KR20230001635A - Method for manufacturing Parenteral formulation using bamboo salt - Google Patents

Abstract

The present invention relates to a method of manufacturing a preparation for parenteral administration using bamboo salt and, more specifically, to a method of manufacturing a preparation for parenteral administration using bamboo salt, comprising the steps of: mixing bamboo salt, basic amino acid, and purified water, adjusting the pH of the mixture to 7.0 to 9.0, and then performing a first sterilized bamboo salt solution by perform high-pressure steam sterilization for the mixture; performing purification for aseptically filtering the first sterilized bamboo salt solution to remove precipitates; mixing an ionic preservative with purified water and then performing high-pressure steam sterilization for the mixture to prepare a preservative mixture; preparing a second sterilized bamboo salt solution by aseptically mixing the purified first sterilized bamboo salt solution and the preservative mixture; and aseptically sealing the second sterilized bamboo salt solution. The stability for the preparation for parenteral administration can be enhanced.

Description

Method for manufacturing parenteral formulation using bamboo salt {Method for manufacturing Parenteral formulation using bamboo salt}

The present invention relates to a method for preparing a preparation for parenteral administration using bamboo salt.

When bamboo is burned with fire, liquid flows out of the bamboo, which is called tabasheer. Traditionally, bamboo shoots have been recorded a lot in books of oriental medicine. Tabasheer has excellent antioxidant power, which is three times higher than vitamin C, and also has high stability, so it is not easily decomposed like vitamin C, so a good effect can be expected. However, tabasheer is very bitter in taste and smells bad, so it is too high to avoid people taking it, so bamboo salt is designed to be easily used. In other words, bamboo salt refers to salt containing bamboo salt, which is a beneficial ingredient of bamboo, by heating and melting the salt several times at high temperature with bamboo to remove harmful ingredients to the body. These bamboo salts are known to have maximized their medicinal effects by repeatedly treating tabasheer and salt, which exhibit anti-inflammatory, anti-cancer, signal control, and toxic reduction effects, at high heat in a firing furnace.

The main components of this bamboo salt are Na and Cl, but it contains many other components such as bamboo components during the manufacturing process, so it is characterized by a dark gray color and a sulfur smell. Bamboo salt contains abundant natural minerals such as iron and magnesium, as well as natural sodium, potassium and calcium, and is known as a useful substance for the balance of trace elements in the human body. There are many attempts at development.

On the other hand, pharmacopuncture therapy is a treatment unique to oriental medicine in which chemical stimulation is added to acupuncture points in the form of acupuncture therapy that physically stimulates acupoints. Herbal medicines purified and extracted from pure herbal materials such as antler are injected in a very small amount at the acupuncture points. This is a therapy that maximizes treatment by combining the action of acupuncture and the action of herbal medicine. Pharmacopuncture therapy uses pure herbal medicines, so there is no addiction, habit, tolerance, etc., and by stimulating the meridians and acupuncture points connected to each organ, the energy of pharmacopuncture is directly delivered to the lesions in the intestines, so that the maximum effect can be obtained with the minimum amount of medication. There are advantages to being In other words, injections used in the medical field inject a large amount of chemical drugs into a certain area to obtain the medicinal effect of the drug, whereas pharmacopuncture injects a small amount of herbal medicine, a natural drug, into the acupoint area where acupuncture is placed. of therapeutic effects can be obtained together.

In addition, many pathological phenomena caused by inflammation are associated with increased metabolic activity and hypoxia, which increase acidification of the outside of the cell. Particularly, in the pain area, nociceptors are activated to secrete polypeptides from nerve terminals in tissues, and promote the production and secretion of inflammatory mediators, thereby amplifying the inflammatory response. In other words, when tissues are damaged by harmful stimuli, acidification of tissues becomes severe, prostaglandin and bradykinin are produced and secreted, and substances such as substance P are secreted from nerve terminals activated by stimuli, further amplifying the inflammatory response. .

Therefore, when bamboo salt preparation, which is a high-concentration ionized alkaline solution, is administered parenterally, it can neutralize acidified tissues and reduce pain, so parenteral preparations using bamboo salt are used as pharmacopuncture. In particular, the evoked potential of the cell membrane is elevated in muscles or tissues where continuous pain is induced, and the administration of such a parenteral preparation of bamboo salt reduces the potential of the cell membrane to reduce pain.

In general, the bamboo salt acupuncture solution is made by sterilizing phosphoric acid bamboo salt with an auto clamp, mixing it with distilled water to make bamboo salt acupuncture solution, and filtering it with a vacuum filter fitted with a membrane filter before using it, but a standardized manufacturing process has not been developed. to be. In addition, as the strong alkalinity of bamboo salt induces pain during administration, there is a sense of rejection by patients. Therefore, it is required to develop a standardized and scientifically based manufacturing process that can be manufactured without generating precipitates during manufacturing by performing a purification and sterilization process so that it can be safely applied without side effects.

Accordingly, the present inventors developed a standardized manufacturing process for a preparation for parenteral administration using bamboo salt, which reduces pain during administration by adjusting alkalinity, prevents the formation of precipitates, and enhances safety, and completed the present invention. did

Republic of Korea Patent No. 10-0805687 Republic of Korea Patent No. 10-2201406 Republic of Korea Patent No. 10-0893203

Therefore, the present invention is a technical solution to provide a method for preparing a preparation for parenteral administration using bamboo salt, which can reduce pain during administration by adjusting alkalinity, prevent the generation of precipitates, and increase safety. .

In order to solve the above problems, the present invention,

Preparing a first sterilized bamboo salt solution by mixing bamboo salt, basic amino acid and purified water, adjusting the pH to 7.0 to 9.0, and sterilizing with high pressure steam;

A purification step of aseptically filtering the first sterilized bamboo salt solution to remove precipitates;

After mixing the ionic preservative and purified water, high-pressure steam sterilization to prepare a preservative mixture;

Preparing a second sterilized bamboo salt solution by aseptically mixing the purified first sterilized bamboo salt solution and a preservative mixture; and

It provides a method for producing a preparation for parenteral administration using bamboo salt, characterized in that it comprises the step of asepticly sealing the second sterilized bamboo salt solution.

Preferably, in the present invention, the basic amino acid is characterized in that it is selected from the group consisting of arginine, lysine, histidine, and mixtures thereof.

In addition, in the present invention, the ionic preservative is characterized in that benzalkonium chloride or benzethonium chloride.

According to the present invention described above, it is possible to prepare a preparation for parenteral administration that can provide the pain relieving effect of bamboo salt while reducing pain during administration by controlling the strong alkalinity of bamboo salt. According to the present invention, it can be prepared by performing a purification and sterilization process so that bamboo salt can be safely administered parenterally without side effects due to impurities or precipitates. In particular, the present invention has an effect of preparing a preparation for parenteral administration with increased safety by controlling the process so that a precipitate is not formed by reacting with a cationic alkali solution, a preservative, a solubilizing agent, etc.

1 is a flow chart showing a manufacturing process according to the present invention.
Figure 2 shows a photograph of red bamboo salt (red bamboo salt) according to an embodiment of the present invention.
Figure 3 shows a photograph after dissolving purple bamboo salt according to an embodiment of the present invention in purified water.
Figure 4 shows a photograph of a bamboo salt preparation prepared according to an embodiment of the present invention and preserved at 80 ° C.
Figure 5 is a precipitate (A) after dissolving purple bamboo salt in purified water to precipitate, adjusting the acidity to alkali and separating the supernatant after centrifugation, and after dissolving after adding acetic acid to the precipitate according to an embodiment of the present invention Photo (B) is shown.
6 shows a photograph of a bamboo salt formulation vial prepared according to an embodiment of the present invention.

Hereinafter, preferred embodiments of the present invention will be described in detail. However, the present invention is not limited to the embodiments described herein and may be embodied in other forms. Rather, the disclosure herein is provided so that it will be thorough and complete, and will fully convey the spirit of the invention to those skilled in the art.

In the present invention, "preparation for parenteral administration" means a low-molecular drug for injection under or through one or more layers of the skin or mucous membrane of an animal such as a human.

The present invention relates to a method for preparing a preparation for parenteral administration using bamboo salt, wherein bamboo salt, basic amino acid and purified water are mixed, and the pH is adjusted to 4.6 to 9.0, followed by high-pressure steam sterilization to prepare a first sterilized bamboo salt solution. ; A purification step of aseptically filtering the first sterilized bamboo salt solution to remove precipitates; After mixing the ionic preservative and purified water, high-pressure steam sterilization to prepare a preservative mixture; Preparing a second sterilized bamboo salt solution by aseptically mixing the purified first sterilized bamboo salt solution and a preservative mixture; And aseptically sealing the second sterilized bamboo salt solution.

First, the step of preparing the first sterilized bamboo salt solution is performed by mixing bamboo salt, basic amino acids and purified water to adjust the pH, followed by high-pressure steam sterilization. In this step, it is important to adjust the pH to the range of 4.6 to 9.0 so as not to cause pain during administration of the formulation for parenteral administration. More preferably, since the pH of our body is 7.4, it is good to adjust it to 7.0 to 9.0 so that the acidity does not vary much.

In addition, the bamboo salt may be gray-white bamboo salt or purple bamboo salt. Gray-white bamboo salt has a strong salty taste and egg yolk taste due to tabasheer and has a pH of 10-10.5, and purple bamboo salt is slightly more alkaline and purple, and the salty taste and egg yolk taste are not so strong. Such bamboo salt is manufactured through the bamboo salt recipe process in which the bamboo salt that has gone through the 8th legal process is legalized at 1,500 ℃ or higher by burning pine trees again.

In one embodiment of the present invention, purple bamboo salt having a stronger alkalinity was used, and a picture of purple bamboo salt is shown in FIG. 1.

In addition, the basic amino acid is added as a solubilizing agent or dispersing agent, and may be selected from the group consisting of arginine, lysine, histidine, and mixtures thereof, and is preferably arginine or lysine. As such a solubilizing agent, the solubility of basic amino acids increases as the amount added increases, but as a preparation for parenteral administration, it is required to maintain a salt concentration of 0.6 to 2%, which is a physiological salt concentration, so it is preferably included within this range. Do.

Therefore, the basic amino acid may be included in an amount of 0.1 to 2% [w/v] based on the total amount of the preparation composition for parenteral administration. If the content of basic amino acids is less than 0.1%, it is difficult to assist solubility and no practical effect is shown, and if it exceeds 2%, gelation may occur due to excessive viscosity, which may cause pain and is economically undesirable. .

Next, the purification step is a step of aseptically filtering the first sterilized bamboo salt solution to remove the precipitate. In the preparation of the preparation for parenteral administration, the quality of the product is determined by the precipitate generated by the reaction between bamboo salt and basic amino acids. This is a step to prevent dropping.

At this time, it is preferable to filter the precipitate produced by cooling to 60 to 80 ° C. after the high-temperature steam sterilization treatment so that it can be effectively precipitated and filtered. In one embodiment of the present invention, the first sterilized bamboo salt solution subjected to high-temperature steam sterilization was maintained at 80 ° C. in a clean bench, and when a precipitate was formed, it was centrifuged to remove the supernatant.

Next, the step of preparing a preservative mixture is a step of mixing an ionic preservative with purified water and then sterilizing it under high pressure. The ionic preservative may be benzalkonium chloride or benzethonium chloride.

Since there are various substances and various ionic substances or ionic groups in natural products, it is necessary to prevent ionic bonding with the ionic preservative. That is, when a solution containing the main component and a solution of an ionic preservative are mixed and sterilized by high temperature steam, a precipitate is formed. In this way, while preparing preparations for parenteral administration, bamboo salt is homogeneously included and impurities are removed, so that it can be used as a standardized process capable of quality control.

In relation to this, in one embodiment of the present invention, as a result of confirming that the ionic preservative was separately prepared and mixed into a mixed preservative solution and mixed with bamboo salt for sterilization, the ionic preservative was separately prepared as a preservative mixed solution. It was confirmed that no precipitate was formed.

Next, the step of preparing the second sterilized bamboo salt solution may be prepared by aseptically mixing the purified first sterilized bamboo salt solution and the preservative mixture. That is, the preservative mixture prepared by mixing the ionic preservative and purified water and sterilizing with high pressure steam is cooled and stored at 60 to 80 ° C, which was cooled during filtration of the first sterilized bamboo salt solution, and then mixed aseptically in this step. This allows mixing while preventing the formation of precipitates. In this case, it is also possible to further perform aseptic treatment through additional heat treatment at 80 ° C. or higher.

Finally, as a step of preparing a formulation for parenteral administration, the second sterilized bamboo salt solution is aseptically sealed. Specifically, it is prepared by transferring a certain amount to a sterilized vial container and sealing it while maintaining an aseptic state.

In addition, as described above, preparations for parenteral administration refer to low-molecular drugs for injection under or through one or more layers of skin or mucous membranes of animals such as humans, and these preparations for parenteral administration are in the form of sterile injection solutions. It can be formulated and used. That is, it is prepared using a surfactant, an acidity regulator, and a solubilizing agent that may be included in the formulation for parenteral administration. Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried formulations, and suppositories. Propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate may be used as non-aqueous solvents and suspensions. As a base for suppositories, witepsol, macrogol, tween-61, cacao butter, laurin paper, glycerogelatin, and the like may be used.

The dosage of the preparation for parenteral administration of the present invention will vary depending on the age, sex, and weight of the subject to be treated, the specific disease or pathological condition to be treated, the severity of the disease or pathological condition, the route of administration, and the prescriber's judgment. Determination of dosage based on these factors is within the level of those skilled in the art, and generally dosages range from 0.001 mg/kg/day to approximately 200 mg/kg/day. A more preferred dosage is 0.1 mg/kg/day to 50 mg/kg/day. Administration may be administered once a day, or may be administered in several divided doses. The dosage is not intended to limit the scope of the present invention in any way.

<Example 1> Precipitate formation test

First, 1.5 g of bamboo salt was collected (see FIG. 2), transferred to a container, and 0.4 g of lysine was weighed and mixed, and about 80 ml of purified water was added and dissolved. At this time, the color of the solution was observed to be light green (see FIG. 3).

The acidity (pH) was adjusted to alkali (particularly pH 8.6) and treated with high-temperature steam sterilization (121 ° C., 15 minutes). This solution was transferred to a clean bench (Clean bench), which is a sterile test bench, and maintained at 80°C. A precipitate was observed finely in this solution, and the supernatant was separated by centrifugation (referred to as A solution).

Separately, 0.01 g of quaternary ammonium ion, benzalkonium chloride, was weighed and dissolved in about 20 ml of purified water, followed by high-temperature steam sterilization to prepare a solution (referred to as B solution). It was confirmed that it was a transparent and clear liquid solution. (drawing not shown)

A sample (sample 1) prepared by mixing solution A and solution B, from which the supernatant was separated, and a sample (sample 2) sterilized by high-pressure steam sterilization by mixing solution A and solution B were stored at 80 ° C after sterilization. A filamentous suspended matter was observed in sample 2, whereas a clear solution was observed in sample 1 stored at 80 °C (see FIG. 4).

From these results, it was confirmed that since precipitates are formed when high-pressure steam sterilization by mixing cationic and anionic materials, bamboo salt and ionic preservatives should be separately sterilized during sterilization, not sterilization of the mixture.

<Example 2> Formulation and sediment content test

2-1 formulation test

In this example, in order to supplement the formulation of Example 1, in order to set an appropriate temperature for mixing Solution A and Solution B of Example 1, the temperature at which precipitation does not occur was checked while maintaining aseptic conditions.

To this end, first, 1.5 g of bamboo salt was collected, transferred to a container, and 0.4 g of lysine was weighed and mixed, and about 80 ml of purified water was added and dissolved. At this time, the color of the solution was observed as light green.

The acidity (pH) was adjusted to 8.6 and high-temperature steam sterilization (121 ℃, 15 minutes) was performed. The solution was transferred to a clean bench and maintained below 80°C. In this solution, the precipitate was observed finely, and this was centrifuged (10,000 rpm, 15 minutes) to separate the precipitate and the solution, and the solution was separated (hereinafter, the separated solution is referred to as C solution). Figure 5A shows the precipitate after centrifugation and separation of the supernatant.

Separately, 0.01 g of Benzalkonium chloride was weighed and dissolved in about 20 ml of purified water, followed by high-temperature steam sterilization (hereinafter referred to as D solution).

The C solution and the D solution were mixed at about 60 ° C. for contamination prevention and worker safety, and the mixed solution was aseptically distributed in a vial, covered with a lid, and then sealed with an aluminum cap. This solution was stored at 80 °C and it was confirmed that no precipitate was generated.

2-2 Sediment content test

In order to determine the content of the precipitate, 100 g of bamboo salt was dissolved in water, centrifuged, dried, and weighed. It was found to be about 25 mg. This was a trace amount corresponding to 0.025%. As reported, in order to confirm that the water-insoluble component of bamboo salt is MgO, acetic acid, a solvent that solubilizes MgO, was added, and it was found that the precipitate was soluble (Fig. 5B).

From the above example, it was confirmed that there was no precipitate when the two ionic solutions were separately autoclaved and mixed at 60 ° C while cooling, and no precipitate was found even when the mixed solution was treated at 80 ° C again (see FIG. 6). This means that after mixing at 60 ° C, sterilization can be performed once more by heat treatment at 80 ° C for possible contamination.

In addition, a high-quality standardized process can be established when a process for removing even a small amount of impurities is performed. As described above, when a process for removing even a small amount of precipitate is performed, the quality It is confirmed that it can be maintained.

Thus, according to the present invention, the acidity is adjusted to 4.6 to 9.0, which is a condition that does not cause pain, and an alkaline amino acid is added as a solubilization and dispersing agent to prepare Brix (sum of solids) to be 2% or less, and to eliminate the reaction between the contents It can be confirmed that the preparation for parenteral administration using bamboo salt can be prepared in a safe and standardized way by separately sterilizing the ionic material by high-pressure steam, cooling, and then mixing.

Therefore, the preparation for parenteral administration of the present invention can be administered to mammals such as rats, livestock, and humans through various routes. All modes of administration can be envisaged, for example by intravenous, intramuscular, subcutaneous, intrauterine intrathecal or intracerebrovascular injection and dermal application. Since the compound of the present invention has little toxicity and side effects, it is a drug that can be safely used even when taken for a long period of time for preventive purposes.

Claims (3)

Preparing a first sterilized bamboo salt solution by mixing bamboo salt, basic amino acid and purified water, adjusting the pH to 7.0 to 9.0, and sterilizing with high pressure steam;
A purification step of aseptically filtering the first sterilized bamboo salt solution to remove precipitates;
After mixing the ionic preservative and purified water, high-pressure steam sterilization to prepare a preservative mixture;
Preparing a second sterilized bamboo salt solution by aseptically mixing the purified first sterilized bamboo salt solution and a preservative mixture; and
Characterized in that it comprises the step of asepticly sealing the second sterilized bamboo salt solution,
A method for preparing a preparation for parenteral administration using bamboo salt. According to claim 1,
The basic amino acid is characterized in that selected from the group consisting of arginine, lysine, histidine and mixtures thereof, a method for preparing a preparation for parenteral administration using bamboo salt. According to claim 1,
The method for preparing a preparation for parenteral administration using bamboo salt, characterized in that the ionic preservative is benzalkonium chloride or benzethonium chloride.

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