KR930011994B1 - Acetaminophen preparation improved bioablity - Google Patents

Abstract

Paracetamol having improved bioavailibility, stability and solubility was prepared by solubilizing with a mixture of polyethyleneglycol and propyleneglycol, heating at 40-130 deg.C. This paracetamol can be formulated in tablets, capsules, syrups, suppositories and expecially injections due to higher bioavailibility.

Description

Method for increasing bioavailability of paracetamol and preparations containing paracetamol with increased bioavailability

1 is a graph showing the average plasma concentration curve after administration of Example 2.

2 is a graph showing the average plasma concentration after administration of the Example 5.

The present invention relates to a method for increasing the bioavailability of paracetamol and to a preparation containing paracetamol with increased bioavailability.

Paracetamol [N- (4-hydroxyphenyl) acetamide: acetaminophen] was first used as an antipyretic and analgesic drug by Von Mering in 1893, after which paracetamol was treated with acetanilide. It has been widely used since 1949 when it was found to be an active metabolite of phenacetin, and was sold in the United States in 1955 without a prescription.

However, this paracetamol has an extremely low solubility in water (solubility: 1:70), and thus cannot be easily dissolved. Thus, paracetamol has not been developed as an injection yet, and it is dissolved by adding a conventional dissolution aid and treating it in a conventional manner. Oral solution also had a problem of easy precipitation.

To date, paracetamol has been used only in tablets, capsules or oral solutions, syrups, suspensions and the like.

When taken orally, it is absorbed by the gastrointestinal tract, metabolized primarily by the liver through the portal vein, and then circulated through the blood.

Cohen's report [GMCohen, OMBakka, and DSDavies, J. Pharm, Pharmacol., 26, 348 (1974)] shows that bioceavaciation of paracetamol, the first metabolism in the liver and circulating blood in rats, is injected intravenously. Only 34% of them reported.

The present inventors have conducted a long study on a method for increasing the bioavailability of paracetamol and have found a surprising fact that the bioavailability can reach 100% even when orally administered, thereby completing the present invention.

It is therefore an object of the present invention to provide a method for increasing the bioavailability of paracetamol.

Paracetamol with high bioavailability prepared in the method of the present invention can be prepared into tablets, capsules, ointments or oral solutions, injections and rectal administration, parenteral preparations and the like.

Accordingly, another object of the present invention is to provide a pharmaceutical formulation containing paracetamol having high bioavailability prepared by the method of the present invention as a main component.

Numerous researchers have invested a lot of money over the years to produce injectables with high bioavailability in the case of paracetamol.

However, paracetamol has a very low solubility in water, and the amount of water used is too high (up to 0.3 g of paracetamol / 20 ml of water) even when a solution is prepared by adding a conventional dissolution aid in a conventional manner and treating in a conventional manner. In addition, since paracetamol precipitates over time even with this preparation, a stable drug having a therapeutically effective amount (about 0.3 g of paracetamol dissolved in about 2 ml of water and having a shelf life of about 2 years at room temperature). ) Could not be produced so far, the production of injectables has not been successful until now.

The inventors have surprisingly been able to prepare a solution of paracetamol at high concentrations (about 0.3 g or more paracetamol / about 2 ml of water) required for injectable paracetamol, and the solution of paracetamol thus prepared is stored at room temperature. It has been found that even after two years of storage, no precipitates are produced and the medicinal effects are preserved. Thus, an injectable drug that has not been successful until now has been produced.

Accordingly, another object of the present invention is to provide a novel injection containing paracetamol having a high bioavailability by the method of the present invention.

The present inventors have not yet found a mechanism for treating paracetamol with the method of the present invention to increase its bioavailability.

However, the paracetamol treated by the method of the present invention, even when administered orally, the bioavailability of 100% was confirmed by the research results of the Institute of Pharmacy affiliated with Seoul National University and the mechanism is still being studied.

In the present invention, excipients commonly used in the preparation of injectables, powders, tablets, capsules, syrups or suppositories in the paracetamol composition of the present invention, for example, lactose, various starches, sucrose, mannitol, sorbitol, inorganic salts (e.g. Calcium phosphate, aluminum, silicate, calcium sulfate, etc.); Binders such as sucrose, glucose, starch, gelatin, carboxymethyl cellulose, methylcellulose, gum arabic, ethylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone; Lubricants such as cornstarch, talc, magnesium stearate, calcium stearate, waxes; Humectants such as glycerin, sorbitol, and the like; Solvents such as water; Buffers such as Zipford buffer, Paliche buffer, Heind-Goyan buffer, Sorenzen buffer and the like; Isotonic agents, for example, sodium chloride, and the like; Preservatives such as paraoxybenzoic acid esters, cationic surfactants, various organic acids, antibiotics; Analgesic agents such as half alcohol, chlorobutanol, various local anesthetics; Ointments or suppositories, such as petrolatum, paraffins, plastibases, silicones, lard, benzoin, vegetable oils, waxes, emulsion type, water-soluble bases, hydrogel bases, etc. Various formulations can be produced in accordance with various production methods.

Next, the method of this invention is demonstrated in detail as an Example.

Example 1

Prescription :

Paracetamol: 150 mg

Polyethylene Glycol: 500mg

Glycerin: 250 mg

Propylene Glycol: 100mg

Sterile distilled water suitable amount: 1ml

Paracetamol is added to this solution and the polyethylene glycol is warmed to about 40-50 degrees. The solution is almost dissolved. Then, the prescribed amount of glycerin and propylene glycol is added to dissolve it completely. Then, water is added to make 1 ml.

Example 2

Prescription :

Paracetamol: 150 mg

Polyethylene Glycol: 500mg

Propylene Glycol: 100mg

Sterile distilled water suitable amount: 1ml

In Example 1, it was prepared without the addition of glycerin to reduce the viscosity.

The viscosity was much lower and did not affect solubility even during solubility and long term preservation.

Example 3

Prescription :

Paracetamol: 150 mg

Polyethylene Glycol: 600mg

Sterile distilled water suitable amount: 1ml

When propylene glycol was not added in Example 2, the liquid was not completely dissolved.

Example 4

Prescription :

Paracetamol: 150 mg

Polyethylene Glycol: 600mg

Sterile distilled water suitable amount: 1ml

When paracetamol was dissolved without adding polyethylene glycol, it was hardly dissolved.

Example 5

Prescription :

Paracetamol: 150 mg

Polyethylene Glycol: 500mg

Propylene Glycol: 100mg

Lidocaine Hydrochloride: 10mg

Total amount of distilled water for injection: 1ml

500 mg of polyethylene glycol is dissolved while warming to about 40-50 degrees.

Add 150 mg of paracetamol to this solution and dissolve to the maximum solubility.

Next, 100 mg of propylene glycol is added and completely dissolved. Lidocaine hydrochloride is dissolved in separate distilled water for injection, and then mixed with the above liquid.

The final solution is cooled to room temperature, and then mixed with benzyl alcohol.

Sodium metasulfite was added to the component of Example 1-5 to 0.03% (W / V) as an improving agent, and the pH was adjusted to 6.5 by adding 4.8 or sodium hydroxide at the first preparation.

Example 6

Prescription Tablet:

Paracetamol: 150 mg

Polyethylene Glycol: 375mg

Propylene Glycol: 75mg

Avicel pH 10 1: 175 mg

Aerosol: 185mg

Talc: 55mg

Lactose: 45mg

Starch: 15mg

Polyethylene glycol and propylene glycol are mixed and warmed for about 30 minutes at 60-70 degrees, and then paracetamol is added thereto and stirred to dissolve (A solution).

Separately, homogenize by mixing acecell pH 101 with aerosol and talc, add A solution to it, mix it, make granules, and pass through a 14 mesh sieve and dry at 60 degrees (B granules).

Separately, make whole starch into lactose, make it homogeneous, make granules through 16 mesh sieve, and dry them at 70 degrees (C granules).

B granules and C granules are mixed with 16 mesh sieves, mixed and tableted.

Example 7

Prescription (Capsule):

Only the B granules prepared in the manufacturing process of the tablet of Example 6 were filled with hard capsules to prepare a capsule of 915 mg in total.

Example 8

Prescription (Syrup):

Paracetamol: 150g

Polyethylene Glycol: 500g

Propylene Glycol: 100g

Sudang: 300g

Flavones: Proper amount

Propylene glycol is added to polyethylene glycol, and the paracetamol is heated and dissolved while being heated to 70 degrees and cooled to room temperature (A solution).

Separately, after dissolving sucrose in 500 ml of water, it was cooled to room temperature (liquid B).

Liquid B was added to liquid A to make a total volume of 2000 ml with water, followed by stirring to prepare a syrup.

It contains 75 mg of paracetamol per ml of this syrup.

Example 9

Prescription suppository:

Paracetamol: 150g

Polyethylene Glycol: 500g

Propylene Glycol: 100g

Glycerin Fatty Acid Glycol: 1200g

(H-5: solid)

Glycerin fatty acid ester H-5 (solid) is dissolved by heating to 80-90 degrees and then cooled to maintain 35-45 degrees (A solution).

After mixing polyethylene glycol and propylene glycol, the mixture is warmed to 70 degrees, paracetamol is dissolved by stirring and maintained at 35-45 degrees (B solution).

A and B are mixed and homogenized, followed by filling and molding at 1950 mg per one with a suppository autofiller.

Experimental Method

Experimental Example 1

Stability Experiment 1:

When the injection or liquid prepared by the method of the present invention was left at room temperature, 40 degrees and light, and tested for stability after 2 years, respectively, the decrease in content was about 1-2%, in particular, the main decomposition product of paracetamol. The content of paraaminophenol is less than 1% of the main component, indicating that the formulation is stable in use.

The experimental results are shown in Table 1 below.

TABLE 1

Experimental Example 2

Stability Experiment 2:

Meanwhile, after preparation, filling, sterilization and sealing as a liquid, sterilization conditions were carried out at 121 degrees for 20 minutes, and the stability test was carried out under the conditions mentioned above.

The results are shown in Table 2 below.

TABLE 2

Experimental Example 3

Stability Experiment 3:

When the liquid formulations are frozen and stored in refrigerators (-15 degrees and 6 degrees), they are simply warmed up to 40-50 degrees, which is the temperature required for dissolution, to dissolve all components and sterilized at 121 degrees for 20 minutes. No crystals were precipitated, and this difference (difference between the non-sterile and sterilized formulations) also appeared in the blood concentration and urinary excretion of paracetamol in the following animal experiment.

The results are shown in Tables 3 and 4 below.

As can be seen from the experimental results, in the case of high temperature treatment at 121 ° C in the liquid solution, no crystal of paracetamol was precipitated in any case, but it was found that the crystal precipitated when not treated at high temperature.

Nevertheless, in the case of liquid preparations, it is preferable to carry out high temperature treatment after the preparation.

TABLE 3

TABLE 4

Experimental Example

Experiments on the increase in pharmacological action of injections:

Experimental Example 4

Analgesic test:

After sterilizing the formulations of Example 2 and Example 5 divided into three dose stages (high dose: 1ml / kg, medium dose: 0.5ml / kg, low dose: 0.25ml / kg) male KICR mice were injected through the femoral muscle and whistle The method of (Whittel, BA, Brit. J. Pharmacol. 22, 246-253, 1964) was slightly modified.

When the number of rides induced by acetic acid was measured after 60 minutes, there was a decrease in riding in a dose-dependent manner compared to the control group (oral administration of paracetamol), and the analgesic effect was 1/4 of oral dose of paracetamol. It was observed that even when reduced to more excellent than oral administration (wherein the control material used here is not a formulation for oral administration prepared by the method of the present invention, it is a conventional oral formulation).

The results are shown in Table 5 below.

TABLE 5

a: Administer the test compound intravenously to the mouse. After 50 minutes, acetic acid is administered intraperitoneally to the animal to cause riding.

The control group received oral paracetamol (ACAP: 150 mg / kg).

The reaction is measured over 10 minutes after 10 minutes of acetic acid administration.

Each value is expressed as mean standard deviation for 5-7 mice.

b: significantly different from the placebo group (Student's t-test, P 0.05)

c: markedly different from the placebo group (Student's t-test, P 0.01)

d: significantly different from the placebo group (Student's t-test, P 0.001)

Experimental Example 5

Antipyretic Experiment:

The antipyretic effect was measured by slightly modifying Nimeigeers et al. (Niemegeers, C.J.E., et al., Arzneim. Forsch, 25 (10), 1519-1524, 1975).

Test substance was subcutaneously injected in a male SD rat (300-400 g) with a 15% suspension of brewer's yeast at a volume of 0.25, 0.5 or 1 ml / kg in a volume of 1 ml / 100 g and after 4 hours [Example 2 ] And [Example 5] were injected through the femoral muscles at doses of 0.25, 0.5 and 1 ml / kg after sterilization.

As a result, the formulation of the present invention showed almost equivalent antipyretic effect even with about 1/2 of paracetamol.

The results are shown in Table 6 below.

TABLE 6

Example 6

Experiments on biocoavailability:

end. The preparation of Example 2 was sterilized and paracetamol was administered by intravenous injection, intramuscular injection and oral administration to rats at a dose of 100 mg / kg, and blood and urine were collected and tested.

Average plasma concentration curves are shown in FIG. After intravenous injection, paracetamol was reduced in polyexponential form and the parent terminal half-life was 32.4 minutes.

The paracetamol uptake was very fast after intramuscular injection. The maximum concentration was reached from 15 to 60 minutes and the highest concentration was 16-53 ug / ml.

After reaching the highest concentration, the concentration remained steady until 90 minutes, after which the termin-al half-life rapidly decreased to 37.9 minutes, which is remarkable.

After oral administration, the absorption of paracetamol was very fast. The highest concentration was reached 30-60 minutes after administration and the highest concentration was 29.5-91 ug / ml.

Five minutes after oral administration, paracetamol was detected in the plasma of all experiments and the concentration range was 7.5-57 ug / ml. After reaching the highest plasma concentration of paracetamol, the termianl half-life rapidly decreased to 36.2 minutes.

Pharmac-okineti-c parameters for paracetamol 100 mg / kg in rats given intravenously, intramuscularly, and orally are shown in Table 7-9 and the averages are shown in Table 10.

TABLE 7

TABLE 8

TABLE 9

TABLE 10

Bioavailability (F) is calculated by the following calculation method.

AUC: Plasma Concentration, Dose: Dose

AUC is described in M.L.Chen, G.L.M.G.Le and W.L.Chiou, Arterial and venous blood sampling in Pharmacokinetic Studies: Griseofulvin, J. Pharm. Sci., 71: 1386-1389 (1982).

As can be seen from the above tables, the formulation prepared by the method of the present invention has a surprising fact that in the bioavailability of 81.3% in intramuscular injection, 105% in oral administration (105% to 5% Experimental error).

This indicates that paracetamol has little effect on the first pass of the gastrointestinal tract and liver. Until now, the general method has been about 60% of the bioavailability when dissolved by simply adding a dissolution aid or orally administered with a tablet or capsule. (Win H. Chiou, Estimation of Hepatic First-Pass Effect of Acetaminophen in Human after Or-al Admintstratio, Journal of Pharmaceutical Sciences Vol 64, No. 10.October 1975, 1734-5). In the present invention, when paracetamol is used in combination with polyethylene glycol and propylene glycol and heat-treated, any chemical changes or chemical bonds occur to stabilize the aqueous solution and are also present in the liver when absorbed in the intestine and transferred to the liver through the context. Free para without active by glucuronic acid or sulfuric acid The process proceeds to directly to the blood tamol state is estimated to represent a drug.

Paracetamol preparations prepared by conventional methods are rarely metabolized and rarely excreted in the urine (3% or less). Most of them are excreted in the form of metabolites. 60% of the metabolites are glucuronic acid and 35% are sulfuric acid. And 5% form glycosides with glycine, respectively, and small amounts of hydroxylated and decetylated metabolites are present (AFGilman, LSGoodman, TWRall and F. Muran, Goodman and Gilman's: The Pharmacological Basis of Therape utics, 7th edition, Mcmillan Pyblishing Co. New York, 1985, p 693-4).

Therefore, the paracetamol preparation prepared according to the present invention is remarkably different from the conventional paracetamol preparation.

Therefore, it can be seen that the oral or parenteral preparation prepared by the method of the present invention is much better than the bioavailability of the conventional oral preparation.

Mean parction of paracetamol excreted in urine received 24 hours upon intravenous injection was 14.8%, intramuscular injection 15.0% and oral administration 12.6%, compared with conventional paracetamol formulations of 3% or less.

The above results show that paracetamol is metabolized in rats as well as in humans.

Renal clearance was 0.572ml / min / kg intravenously, 0.770ml / min / kg intramuscularly and 0.327ml / min / kg orally.

The mean CL was 19.2ml / min / kg, the average Vdss was 892ml / kg, and the mean fraction of CLr for CL was 2.97% (Table 7).

In conclusion, the paracetamol preparation of the present invention is considered to have a high bioavailability and much less toxicity than a conventionally used preparation (a research report of the Institute of Pharmacy affiliated with the College of Pharmacy, Seoul National University).

The preparation prepared in Example 5 was administered intravenously, intramuscularly, and orally administered to rats at a dose of paracetamol 100 mg / kg, and blood and urine were collected and tested.

The mean plasma concentration curve is shown in FIG.

After intravenous injection, the plasma concentration of paracetamol decreased to polyexponential form and mean apper-ent terminal half-life was 28.1 minutes.

The paracetamol uptake was very fast upon intramuscular injection.

Peak concentrations were reached at 15 to 45 minutes, with peak concentrations ranging from 14 ul / ml to 26 ul / ml.

After reaching the highest concentration, the concentration remains steady until 90 minutes and then the terminal half-life is 44.4 minutes, which is very noteworthy.

In the case of the addition of lidocaine, there was no increase in half-life during intramuscular injection, which is thought to be due to the added lidocaine.

The absorption of paracetamol after oral administration was very fast and reached the highest concentration within 5-10 minutes, and the maximum concentration range was 16-80ug / ml.

Paracetamol was detected 5 minutes after oral administration in all rats and the concentration range was 9-41 ug / ml.

After reaching the highest concentration, paracetamol showed a similar trend to intravenous injection, and the mean terminal half-life was 29.2 minutes (19.4-79.6 minutes).

In the case of paracetamol administration, intramuscular injection showed the lowest concentration than intravenous or oral administration.

The effect of intramuscular injection with lidocaine was lower than with other pathways, but the exact mechanism is known, but it may be due to the decrease in F as described below.

Paracetamol 100 mg / kg was added to the lidocaine and the Pharmacokinetic Parameters for intravenous, intramuscular and oral administration to rats are shown in Tables 11-13.

TABLE 11

TABLE 12

TABLE 13

Bioavailability was 42.5% for intramuscular injection and 85.0% for oral administration.

This case is thought to be due to the addition of lidocaine, with a decrease in F, resulting in lower plasma concentrations during intramuscular injection (see FIGS.

Most of the mean fraction excreted with urine received 24 hours after intravenous injection was 12.4% (7.72-14.5%).

A similar figure of 12.9 0.6% has been reported in rat studies (D. Jung, Dispositi-on of acetaminophen in protem-calorie malnu-trition, J. Pharmacol. Exp.Ther., 232: 178-182 (1984)). ).

As a result, it can be seen that most of the paracetamol in the rat is metabolized.

Renal clearance was 0.576 ml / min / kg (0.442 ml / min / kg-0.964 ml / min / kg), which was as low as expected.

The mean CL was 17.5 ml / min / kg (2.1-25.3 ml / min / kg) and the average Vdss was 782 ml / kg (619-1030 ml / kg).

The mean fraction of the CLR for CL is 3.29% (2.90% -3.47%).

In conclusion, the Pharmcokinetic Parameters of the formulation of the present invention are almost similar regardless of the route, but F was significantly decreased during intramuscular injection and oral administration in the case of the addition of lidocaine, which is considered to be due to the added lidocaine.

Experimental Example 7

Acute Toxicity Test

The sterile preparations prepared in Examples 2 and 5 were administered to male rats and mice via intramuscular injection to perform acute toxicity experiments.

The highest dose that could be technically administered was 3ml / kg at high dose and azeotropic 1/2, and the medium and low doses were respectively administered to the experimental animals and observed for 2 weeks.

Immediately after the administration of the test substance, some animals in the high-dose group of female rats and mice showed a temporary decrease in motility for 1-2 hours.

On the other hand, no abnormal general symptoms were observed in all animals during the observation period of two weeks from the next day of administration.

No deaths occurred during the two weeks of observation.

Therefore, the LD50 of the formulation of the present invention was more than 3ml / kg, but could not obtain a reliable range of LD50.

This dose (3 ml / kg) is 90 times the dose of an adult when weighing 60 kg.

All animals survived until the end of the observation period of 2 weeks after the administration of the test substance or the control material, but no abnormal lesions were thought to be due to the administration of the test substance.

The mean body weight at the beginning and the end of the experiment did not show any difference between the control group and the experimental substance-treated group in both male rats and mice, and there was no difference in weight gain during the experimental period.

Based on the above experimental results, it is considered that the formulation of the present invention has extremely low acute toxicity to rats and mice.

As can be seen from the above results, the paracetamol preparation treated by the method of the present invention is not only extremely soluble in water, but also stable, has a very high bioavailability, and is absorbed into the gastrointestinal tract, which is generally expressed by oral administration. In this context, the drug is not metabolized even if it is transited to the liver.

Claims (7)

Paracetamol is dissolved in a mixed solvent of polyethylene glycol and propylene glycol and heat-treated to increase the solubility and stability of paracetamol in water and increase its bioavailability. The paracetamol composition of claim 1 which is heated to a temperature range of 40-130 degrees to increase the solubility and stability of paracetamol in water and increase its bioavailability. An injection containing paracetamol as a main component prepared by sterilizing the paracetamol composition according to claim 1 and 2, followed by sterilizing with addition of an adjuvant selected from water, an antioxidant, an analgesic agent, a dissolving aid, a pH adjusting agent, and the like. Tablet of paracetamol with increased bioavailability prepared by adding the paracetamol composition according to claim 1 and 2 with an adjuvant selected from excipients, disintegrants, suspending agents, and binders used in conventional tablets and tableting by conventional methods for preparing tablets. A paracetamol capsule product having increased bioavailability, wherein the paracetamol composition according to claims 1 and 2 is added to an adjuvant selected from an excipient used in a conventional capsule preparation and prepared by a conventional method for preparing a capsule preparation. A paracetamol syrup having increased bioavailability, wherein the paracetamol composition of claims 1 and 2 is added to an excipient, a flavoring agent and water used in a conventional syrup, and prepared by a conventional method for preparing a syrup. A paracetamol suppository having the increased bioavailability of the paracetamol composition according to claim 1 and 2, wherein the paracetamol composition is added to a suppository base used in a conventional syrup, and the bioavailability is increased.