ 9 × 10 ⁵ , polyvinylpyrrolidone is most preferably the case of a molecular weight of 630,000, but can be used in addition to those having a variety of molecular weight, these molecular weights The smaller the viscosity, the higher the molecular weight, the higher the viscosity, so that the formulation for rectal administration can be designed using an appropriate molecular weight if necessary.

The composition for rectal administration of the present invention includes antiseptics, such as sodium benzoate, potassium sorbate and parabens, as well as preservatives such as diclofenac sodium, poloxamer and polyethylene oxide or polyvinylpyrrolidone as anti-inflammatory and analgesic agents, such as hydrochloric acid, citric acid, sodium hydroxide, and the like. It may contain one or more additives commonly used in conventional rectal dosage forms such as pH adjusters or stabilizers such as methionine.

Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited thereto.

Examples 1-8

A composition for rectal administration containing diclofenac sodium was prepared in the composition shown in Table 1. First, a polymer material including poloxamer was dissolved in water, and then, drugs and other ingredients were dissolved in order, followed by replenishment of water to make a total amount of 100 g, thereby preparing a composition for rectal administration.

Comparative Examples 1 to 8

In Examples 1 to 8 instead of polyethylene oxide and polyvinylpyrrolidone to prepare a composition using an acrylic polymer, a cellulose polymer or a natural polymer, the composition is shown in Table 2.

Comparative Examples 9-16

Except that polyethylene oxide and polyvinylpyrrolidone were not added, the compositions prepared in the same compositions as in Examples 1 to 8 were used as Comparative Examples 9 to 16, respectively.

Comparative Examples 17-20

The composition was prepared as in Table 3, in the same manner as in Examples 1-8.

                                                   (Unit: g) Furtherance Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 Example 8 Poloxamer 407 15 15 15 17 12 14 16 13 Poloxamer 188 18 19 19 19 18 18 20 17 Polyethylene Oxide (MW = 3 × 10 ⁵ ) 0.1 0.3 0.2 Polyethylene oxide (MW = 9 × 10 ⁵ ) 0.3 0.6 0.5 Polyvinyl pyrrolidone 1.0 0.7 Diclofenac Sodium 2 2 2 2 2 2 2 2 Methylparaben 0.06 0.06 0.05 0.07 0.06 Profile paraben 0.02 0.03 0.05 0.03 0.04 Sodium benzoate 0.1 0.1 0.1 water Quantity Quantity Quantity Quantity Quantity Quantity Quantity Quantity Gross weight (g) 100 100 100 100 100 100 100 100

                                                    (Unit: g) Furtherance Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 Comparative Example 6 Comparative Example 7 Comparative Example 8 Poloxamer 407 15 15 15 17 12 14 16 13 Poloxamer 188 18 19 19 19 18 18 20 17 Polycarbophil 0.3 0.7 Cabopol 0.3 Hydroxypropylmethyl cellulose 1.0 0.2 Sodium alginate 0.1 0.5 Chitosan 0.6 Diclofenac Sodium 2 2 2 2 2 2 2 2 Methylparaben 0.06 0.06 0.05 0.07 0.06 Profile paraben 0.02 0.03 0.05 0.03 0.04 Sodium benzoate 0.1 0.1 0.1 water Quantity Quantity Quantity Quantity Quantity Quantity Quantity Quantity Gross weight (g) 100 100 100 100 100 100 100 100

                                                   (Unit: g) Furtherance Comparative Example 17 Comparative Example 18 Comparative Example 19 Comparative Example 20 Poloxamer 407 15 15 9 19 Poloxamer 188 18 19 9 23 Polyethylene Oxide (MW = 3 × 10 ⁵ ) 0.01 1.5 0.3 0.3 Diclofenac Sodium 2 2 2 2 Methylparaben 0.06 0.05 Profile paraben 0.02 0.04 Sodium benzoate 0.1 0.1 water Quantity Quantity Quantity Quantity Gross weight (g) 100 100 100 100

The composition prepared according to Examples 1 to 8 was formed as a clear, transparent and viscous composition for rectal administration, but the composition prepared according to Comparative Examples 1 to 8 was unable to properly make the composition while appearing entangled during manufacture. That is, acrylic polymers such as carbopol, polycarbophil, cellulose-based polymers such as hydroxypropylmethylcellulose, and natural polymers such as sodium alginate and chitosan are not suitable for the composition according to the present invention because they exhibit entanglement with diclofenac sodium. Turned out to be.

Performance experiments of the compositions prepared according to Examples and Comparative Examples were carried out according to the following Experimental Examples.

Experimental Example 1 Measurement of Gelation Temperature

About 10 g of each composition sample of Examples and Comparative Examples was placed in a 20 ml container with a magnetic bar, placed in a thermostat at 4 ° C., and a digital thermometer was placed in the sample so as not to contact the magnetic bar. The temperature at which the magnetic bar stops completely was raised to the gelation temperature while raising the temperature at a rate of 1 ° C./min while stirring at a constant speed (Miyazaki, S., Nakamura, T., Takada, M., 1991. Thermosensitive sol-gel transition of Pluronic F-127, Yakuzaigaku 51 , 36-43). The results are shown in Table 4.

Experimental Example 2: Measurement of Gel Strength

50 g of each composition was put in 100 ml of a measuring cylinder, and equilibrated in a 36.5 ° C. thermostat for 30 minutes, and then the gel strength measuring instrument was placed on the measuring cylinder, and the time (sec) when the gel strength measuring instrument was lowered was measured (Schmolka, IR, 1972, Artificial skin I. Preparation and properties of Pluronic F-127 gels for treatment of burns, J. Biomed. Mater. Res. 6 , 571-582). The results are shown in Table 4.

Experimental Example 3: Bioadhesion Test

Rectal mucosa of rabbits was attached to both vials of the bioadhesion measuring device, and a certain amount of the composition was placed therebetween. Ryu, SJ Yoon, YK Oh and CK Kim, 1998, Development of in situ-gelling and mucoadhesive acetaminophen liquid suppository, Int. J. Pharm., 165, 33-44). The results are shown in Table 4.

Experimental Example 4: Measurement of Anal Deviance

The rectal composition was inserted into the anus of the rabbit at a depth of 5 cm using a rat oral sonde needle for rats. Evaluation was appropriate. The results are shown in Table 4.

Gelation temperature (℃) Gel strength (sec) Bioadhesive force (dyne / cm ² ) × 10 ² Anal deviation Example 1 Comparative Example 9 34 39 27.2 3.4 140 8.7 Do not exit Exit Example 2 Comparative Example 10 33 38 34.7 5.6 347 12.5 Do not exit Exit Example 3 Comparative Example 11 33 37 37.1 7.8 620 17.2 Do not exit Exit Example 4 Comparative Example 12 33 36 28.3 9.2 117 25.8 Do not exit Exit Comparative Example 17 37 11.2 Not measurable Breakaway Comparative Example 18 30 Not measurable Not measurable - Comparative Example 19 Not gelated Not measurable Not measurable - Comparative Example 20 20 Not measurable Not measurable -

As shown in Table 4, the gelation temperature of the composition for rectal administration of the present invention (Examples 1 to 4) is 33 to 34 ° C, which is 3 to 5 ° C than the 36 to 39 ° C which is the gelation temperature of the compositions of Comparative Examples 9 to 12. It is low, the gel strength and bioadhesive power of the composition for rectal administration of the present invention is about 3 to 8 times and 4 times higher than the composition of the comparative example, respectively. As shown in the experimental results, the composition for rectal administration according to the present invention has a lower gelation temperature and titration, higher gel strength, and higher bioadhesive power than the composition of Comparative Examples 9 to 12 without containing polyethylene oxide or polyvinylpyrrolidone. It was excellent in that it was excellent and did not escape from the anus.

In addition, Comparative Example 17 has a high gelation temperature, the gel strength is too low and the bioadhesive power is low, so it is easily released from the anus. It was.

Experimental Example 5: Dissolution Test

The compositions for rectal administration prepared in Examples 2 and 3 were placed in a semipermeable membrane, and both sides were tied with a thread, and the dissolution test was performed at 100 rpm in a pH 6.7 phosphate buffer solution. Samples were analyzed at 1 hour intervals. As a result of comparing the elution degree of the existing diclofenac sodium suppository (trade name: Voltaren) and the drug, the compositions of the examples showed a tendency of sustained release, respectively (see Fig. 1).

Experimental Example 6: biological mucosal damage test

Rectal administration compositions (Examples 2 and 3) and conventional diclofenac sodium suppositories (trade name: Voltaren) were inserted into the anus of rats 5 cm deep using the oral sonde above, and after 6 hours, the rectum was collected and cut with a knife. Cut and washed thoroughly with saline solution. The rectum was neutralized with 10% neutral carbonate-buffer formaldehyde, then embedded in paraffin using an embedding center and cut into thin slices. This thin piece was stained with hematocillin-eosin and examined under a microscope. In other words, the changes of the rectal mucosa were classified into types I, II and III (AS Reid, et. Al., Int. J. Pharm. , 40 , 181 (1987)). On the basis of Type III, which has the highest degree of damage, it was found that the conventional diclofenac sodium suppository increased the tissue damage of the rectal mucosa by 2 to 3 times more than the compositions of Examples 2 and 3 (see Table 5). In addition, tissue damage was not found when comparing the rectal mucosa (B) 6 hours after the rectal administration of the composition of Example 2 with the rectal mucosa (A) before the rectal administration (see FIG. 2).

Injury rate by type of rectal mucosa (%)  division Number of test animals (N) Changes in the rectal mucosa Type I ^a) Type II ^b) Type III ^c) Control One 5.0 4.5 0.5 Comparison 5 5.8 ± 0.60 10.4 ± 1.22 7.5 ± 3.96 Example 2 5 5.0 ± 0.45 9.1 ± 1.81 2.8 ± 1.09 Example 3 5 6.1 ± 0.57 9.2 ± 2.04 3.5 ± 2.22

* Control group: non-administration

* Comparative group: conventional diclofenac sodium suppository (trade name: Voltaren)

a) Type I: Part of the epithelial cell falling off or falling off

b) Type II: Overall height of epithelial cells

c) Type III: The epithelial cells are completely separated and the mucosal laminae are exposed.

Experimental Example 7: Rectal Composition Positioning Experiment

Rectal administration composition containing 0.1% blue No. 1 lake pigment to rectal administration composition was inserted into rat anus 5 cm deep using rat oral sonde, and rectal administration of rat rectum was taken after 5 minutes and 4 hours. The position of the composition was confirmed. It was confirmed that the composition for rectal administration after 5 minutes or 4 hours after rectal administration did not proceed to the colon terminal.

As can be seen from the above experimental results, the present invention significantly reduced the degree of damage to the rectal mucosa as well as the physicochemical aspects of gelation temperature, gel strength, bioadhesive force, and site retention, and the composition was not transferred to the colon end. In addition, the present invention provides a composition for rectal administration which is very useful as a suppository composition due to its sustained release characteristics.

Claims (3)

1-5% by weight of diclofenac sodium; 25-40% by weight of two or more solid fluorosamer mixtures; And 0.1 to 1.0% by weight of at least one polymer selected from polyethylene oxide and polyvinylpyrrolidone. The composition for rectal administration according to claim 1, wherein the solid poloxamer mixture is a mixture of poloxamer 407 and poloxamer 188. The composition for rectal administration according to claim 2, wherein the weight ratio of poloxamer 407 and poloxamer 188 is 1: 1 to 1.5.

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