CN112823787B - Injection containing meloxicam and preparation method thereof - Google Patents
Injection containing meloxicam and preparation method thereof Download PDFInfo
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
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Abstract
The invention relates to the field of pharmaceutical preparations, and relates to a meloxicam injection, which consists of meloxicam, arginine and water, wherein the mass ratio of meloxicam to arginine is 4. The injection is used in basic amino acid, so that the solubility of meloxicam is effectively improved under the condition of not adding other solubilizers, the prescription of meloxicam solution is effectively improved, the preparation method of meloxicam solution is simplified, the bioavailability of the drug is further improved, and the therapeutic effect of the drug is greatly improved.
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations, and relates to a pharmaceutical composition containing a non-steroidal anti-inflammatory drug, in particular to a pharmaceutical composition containing meloxicam.
Background
Meloxicam (Meloxicam) is a new type of enol amide NSAIDs developed by BOEDIRINGER INGELHEIM in Germany, has unique pharmacological and pharmacodynamic effects, has almost the same internal constitution as similar piroxicam, tenoxicam and the like, and is generally used for treating Osteoarthritis (OA), acute sciatica, rheumatoid Arthritis (RA) and other diseases in clinic. Since the incidence of gastrointestinal adverse reactions with meloxicam is much less than with other nsaids, many hospitals and doctors have begun using meloxicam instead of other nsaids.
The meloxicam is a water-insoluble weakly acidic compound, the solubility is pH-dependent, the solubility is lowest at pH4 and increases with the increase of pH, so that a proper pH range is required for the meloxicam to dissolve when preparing a meloxicam preparation, and the stability of the solution in the storage process is ensured, which becomes a key and difficult point in the preparation process of the meloxicam solution.
Patent document CN018115608 discloses a cyclodextrin-free solution of meloxicam for oral or parenteral administration, which improves the solubility of meloxicam in meloxicam solution by forming meloxicam sodium salt or methylglucamine salt and simultaneously adjusting the pH of the solution, and the pH-dependent solubility characteristics of meloxicam and its sodium salt or meglumine salt in aqueous solution make the meloxicam injection extremely irritant during use, so that the meloxicam injection can only be used for intramuscular injection at present, and patent document CN031108024 discloses a meloxicam liquid preparation using cyclodextrin derivative as solubilizer and stabilizer, and the pH of the meloxicam liquid preparation is adjusted by adding other excipients and certain buffers, so as to achieve the purpose of improving the solubility of meloxicam.
CN 201910390430.1 discloses a meloxicam composition, a preparation method and application thereof, in the method, an organic solvent PEG is used as a cosolvent to increase the solubility of API, FDA IIG does not have dosage information of PEG-300/PEG-400 for injection, and no relevant injection is listed, so that clinical safety risk exists.
The pharmaceutical composition according to claim 2 of the present invention is preferably free of solubilizing agents or/and surfactants; the invention observes through practice experiments, wherein amino acid in the prior art is only used as a pH regulator, and the pH of the solution is adjusted to about 7 by adding acid in the preparation process, so that active ingredients are not dissolved, the amino acid is a regulator and a solubilizer, and the pH is controlled to be more than 8, thereby realizing the solubilization effect.
Disclosure of Invention
The invention aims to provide a pharmaceutical composition containing meloxicam, and provides a composition containing meloxicam for oral or parenteral administration, in particular the composition can be used for intravenous injection, and the specific invention is as follows:
the invention provides a pharmaceutical composition containing meloxicam, which is characterized in that the pharmaceutical composition contains meloxicam and basic amino acid, wherein the mass or weight ratio of meloxicam to basic amino acid is 4.
As one of the embodiments, the mass or weight ratio of meloxicam to basic amino acid in the composition is preferably 3; further preferably 2.5: 1-1; further selected from the group consisting of 2.
As one embodiment, the molar ratio of meloxicam to basic amino acid in the composition is 1.98; preferably 1.49; further preferably 1; further selected from 1.
As one embodiment, the basic amino acid is present in the composition in an amount of 0.10% to 3.5% (w/w); preferably 0.13% to 2.75% (w/w); further preferably 0.13% -1.47%; even more preferably 0.13% to 1.09%; still further preferably 0.2% -1.09%; again preferably 0.13% -0.98%; most preferably 0.2% to 0.98%.
As one of the embodiments, the basic amino acids include arginine, lysine, histidine; arginine is preferred.
As an embodiment, the drug concentration of meloxicam in the compositions according to the invention is greater than or equal to 1.0 mg/ml, preferably 2.0 mg/ml, again preferably 2.5 mg/ml, further preferably greater than or equal to 3.0 mg/ml; even more preferably 3.0-11 mg/ml; still more preferably from 3.45 to 11 mg/ml, most preferably from 4.14 to 10.6 mg/ml.
The study finds that the non-steroidal anti-inflammatory drug is used as COX-1 and COX-2 inhibitors, and researchers select arginine as the excipient of the invention, surprisingly, the solubility of the meloxicam is obviously improved after the arginine is added. The solubility of the meloxicam is enhanced, the bioavailability of the medicine is further improved, and the treatment effect of the medicine is greatly improved. By using the arginine, the solubility of the meloxicam can be effectively improved under the condition of not adding other solubilizers, the prescription of the meloxicam solution is effectively improved, and the preparation method of the meloxicam solution is simplified. Meanwhile, the invention further researches and discovers that other basic amino acids with similar properties to arginine can also improve the solubility of the meloxicam, such as lysine or histidine, and although the effect cannot be obviously improved as that of the arginine, compared with other basic substances, the solubility of the meloxicam is also obviously improved under the condition of not adding other solubilizing agents.
Furthermore, in the meloxicam pharmaceutical composition of the present invention, in order to further increase the solubility of meloxicam, a surfactant may be further added. As one of the embodiments, the surfactant includes, but is not limited to, one or more of the following: a monoester of a polyoxyethylene sorbitan fatty acid, a monoester of a sorbitan fatty acid, polyethylene glycol 15-hydroxystearate (Solutal HS-15), a polyethylene glycol ester of a fatty acid, a polyoxyethylene glycol ester, a polyoxyethylene castor oil, a polyglycerol ester of a fatty acid, a polyethylene glycol ether, a poloxamer, a polyoxyethylene phenyl ether, a tween, span, or a mixture thereof.
As one of the embodiments, it is possible to, particularly preferred surfactants are polyethylene glycol (25) -octadecyl/hexadecyl ether, polyethylene glycol 1100 mono (hexadecyl/octadecyl) ether, poloxamer 188, poloxamer 407, polyethylene glycol glycerol monoricinoleate, PEG-35 castor oil, polyoxyethylene-35 hydrogenated castor oil, polyoxyethylene-35 castor oil, polyethylene glycol (15) -hydroxystearate, polyoxyethylene 12-hydroxystearate, polyethylene glycol 15 hydroxystearate, polyethylene glycol glycerol hydroxystearate PEG-40 castor oil, polyoxyethylene 40 hydrogenated castor oil, polyethylene glycol 300, poly (ethylene glycol) -block-poly (propylene glycol) -block-poly (ethylene glycol)' cetyl alcohol, diethylene glycol monocetyl ether-2, diethylene glycol monocetyl ether-20, PEG-40 hydrogenated castor oil, PEG-60 hydrogenated castor oil, lauryl alcohol, laureth-12 and the like, oleyl alcohol-10 and the like, oleyl alcohol, PEG-15 stearyl ether, stearyl alcohol, steareth-2 and the like, cetostearyl ether-20, trideceth-12, glyceryl stearate and PEG-100 stearate, glyceryl stearate, PEG-40 stearate, cetostearyl-20, stearyl stearate, PEG-20 stearate, sorbitan sesquioleate, sorbitan oleate, sorbitan palmitate, sorbitan stearate, polysorbate 85, sorbitan fatty acid ester, sorbitan tristearate, polysorbate 60, PEG-2 laurate SE, ethylene glycol distearate, glyceryl stearate, ethylene glycol stearate and stearamide AMP and polyethylene glycol-glyceryl hydroxystearate.
As one embodiment, the further surfactant may be one or more selected from polyethylene glycol 15-hydroxystearate, poloxamer, span, tween.
As one of the embodiments, in certain embodiments the surfactant is Solutal HS-15, a poloxamer, or a combination of both.
Polyethylene glycol 15 hydroxystearate (Solutol HS-15) is a mixture of predominantly mono-and diesters of 12-hydroxystearic acid and polyethylene glycol, which is obtained by ethoxylation of 12-hydroxystearic acid. The number of moles of ethylene oxide reacted per mole of 12-hydroxystearic acid was 15. It contains about 30% free polyethylene glycol. Polyethylene glycol 15 hydroxystearate forms spherical micelles, and the incorporation of a poorly water-soluble drug into the micelles is an advantageous method for obtaining an adequate and suitable drug solution, and contributes to further improving the solubility of meloxicam, and at the same time, polyethylene glycol 15 hydroxystearate has another advantage in that it is not affected by the sterilization process, and no change in properties after sterilization is found in the test process, thereby proving that it is not hydrolyzed and the diameter of the micelles remains unchanged, so the addition of Solutol HS-15 solubilizer contributes to further enhancing the solubility of meloxicam, and at the same time, ensures that the stability of the drug does not change.
As one embodiment, the pharmaceutical composition of meloxicam according to the present invention comprises meloxicam, a basic amino acid, and Solutal HS-15.
As one embodiment, the meloxicam pharmaceutical composition according to the present invention comprises meloxicam, a basic amino acid, and a poloxamer.
As one embodiment, the pharmaceutical composition of meloxicam according to the present invention comprises meloxicam, a basic amino acid, solutal HS-15, and a poloxamer.
As one embodiment, the meloxicam pharmaceutical composition according to the present invention comprises meloxicam, arginine, and Solutal HS-15.
As one embodiment, the meloxicam pharmaceutical composition according to the present invention comprises meloxicam, arginine, and a poloxamer.
As one embodiment, the pharmaceutical composition of meloxicam comprises meloxicam, arginine, solutal HS-15 and poloxamer.
As one embodiment, the meloxicam pharmaceutical composition according to the present invention may further comprise water, wherein the water in the composition may be water for injection, distilled water, or purified water.
As one embodiment, the present invention provides a formulation of the composition of the present invention, which includes, but is not limited to, oral formulation, injection or lyophilized powder.
As one embodiment, when the injection is an injection, the injection consists of meloxicam, arginine and water, and the mass ratio of meloxicam to arginine is 4.
The invention provides a meloxicam injection, which consists of meloxicam, arginine and water, wherein the mass or weight ratio of the meloxicam to the arginine is (4).
As one embodiment, the injection has a mass ratio or weight ratio of meloxicam to arginine of 3; preferably 2.5.
As one of the embodiments, the mass ratio or weight ratio of meloxicam to arginine in the injection is 2; 1:0.85, 1:0.75, 1:0.65.
or the molar ratio of meloxicam to arginine is 1.98; preferably 1.49; further preferred are 1; further selected from 1.
In one embodiment, the arginine is present in an amount of 0.10% to 3.5% (w/w), based on the weight of the injection; preferably 0.13% to 2.75% (w/w); further preferably 0.13% -1.47%; even more preferably 0.13% to 1.09%; still further preferably 0.2% -1.09%; again preferably 0.13% -0.98%; most preferably 0.2% to 0.98%.
As one embodiment, the drug concentration of meloxicam in the injection solution is greater than or equal to 1.0 mg/ml, preferably 2.0 mg/ml, again preferably 2.5 mg/ml, and further preferably greater than or equal to 3.0 mg/ml, based on the volume of the injection solution; even more preferably 3.0-11 mg/ml; still more preferably 3.45-11 mg/ml, most preferably 4.14-10.6 mg/ml.
As one embodiment, the injection further comprises a surfactant, wherein the surfactant is Solutal HS-15 or poloxamer, or a combination thereof.
As one embodiment, the amount of the surfactant in the injection is 1% to 12.04% by mass of the injection; preferably 1% -10%, and further preferably 2% -6%; as an illustrative illustration, it may be 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, or 6%.
As one of the embodiments, the water includes, but is not limited to, water for injection, distilled water, or purified water.
As one embodiment, the injection solution is prepared from
Meloxicam 0.025g
Arginine 0.040g and
4.946g of water for injection;
as one embodiment, the injection solution is prepared from
As one embodiment, the injection solution is prepared from
As one embodiment, the injection solution is prepared from
As one embodiment, the injection solution is prepared from
As one embodiment, the injection solution is prepared from
As one embodiment, the injection solution is prepared from
Or is made of
Or is made of
Or is made of
In the present invention, as one embodiment, the injection further comprises an osmotic adjusting agent selected from sodium chloride, glucose; sodium chloride is further preferred.
In the present invention, as one embodiment, the injection solution is prepared from
As one embodiment, the present invention may be used for oral administration or intravenous administration; intravenous administration is preferred.
In one embodiment, the injection according to the invention has a pH of 7 to 9, preferably 8 to 9.
The present invention is primarily intended for intravenous administration, which is the fastest way to deliver a drug to a target site, as compared to other routes of administration, and is also the most efficient and accurate route, however, adverse reactions associated with this route of administration may be harmful to the patient or cause discomfort. The non-physiological osmotic pressure, viscosity or pH of the drug solution are mechanisms that cause inflammation and tissue changes in blood vessels, resulting in discomfort to patients under such treatment, and the present invention is directed to reducing the side effects of intravenous administration of meloxicam while increasing the solubility of meloxicam.
The pain and stimulation at the injection part can be related to a preparation solvent, particularly a preparation solvent with high osmotic pressure, an organic solvent is not used in the preparation, only water is used as the preparation solvent, the dependence of an active substance on pH is greatly reduced, the pain stimulation during injection is effectively reduced, and meanwhile, the preparation formula has simple and safe auxiliary materials, and the side effect of the preparation is greatly reduced.
As one embodiment, when the injection is used for intravenous administration, the injection can be directly prepared, or the composition can be subjected to freeze-drying treatment to prepare a meloxicam freeze-dried product, and when the injection is used, the meloxicam freeze-dried product is subjected to intravenous administration after being dissolved, and a re-solvent of the injection can be selected from water for injection, normal saline, glucose and other re-solutions suitable for injection.
As one embodiment, the meloxicam pharmaceutical composition of the present invention may be added with a lyophilization stabilizer during the lyophilization process, including but not limited to the following types: sucrose, lactose, maltose, glucose, raffinose, fructose, dextrin, and the like.
As an embodiment, the meloxicam pharmaceutical composition according to the invention, which is sterilized without any change in weight of the sterilized product, can be sterilized by autoclaving or filtration, preferably autoclaving, wherein the sterilization temperature is 100 ℃ to 150 ℃, preferably 110 ℃ to 130 ℃.
As an embodiment, the formulation according to the invention further comprises a solution of the composition sealed under inert gas and finally sterilizable in a final container comprising an ampoule or vial of penicillin, preferably penicillin, and sealed with a rubber and aluminium cap.
The invention provides a preparation method of the pharmaceutical composition, which comprises the following steps: weighing each component of the composition according to the prescription amount, dissolving the components in water to form a clear solution, filling the clear solution into a penicillin bottle, and sterilizing at high pressure or 121 ℃ to obtain the meloxicam solution.
As one embodiment, the present invention provides a method for preparing an injection, comprising: weighing the components according to the prescription amount, dissolving in water to form a clear solution, filling into a penicillin bottle, and sterilizing at high pressure or 121 ℃ to obtain the meloxicam solution for injection.
The meloxicam composition is mainly used for preparing a medicine for treating pain, wherein the pain comprises acute pain, chronic pain, visceral pain or mixed pain, the acute pain comprises postoperative pain, obstetrical pain, acute injury pain of soft tissues and joints and the like, the chronic pain comprises cancer pain, inflammatory pain and the like, and the cancer pain comprises late tumor pain or tumor metastasis pain.
The invention provides a preparation prepared from the pharmaceutical composition, which comprises an oral preparation, an injection, a freeze-dried preparation and the like.
As one embodiment, the injection or lyophilized formulation is for intravenous administration.
The technical effects are as follows:
according to the pharmaceutical composition containing meloxicam, the basic amino acid can greatly achieve the effect of solubilizing meloxicam, the effect of improving the solubility of meloxicam can be achieved without adding any other solubilizing agent except the specific basic amino acid, secondly, meloxicam is directly used as an active substance in the invention, and on the basis of using the basic amino acid as the solubilizing agent, the dependence of the solubility of meloxicam on pH is reduced, so that the irritation of meloxicam injection is greatly reduced, the compliance of patients is improved, the pharmaceutical composition is more suitable for clinical intravenous injection, thirdly, the pharmaceutical composition does not contain any organic solvent, the adverse reaction of a pharmaceutical preparation can be effectively avoided, the use of the pharmaceutical composition is safer, and the pollution of the pharmaceutical to the environment in the preparation process is reduced.
Detailed Description
The meloxicam solutions of the present invention are illustrated by the following examples, which are to be understood by those skilled in the art as being illustrative only and not limiting in scope.
EXAMPLE 1 Meloxicam solution
The formula is as follows:
meloxicam 0.025g
Arginine 0.040g
4.946g of water for injection
The preparation method comprises the following steps: weighing the meloxicam and arginine according to the prescription amount, dissolving the meloxicam and arginine in water for injection to form a clear solution, filling the clear solution into a penicillin bottle, and sterilizing at 121 ℃ to obtain the meloxicam solution, wherein the medicine content of the solution is detected to be 5.12 mg/ml.
EXAMPLE 2 Meloxicam solution
The formulation of meloxicam and arginine is shown in tables 1 and 2, based on the examination of the dosage ratio of meloxicam and arginine:
TABLE 1-1
Tables 1 to 2
Through the API: and (3) screening out results of the dissolution state and stability of Arg in different proportions to obtain API: the proportion range of Arg is preferably pH 7-9, further 8-9, and the comprehensive dissolution state and pH value, considering that the administration route of the product is intravenous injection, and in order to reduce irritation and improve safety, API: arg is 1:1-1:0.65
The preparation method comprises the following steps: prepared according to the method of example 1. As shown in table 1, the prepared compositions have concentrations of 2mg/mL or more, and the final prepared solutions have different drug concentrations according to the mass ratio of meloxicam to arginine, and when the mass ratio of meloxicam to arginine is further preferably 2: 1-1:0.65.
EXAMPLE 3 Meloxicam solution
Formulation(s)
The preparation method comprises the following steps: weighing meloxicam, arginine and Solutol HS15 according to the prescription amount, dissolving in water to form a clear solution, filling into a penicillin bottle, and sterilizing at 121 ℃ to obtain the meloxicam solution, wherein the medicine content of the detected solution is 10.13 mg/ml.
EXAMPLE 4 Meloxicam solution
Formulation of
The preparation method comprises the following steps: weighing meloxicam, arginine, solutol HS15 and poloxamer according to the prescription amount, dissolving in water to form a clear solution, filling into a penicillin bottle, and sterilizing at 121 ℃ to obtain the meloxicam solution, wherein the medicine content of the detected solution is 5.28 mg/ml.
EXAMPLE 5 Meloxicam solution
Formulation of
The preparation method comprises the following steps: weighing the meloxicam, arginine, solutol HS15 and poloxamer according to the prescription amount, dissolving the mixture in water to form a clear solution, filling the clear solution into a penicillin bottle, and sterilizing the solution at 121 ℃ to obtain the meloxicam solution, wherein the medicine content of the solution is 5.17 mg/ml.
EXAMPLE 6 Meloxicam solution
Meloxicam 0.025g
Histidine 0.031g
4.912g of water for injection
The preparation method comprises the following steps: weighing meloxicam and histidine according to the prescription amount, dissolving in water to form a solution, filling a penicillin bottle, and sterilizing at 121 ℃ to obtain the meloxicam solution, wherein the drug content of the solution is detected to be 3.47 mg/ml.
EXAMPLE 7 Meloxicam solution
Meloxicam 0.025g
Lysine 0.033g
4.935g of water for injection
The preparation method comprises the following steps: weighing the meloxicam and the lysine according to the prescription amount, dissolving the meloxicam and the lysine into water to form a solution, filling a penicillin bottle, and sterilizing at 121 ℃ to obtain the meloxicam solution, wherein the medicine content of the solution is detected to be 3.56 mg/ml.
Example 8
The preparation method comprises the following steps: weighing the meloxicam, arginine, solutol HS15 and poloxamer according to the prescription amount, dissolving the mixture in water to form a clear solution, filling the clear solution into a penicillin bottle, and sterilizing the solution at 121 ℃ to obtain the meloxicam solution, wherein the medicine content of the solution is detected to be 5.13 mg/ml.
Example 9
The preparation method comprises the following steps: weighing the meloxicam, arginine, solutol HS15 and poloxamer according to the prescription amount, dissolving the mixture in water to form a clear solution, filling the clear solution into a penicillin bottle, and sterilizing the solution at 121 ℃ to obtain the meloxicam solution, wherein the medicine content of the solution is 5.24 mg/ml.
Example 10
The preparation method comprises the following steps: weighing meloxicam, arginine, solutol HS15 and poloxamer according to the prescription amount, dissolving in water to form a clear solution, filling into a penicillin bottle, and sterilizing at 121 ℃ to obtain the meloxicam solution, wherein the medicine content of the detected solution is 3.45 mg/ml.
EXAMPLE 11 Meloxicam solution
The preparation method comprises the following steps: weighing meloxicam, arginine, solutol HS15 and sodium chloride according to the dosage of the prescription, dissolving in water to form a clear solution, filling into a penicillin bottle, and sterilizing at 121 ℃ to obtain the meloxicam solution.
Comparative example
Comparative example 1 Meloxicam solution
Formulation(s)
Meloxicam 0.025g
Glycine 0.045g
4.915g of water for injection
The preparation method comprises the following steps: weighing the meloxicam and the glycine according to the prescription amount, dissolving the meloxicam and the glycine in water to form a solution, filling a penicillin bottle, and sterilizing at 121 ℃ to obtain the meloxicam solution, wherein the medicine content of the solution is detected to be 0.58 mg/ml.
Comparative example 2 Meloxicam solution
Formulation(s)
Meloxicam 0.025g
Sodium phosphate 0.042g
4.915g of water for injection
The preparation method comprises the following steps: weighing meloxicam and sodium phosphate in a prescribed amount in water to form a solution, filling a penicillin bottle, and sterilizing at 121 ℃ to obtain the meloxicam solution, wherein the drug content of the solution is detected to be 0.78 mg/ml.
Comparative example 3 meloxicam solution formulation
The preparation method comprises the following steps:
dissolving 0.02g of meloxicam in 2ml of meglumine aqueous solution (0.007 g/ml) at 90 ℃, sequentially adding other excipients into the solution according to the formula, using 1M hydrochloric acid and 1M sodium hydroxide solution to enable the pH to reach 8.8, adding water into the solution, filling into a penicillin bottle, and sterilizing at 121 ℃ to obtain the meloxicam solution, wherein the drug content of the solution is 4.07 mg/ml.
Stability test of Meloxicam injection
The sample formulations prepared in examples 1, 3, 4, 5, and 6 were placed at a temperature of 25 ℃. + -. 2 ℃ and a relative humidity of 45%. + -. 5% for 3 months, 6 months, and 12 months, and the change in the drug concentration was measured, and the results are shown in Table 2:
TABLE 2 Meloxicam injection stability test
As can be seen from Table 2, the drug concentration of the preparation of the invention is obviously enhanced, and after the sterilization treatment, the preparation can keep good drug concentration after being placed through a long-term stability test, so that the preparation is more stable, which not only is beneficial to drug storage, but also ensures the drug safety.
Stability test of Meloxicam lyophilized preparation
The samples prepared in examples 1, 3, 4 and 5 were lyophilized to obtain a homogeneous and loose cake, and the cake was placed at 25 ℃ ± 2 ℃ and 45% ± 5% relative humidity for 3 months, 6 months and 12 months, reconstituted with water, and the reconstituted drug concentration was determined, the results of which are shown in table 3:
TABLE 3 stability test of Meloxicam lyophilized products
The results in table 3 show that the product of the invention has stable shape after being processed by the freeze-drying process, the product has good solubility after redissolution, no generation of insoluble substances is found, the drug concentration is basically guaranteed unchanged, and the results of stability examination show that the product concentration can keep good drug concentration after freeze-drying and can be stably stored.
Rat incision pain model experiment
Experimental methods
Male SD rats weighing 250g were randomized into 5 groups of 10 rats each. After the animal is anesthetized with isoflurane, the right hind foot of the rat is sterilized, a longitudinal incision with the length of about 1.0cm is made from the beginning of 0.5cm of the proximal end of the sole to the toe by using a scalpel according to a Brennan method, the muscle under the foot is picked up by using an ophthalmic forceps or a hemostatic forceps after the skin is cut, the left and right longitudinal incisions are performed, the integrity of the attachment point of the muscle is ensured, the hemostatic is pressed, then, the thin line suture is used, and then, the drug is administered. And measuring the pain threshold 2.5-3h after the operation.
The dose of the meloxicam injection is about 2 times of the clinical highest dose of 15mg of meloxicam tablets, while the dose of Kefen (flurbiprofen axetil fat emulsion injection, beijing Taide pharmaceutical Co., ltd.) is about 6 times of the common clinical dose (50 mg), namely the dose of Kefen is 35mg/kg, and the dose of the meloxicam injection is 4mg/kg.
And (3) after administration for 40min, placing the rat in a detection cage to adapt to the environment for 20min, slowly and softly stimulating the middle part of the pelma of the hind limb to be detected by using a pain instrument probe after the rat is quiet, and recording the reading (g) when the paw generates a foot contraction reaction if the rat generates a rapid foot contraction reaction due to stimulation. The withdrawal response due to the physical activity of the rats was not counted. Eight repeated measurements were made and the results were recorded, the mean being the pain threshold of the animal, and the pain threshold change of each group of animals after about 3 hours of molding is shown in table 4 below.
TABLE 4 analgesic effect of meloxicam injection on rat incision pain
| Group of | Dosage (mg/kg) | Animal number (only) | Pain threshold (g) |
| Model set | / | 10 | 14.4±3.3 |
| Kaifen dispute | 35 | 10 | 20.2±4.1** |
| Example 1 | 4 | 10 | 19.9±5.1* |
| Example 4 | 4 | 10 | 23.3±3.2** |
| Example 8 | 4 | 10 | 22.3±5.0** |
* P <0.05 compared to model group; * P <0.001
The experimental results show that the meloxicam injection preparation prepared by the invention has extremely strong analgesic effect on the incision pain, and the action intensity is at least 8 times of Kefang.
Toxicity test study
Experimental method
45 SD rats were randomly divided into 3 groups of 15 rats each. 1.6mg/kg of the meloxicam raw material drug is orally administered and 6.3mg/kg of the injection solution of example 9 and example 10 is intravenously administered, and the administration is continued for 7 days. Wherein the amount administered orally is about 15mg of the clinically maximum amount of the oral formulation.
Animals were observed daily. The animal body weight was weighed daily. After 7 days of continuous administration, 10 animals in each group were subjected to pathological dissection, and 5 animals were in the recovery phase, which was 7 days. After the end of the recovery period all animals were pathologically dissected and the results of the examination are summarized in table 5.
TABLE 5 results of the dissection examination of meloxicam 7 days after continuous administration
| Is administered orally | Example 9 | Example 10 | |
| Gastric wall cavity | 3 | 3 | 2 |
| Thinning of stomach wall | 3 | 2 | 3 |
The weight average of animals in each administration group has no obvious reduction trend in the administration period, compared with the oral administration group, the weight change of the animals in the intravenous injection group and the occurrence probability of gastrointestinal tract abnormality are basically equivalent, but the safety of the injection prepared by the invention is obviously higher than that of the oral preparation because the intravenous administration dosage is 4 times of that of the oral administration.
Claims (28)
1. The meloxicam injection is characterized in that the injection consists of meloxicam, arginine, a surfactant and water, the mass or weight ratio of the meloxicam to the arginine is 3-1 to 8, the pH value of the injection is 7-9, and the surfactant is Solutal HS-15 or the combination of Solutal HS-15 and poloxamer.
2. The injection according to claim 1, wherein the mass or weight ratio of meloxicam to arginine in the injection is 2.5.
3. The injection according to claim 1, wherein the mass or weight ratio of meloxicam to arginine in the injection is 1.
4. The injection according to claim 2, wherein the mass or weight ratio of meloxicam to arginine in the injection is 2; 1:0.85, 1:0.75, 1.
5. The injection according to claim 1, wherein the arginine is present in an amount of 0.10% to 3.5% (w/w) based on the weight of the injection.
6. The injection of claim 1, wherein the meloxicam drug concentration in the injection is greater than or equal to 1.0 mg/ml based on the volume of the injection.
7. The injection according to claim 1, wherein the amount of the surfactant in the injection is 1% to 12.04% by mass of the injection.
8. The injection according to claim 1, wherein the water is selected from water for injection, distilled water or purified water.
9. The injection solution of claim 8, wherein the injection solution is prepared from
Or is made of
Or is made of
Or is made of
Or is made of
Or is made of
Or is made of
Or is made of
Or is made of
10. The meloxicam injection is characterized in that the injection consists of meloxicam, arginine, a surfactant, an osmotic adjusting agent and water, the mass or weight ratio of the meloxicam to the arginine is 3-1.
11. The injection solution of claim 10, wherein the injection solution is prepared from
12. The injection according to any one of claims 1 to 11, wherein the pH of the injection is 8 to 9.
13. A method of preparing an injection according to any one of claims 1 to 12, said method comprising: dissolving the components in water to obtain clear solution, bottling, and sterilizing under high pressure or at 121 deg.C.
14. The injection according to claim 5, wherein the arginine is present in an amount of 0.13% to 2.75% (w/w) based on the weight of the injection.
15. The injection according to claim 5, wherein the arginine is contained in an amount of 0.13 to 1.47 percent by weight of the injection.
16. The injection according to claim 5, wherein the arginine is present in an amount of 0.13% to 1.09% by weight of the injection.
17. The injection according to claim 5, wherein the arginine is present in an amount of 0.2% to 1.09% by weight of the injection.
18. The injection according to claim 5, wherein the arginine is contained in an amount of 0.13 to 0.98% by weight of the injection.
19. The injection according to claim 5, wherein the arginine is contained in an amount of 0.2 to 0.98% by weight of the injection.
20. The injectable solution of claim 6, wherein the pharmaceutical meloxicam concentration in the injectable solution is greater than or equal to 2.0 mg/ml based on the volume of the injectable solution.
21. The injection of claim 6, wherein the meloxicam drug concentration in the injection is greater than or equal to 2.5 mg/ml based on the volume of the injection.
22. The injectable solution of claim 6, wherein the pharmaceutical meloxicam concentration in the injectable solution is greater than or equal to 3.0 mg/ml based on the volume of the injectable solution.
23. The injection of claim 6, wherein the pharmaceutical concentration of meloxicam in the injection is 3.0 to 11 mg/ml based on the volume of the injection.
24. The injection according to claim 6, wherein the drug concentration of meloxicam in the injection is 3.45 to 11 mg/ml based on the volume of the injection.
25. The injection according to claim 6, wherein the drug concentration of meloxicam in the injection is 4.14 to 10.6 mg/ml based on the volume of the injection.
26. The injection according to claim 7, wherein the amount of the surfactant in the injection is 1% to 10% by mass of the injection.
27. The injection according to claim 7, wherein the amount of the surfactant in the injection is 2 to 6% by mass of the injection.
28. The injection of claim 10, wherein the osmotic agent is sodium chloride.
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| CN1437472A (en) * | 2000-06-20 | 2003-08-20 | 贝林格尔·英格海姆维特梅迪卡有限公司 | Highly concentrated stable meloxicam solutions |
| WO2005021041A1 (en) * | 2003-08-30 | 2005-03-10 | Archimedes Development Limited | Intranasal formulations of meloxicam |
| WO2019037757A1 (en) * | 2017-08-24 | 2019-02-28 | 江苏恒瑞医药股份有限公司 | Injectable pharmaceutical composition containing meloxicam, and preparation method therefor |
| CN110464846A (en) * | 2018-05-11 | 2019-11-19 | 南京清普生物科技有限公司 | A kind of Meloxicam composition, preparation and the preparation method and application thereof |
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| CN1437472A (en) * | 2000-06-20 | 2003-08-20 | 贝林格尔·英格海姆维特梅迪卡有限公司 | Highly concentrated stable meloxicam solutions |
| WO2005021041A1 (en) * | 2003-08-30 | 2005-03-10 | Archimedes Development Limited | Intranasal formulations of meloxicam |
| WO2019037757A1 (en) * | 2017-08-24 | 2019-02-28 | 江苏恒瑞医药股份有限公司 | Injectable pharmaceutical composition containing meloxicam, and preparation method therefor |
| CN110464846A (en) * | 2018-05-11 | 2019-11-19 | 南京清普生物科技有限公司 | A kind of Meloxicam composition, preparation and the preparation method and application thereof |
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