Preparation method of stable veterinary oral paste composition

Abstract

The present invention relates to a suitable pharmaceutical composition carrier for delivering a pharmaceutically acceptable active ingredient proton pump inhibitor to mammals or human subjects for the treatment of gastric ulcer related diseases caused by hypersecretion of gastric acid in humans or mammals. The invention relates to a preparation method of a veterinary oral paste composition which is more physically stable. The composition is suitable for treating related diseases of animals such as horses, cows, sheep and the like. Belongs to the technical field of medicine. The oral paste prepared by the process method has better physical stability than the original paste or oral paste in storage life.

Description

Field of the Invention

[0001] The present invention relates to a method for manufacturing an oral paste with better stability for drug delivery, belonging to the field of pharmaceutical technology. Background of the Invention

[0003] Proton pump inhibitor is a new type of proton pump inhibitor. It was first synthesized in 1979 by Ylva Ortengren of Astra (now AstraZeneca) in Sweden. Its efficacy was discovered in 1983, and it was first marketed in Sweden under the trade name Losec in 1988, and in the United States under the trade name Prilosec on September 14, 1989. It was marketed in China in March 2001 under the trade name (Losec@).

[0004] On March 16, 1999, the US FDA approved the marketing of the proton pump inhibitor oral paste (Omeprazole Oral Paste for Equine Ulcers) developed by Merial Limited, with a specification of 6.16 g: 2.279 g (37% w / w), and the trade name GastroGard, for use in EQUIDS (horses, foals over 4 weeks old, non-food horses). On February 18, 2004, the US FDA approved the marketing of the proton pump inhibitor oral paste (Omeprazole Oral Paste for Equine Ulcers) developed by Merial Limited, with a specification of 6.16 g: 2.279 g (37% w / w), and the trade name UlcerGard@, for use in EQUIDS (horses, with no express or implied indication of the use category).

[0005] The preferred proton pump inhibitor used in the present invention is a compound known as a proton pump inhibitor. The proton pump inhibitor used in the present invention is a compound known in the art, and its preparation method can be referred to in the literature. For example, EP5129, EP174726, EP166287, and GB2163747, etc. It has been widely used in the treatment of gastrointestinal diseases caused by excessive gastric acid secretion in humans or animals.

[0006] The patent CN1080119 provides a stable and ready-to-use PPI oral drug paste composition, which is easily administered to animals such as horses. More specifically, the composition of the present invention contains: one or several proton pump inhibitors, a hydrophobic oily liquid carrier, a basifying agent, and a thickening agent. It is described that it is prepared by dispersing the active ingredient, the proton pump inhibitor in powder form, in a hydrophobic liquid carrier containing any excipients other than the thickening agent. Then a thickening agent is added to the mixture and mixed to obtain the required consistency. The paste thus obtained can be used to fill a syringe, which is directly used to administer the active drug to the animal in need of treatment. At the same time, its chemical stability during storage is ensured.

[0007] However, there is no research or report on increasing physical stability in the patent CN1080119 or other domestic and foreign literatures. In our research, a preparation process can enhance the physical stability of such proton pump inhibitor oral pastes without reducing chemical and other stabilities and efficacies. Summary of the Invention

[0009] The preparation of the present invention is a stable semi-solid oral paste, containing proton pump inhibitor drugs, which can be used to treat animals such as horses, sheep, cows, etc. that are not suitable for taking tablets, and even humans. Particularly acceptable are horses, cows, and sheep. The oral paste prepared by the process of the present invention has good stability when placed at room temperature and is convenient for clinical use.

[0010] During the process of imitating this preparation by our company, it was found through research that the physical stability of the original preparation is not superior to that of the imitation preparation developed by our company. And our company found that on the basis of the existing prescription process, controlling the API particle size so that D90 is not greater than 20 microns, adding a certain proportion of colloidal silica, and pre-mixing and grinding the API with colloidal silica through the preparation process can make the physical stability of this product superior to that of the original preparation. And through BE tests, it is confirmed that this preparation is bioequivalent to the original preparation, has good stability, is easy to promote and industrialize, and has better commercial significance.

[0011] The following examples are provided to more comprehensively and detailedly illustrate the present invention, but should not be construed as limiting the scope of the present invention in some aspects.

[0012] The present invention provides a preparation method of an oral paste composition. Specifically, the composition of the present invention contains: the active ingredient proton pump inhibitor drugs, matrix carriers, consistency and viscosity regulators, etc.

[0013] The oral paste pharmaceutical composition prepared by the process of the present invention can significantly improve the physical stability of this product during storage compared with the product that does not control the raw material drug and colloidal silica as a stabilizer and is expected to be ground and mixed.

[0014] In the present invention, controlling the raw material particle size below a certain range is not for enhancing the in vivo dissolution behavior familiar to those skilled in the art, but for increasing the dispersion degree and stable state of the active pharmaceutical ingredient in the matrix to a greater extent, which is more conducive to the stability of the system and avoiding the unexpected aggregation and stratification precipitation of insoluble components. However, it is not sufficient to achieve a physical stability period of up to 36 months.

[0015] In the present invention, adding a certain proportion of colloidal silica is for enhancing the physical stability of the preparation. Through research, it is found that it can indeed relatively improve the physical stability of the preparation because the particle size of colloidal silica is very small. As a thickening agent, the preparation does not appear rough even after addition. It is often used as a stabilizer (thickening and suspending aid) for semi-solid preparations, and its function is not affected by temperature (the consistency of most other thickening agents is greatly affected when the temperature rises or the season changes). However, simply adding it cannot significantly increase the physical stability time. Co-grinding and mixing the API with colloidal silica can significantly improve the final physical stability of the oral paste. It is speculated that the possible reason is that colloidal silica has a certain adsorption property and can more tightly adsorb and wrap the API, which is beneficial to slowing down the stratification and aggregation speed of the API compared with other components when the environment changes, thus achieving a slower aggregation speed and being more stable.

[0016] In summary: The oral paste of the pharmaceutical composition of the present invention has good physical stability, is easy to commercialize, and has good economic benefits. Detailed Description of the Invention

[0018] The active substance used in the present invention is a proton pump inhibitor chemical. Such drugs are compounds known in the art, and their preparation methods can refer to relevant literature and patents. The content of the active substance is between 0.01 - 50%, preferably 10 - 45%, and more preferably between 36 - 38%.

[0019] The matrix carrier is one or a combination of more of triacetin, propylene glycol dicaprylate / dicaprate, monoethanolamine, starch, potassium sorbate, pigment, colloidal silica, peanut oil, sesame oil, cinnamon oil, soybean oil. Preferably, it is propylene glycol dicaprylate / dicaprate, monoethanolamine, potassium sorbate, pigment, and the content is between 49.5 - 99.49%, preferably 50 - 89%, and more preferably between 60 - 62.8%.

[0020] The viscosity regulator is one or a combination of more of thickening agent compounds such as sodium stearate, calcium stearate, hydrogenated castor oil, colloidal silica. Preferably, it is sodium stearate, calcium stearate, hydrogenated castor oil, colloidal silica, and the content is between 0.1 - 10.0%, preferably 0.1 - 5%, and more preferably 0.2 - 2.0%.

[0021] The active substance used in the present invention is a proton pump inhibitor raw material whose particle size D90 is controlled to be less than 20 microns, and preferably the proton pump inhibitor raw material D90 is less than 10 microns.

[0022] The preparation method of the present invention comprises the following steps: firstly, pre-screening the solid material through a 60-mesh sieve to remove lumps, grinding and mixing the proton pump inhibitor and colloidal silicon dioxide uniformly for standby use; adding a uniformly mixed liquid auxiliary material into a container, then adding monoethanolamine, potassium sorbate, sodium stearate, calcium stearate, pigment and the like and stirring uniformly, then adding the proton pump inhibitor API and the colloidal silicon dioxide grinding mixture and stirring (including homogenization) until uniform, and then continuing to add hydrogenated castor oil and stirring (including homogenization) until uniform; and finally filling the mixture into a suitable dispenser.

[0023] The oral paste prepared by the present invention is bioequivalent to the original product after oral administration. At the same time, we found that the oral paste prepared by controlling the particle size of the raw materials and adopting the prescription is convenient for clinical equine administration, has good palatability, and has stable paste quality. In particular, the physical stability is longer than that of the sample of the prescription process without controlling the particle size and adding colloidal silica, which is more commercially significant (see the examples for details).

[0024] The following examples are provided to more fully illustrate the present invention in detail, but are not intended to limit the present invention, which is defined entirely by the appended claims. Embodiment 1:

[0025] The prescription composition is as follows:

[0026] Raw and auxiliary materials Dosage ratio (%) Proton pump inhibitor (micronized) 37 Propylene glycol dicaprylate / dicaprate 59.2 Monoethanolamine 0.25 Colloidal silicon dioxide 0.5 Potassium sorbate 0.2 Sodium stearate 0.2 Calcium stearate 0.2 Cinnamon oil 0.5 Sesame oil 0.25 Yellow ferric oxide 0.2 Hydrogenated castor oil 1.5 Manufactured into 1000 pieces 100

[0027] Preparation method: (1) Processing of raw materials and auxiliary materials: After micronization, the proton pump inhibitor raw materials that meet the D90 of less than 10 microns are sieved and ground together with colloidal silicon dioxide for 30 minutes. Potassium sorbate, yellow iron oxide, sodium stearate, calcium stearate, and hydrogenated castor oil are sieved and set aside. (2) Preparation: Weigh the prescribed amount of propylene glycol dicaprylate / dicaprate, monoethanolamine, cinnamon oil, and sesame oil in a preparation container and stir for about 5-10 minutes; weigh the prescribed amount of potassium sorbate, sodium stearate, calcium stearate, and yellow iron oxide in a preparation container and stir for about 5-10 minutes; weigh the prescribed amount of proton pump inhibitor raw materials and grind the mixture with colloidal silicon dioxide, slowly add it to the preparation container until it is added, and stir for about 15-20 minutes; weigh the prescribed amount of hydrogenated castor oil in the preparation container and stir and homogenize it for about 25-35 minutes. (3) Filling: Manual filling in a pre-filled dispenser.

[0028] Comparative Example 2:

[0029] The prescription composition is as follows:

[0030]

[0031]

[0032] Preparation method: (1) Pretreatment of raw and auxiliary materials: Sieving the proton pump inhibitor raw drug, potassium sorbate, yellow ferric oxide, sodium stearate, calcium stearate, and hydrogenated castor oil, and setting aside. (2) Formulation: Weigh the prescribed amounts of propylene glycol dicaprylate / dicaprate, monoethanolamine, cinnamon oil, and sesame oil into a formulation container and stir for about 5 - 10 min; weigh the prescribed amounts of potassium sorbate, sodium stearate, calcium stearate, and yellow ferric oxide into the formulation container and stir for about 5 - 10 min; weigh the prescribed amount of proton pump inhibitor raw material and slowly add it to the formulation container until it is completely added, and stir for about 15 - 20 min; weigh the prescribed amount of hydrogenated castor oil into the formulation container and mix it by stirring and homogenization for about 25 - 35 min. (3) Filling: Manually fill it into a pre-filled syringe.

[0033] Comparative Example 3:

[0034] The prescription composition is as follows:

[0035] Raw and auxiliary materials Dosage ratio (%) Proton pump inhibitor (micronized) 37 Propylene glycol dicaprylate / dicaprate 59.7 Monoethanolamine 0.25 Potassium sorbate 0.2 Sodium stearate 0.2 Calcium stearate 0.2 Cinnamon oil 0.5 Sesame oil 0.25 Yellow ferric oxide 0.2 Hydrogenated castor oil 1.5 Manufactured into 1000 pieces 100

[0036] The preparation method is the same as that of Example 1.

[0037] Comparative Example 4:

[0038] The prescription composition is as follows:

[0039]

[0040]

[0041] Preparation method: (1) Pretreatment of raw and auxiliary materials: Sieving the proton pump inhibitor, silica, potassium sorbate, yellow ferric oxide, sodium stearate, calcium stearate, and hydrogenated castor oil, and setting aside. (2) Formulation: Weigh the prescribed amounts of propylene glycol dicaprylate / dicaprate, monoethanolamine, cinnamon oil, and sesame oil into a formulation container and stir for about 5 - 10 min; weigh the prescribed amounts of potassium sorbate, sodium stearate, calcium stearate, colloidal silica, and yellow ferric oxide into the formulation container and stir for about 5 - 10 min; weigh the prescribed amount of proton pump inhibitor raw material and slowly add it to the formulation container until it is completely added, and stir for about 15 - 20 min; weigh the prescribed amount of hydrogenated castor oil into the formulation container and mix it by stirring and homogenization for about 25 - 35 min. (3) Filling: Manually fill it into a pre-filled syringe.

[0042] We conducted a stability study on the samples prepared in Example 1, Comparative Example 2, Comparative Example 3, and Comparative Example 4, and the results are as follows:

[0043] The samples of Example 1 were placed in accelerated tests (30°C ± 2°C, RH 65% ± 5%) and long-term tests ((25°C ± 2°C, RH 60% ± 10%)), and the key detection indexes were compared with those at month 0. The results are as follows. The results show that the paste of Prescription 1 is very stable under the accelerated and long-term storage conditions, and there is no difference in each detection index compared with day 0, which is significantly better than other examples:

[0044]

[0045]

Claims

1. A preparation method of a pharmaceutical composition of a physically more stable veterinary oral paste, the composition comprising an active ingredient proton pump inhibitor, a matrix carrier, a viscosity regulator and a hydrophobic liquid carrier, and the active ingredient being a proton pump inhibitor.

2. The pharmaceutical composition according to claim 1, characterized in that The following preparation method: 1) The particle size limit of the proton pump inhibitor raw material in the composition is that D90 does not exceed 20 microns, and the viscosity regulator particularly contains colloidal silica; 2) Pass the micronized proton pump inhibitor through an 80-mesh sieve, and pass potassium sorbate, yellow iron oxide, sodium stearate, calcium stearate, colloidal silica, and hydrogenated castor oil through a 60-mesh sieve for later use; 3) Weigh the prescribed amount of micronized proton pump inhibitor and colloidal silica, place them in a mixer and premix evenly, and then grind them in a ball mill for 60 minutes; 4) Weigh the prescribed amount of propylene glycol dicaprylate / dicaprate, monoethanolamine, cinnamon oil, and sesame oil in a dispenser and stir for about 5 minutes; weigh the prescribed amount of potassium sorbate, sodium stearate, calcium stearate, and yellow iron oxide in a dispenser and stir for about 5 minutes; weigh the prescribed amount of the ground mixture of the raw material proton pump inhibitor and colloidal silica, and slowly add it to the dispenser until it is completely added, and stir for about 20 minutes; weigh the prescribed amount of hydrogenated castor oil in the dispenser and mix it by stirring and homogenizing for 25 - 35 minutes. 5) Fill it into a pre-filled syringe.

3. The pharmaceutical composition according to claim 1, wherein the active ingredient proton pump inhibitor refers to a class of compounds of general formula (I), 4. The pharmaceutical composition according to claim 1, wherein the active ingredient proton pump inhibitor refers to an H+-K+-ATPase inhibitor, especially the active ingredients of common drugs such as omeprazole, lansoprazole, pantoprazole, rabeprazole, esomeprazole, ilaprazole, etc. and their salts, and preferably omeprazole and its salts.

5. The pharmaceutical composition according to claim 1, the active ingredient of formula I can be used in its natural form or as a salt. When it is desired to form a stable non-toxic acid or base salt, it may be appropriate to administer the compound as a pharmaceutically acceptable salt. Pharmaceutically acceptable salts of the active ingredient of formula 1 include acetate, ascorbate, aspartate, benzoate, benzenesulfonate, bicarbonate / carbonate, bisulfate / sulfate, borate, camphorsulfonate, citrate, edisylate, etoglutarate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, glycerophosphate, hexafluorophosphate, hibenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, hydroxyethylsulfonate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-naphthalenesulfonate, hydrochloride, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / monophosphate / diphosphate, saccharate, stearate, succinate, tartrate, toluenesulfonate and trifluoroacetate.

6. The pharmaceutical composition according to claim 1, wherein the matrix carrier is one or a combination of propylene glycol dicaprylate / dicaprate, monoethanolamine, potassium sorbate, cinnamon oil, sesame oil, pigment, hydrogenated castor oil.

7. The pharmaceutical composition according to claim 1, wherein the matrix carrier can also be extended to triacetin, medium and short chain monoglycerides, diglycerides or triglycerides, glycerol, water, propylene glycol, N-methylpyrrolidone, glycerol formaldehyde, polyethylene glycol, polyethylene glycol-polypropylene glycol-polyethylene glycol triblock copolymer, trans alcohol, benzyl alcohol, N,N-dimethylformamide and dimethyl sulfoxide.

8. The pharmaceutical composition according to claim 1, wherein the thickening agent is selected from sodium stearate, calcium stearate, cellulose, starch, monothioglycerol, hydroxypropyl cellulose, xanthan gum or hydroxyethyl starch, polymers or copolymers of polyvinylpyrrolidone, polymers and copolymers of (meth)acrylates, and natural gums.

9. The pharmaceutical composition according to claim 1, wherein the viscosity regulator is a combination of one or more of various thickening compounds, selected from vegetable oil or hydrogenated vegetable oil, monoethanolamine, colloidal silica, potassium sorbate, with a content between 0.1 - 5%, preferably 0.2 - 2%.

10. The pharmaceutical composition according to claim 1, wherein the viscosity regulator can also be extended to hydroxypropyl methylcellulose (various viscosities), hydroxypropyl cellulose (various viscosities), xanthan gum or hydroxyethyl starch (different molecular weights), etc., with a dosage of about 0.1 - 10%, preferably 0.5 - 5%.

11. The pharmaceutical composition according to claim 1, wherein the hydrophobic liquid carrier can be any pharmaceutically acceptable oil that is insoluble or almost insoluble in water; examples include mineral oil, almond oil, cottonseed oil, ethyl oleate, isopropyl myristate, isopropyl palmitate, myristyl alcohol, stearyl alcohol, olive oil, peanut oil, safflower oil, sesame oil, soybean oil and squalene. The preferred hydrophobic oily liquid is one or several triglycerides of C6-C 18 carboxylic acids or a mixture thereof in different proportions.

12. For the pharmaceutical composition according to claims 1 - 10, the process adopted is to uniformly mix the proton pump inhibitor meeting the particle size requirements with colloidal silica and then grind them in a ball mill for 5 - 120 minutes, preferably 50 - 70 minutes.

13. For the pharmaceutical composition according to claims 1 - 10, the process can also be other grinding and mixing equipment similar to a ball mill. The core is to reduce the particle size of each insoluble component, especially the proton pump inhibitor and colloidal silica, and wrap the large particles within a large number of colloidal silica microparticles to form a relatively stable thermodynamic system or mixture.

14. For the pharmaceutical composition according to claims 1 - 10, its preparation method is to adopt a conventional paste preparation process or an approximate process: first mix the liquid excipients uniformly, then add the solid excipients to the mixture, then add the ground mixture of the proton pump inhibitor raw material and colloidal silica, mix uniformly (including homogenization), and finally fill the mixture into a suitable dispenser.

15. The pharmaceutical composition prepared as described in claims 1-10, in addition to being chemically stable and conducive to long-term storage, especially has better physical stability in terms of storage period than conventional veterinary preparations.

Images