Olanzapine orally disintegrating tablet and preparation method thereof

Abstract

The invention provides an olanzapine freeze-drying oral disintegrating tablet based on emulsion and a preparation method thereof, the oral disintegrating tablet is composed of olanzapine, an oil phase, an emulsifier, a co-emulsifier, a freeze-drying adhesive, a freeze-drying skeleton agent and a flavoring agent, an oil-in-water emulsion system is adopted to disperse olanzapine raw material medicine, and then a freeze-drying method is adopted to prepare the oral disintegrating tablet. After oral administration, the orally disintegrating tablet is mixed with gastrointestinal fluid to spontaneously form a microemulsion, the specific surface area is increased, the contact area of the medicine and gastrointestinal walls is increased, on one hand, absorption is promoted, bioavailability is improved, on the other hand, the orally disintegrating tablet can be rapidly disintegrated and dispersed in the oral cavity, part of the orally disintegrating tablet can be absorbed through sublingual, and the orally disintegrating tablet is convenient to carry and improves patient compliance. The phenomenon that a patient spits out of Tibetan medicine is avoided, taking is convenient, and oral compliance is good.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical preparations and relates to an olanzapine orally disintegrating tablet and a preparation method thereof. Background Art

[0002] Olanzapine is an atypical antipsychotic drug used to treat schizophrenia. For patients who respond to initial olanzapine treatment, consolidation treatment can effectively maintain clinical symptom improvement. For patients with manic episodes who respond to olanzapine treatment, olanzapine can prevent the recurrence of bipolar disorder.

[0003] Olanzapine preparations were developed by Eli Lilly. Olanzapine tablets were approved for marketing by the U.S. Food and Drug Administration (FDA) on September 30, 1996. Olanzapine orodisintegrating tablets (lyophilized) were produced by Catalent UK Swindon Zydis Ltd. on April 6, 2000 under the trade name " ZydisTM" has been approved by the FDA for marketing. Its inactive ingredients include gelatin, mannitol, aspartame, sodium methylparaben and sodium propylparaben.

[0004] Olanzapine belongs to BCS class II, which is a low-solubility, high-permeability drug with low solubility in water. Ordinary tablets have poor dissolution and low bioavailability. Emulsion systems can increase the solubility of poorly soluble drugs in water, promote drug absorption, and improve bioavailability. For poorly soluble drugs such as olanzapine, it is very necessary to develop drugs with high bioavailability, easy absorption and good compliance. Currently, the freeze-dried olanzapine orodisintegrating tablets on the market contain preservatives, including sodium methylparaben (sodium methylparaben) and sodium propylparaben (sodium propylparaben). Preservatives are potentially irritating and potentially dangerous to newborns with excessive blood bilirubin. They can cause allergic reactions in a small number of people with poor immunity. In view of the harmfulness of preservatives, it is also very necessary to develop olanzapine orodisintegrating tablets that do not contain preservatives. Summary of the invention:

[0005] The invention provides an emulsion-based olanzapine freeze-dried orally disintegrating tablet and a preparation method thereof. The olanzapine raw material is dispersed in an oil-in-water emulsion system, and then the orally disintegrating tablet is prepared by freeze drying. After oral administration, the orally disintegrating tablet is mixed with gastrointestinal fluid to spontaneously form a microemulsion, and the specific surface area is increased, and the contact area between the drug and the gastrointestinal wall is increased. On the one hand, absorption is promoted and bioavailability is improved; on the other hand, the orally disintegrating tablet can be rapidly disintegrated and dispersed in the oral cavity, and a part of the orally disintegrating tablet can be absorbed sublingually, so that the orally disintegrating tablet is easy to carry and improves the compliance of patients, avoids the phenomenon of patients hiding and vomiting the drugs, and is convenient to take.

[0006] An object of the present invention is to provide an olanzapine freeze-dried orally disintegrating tablet, which comprises the following raw material and auxiliary material components by weight: 100 parts of olanzapine, 20-50 parts of oil phase, 1-10 parts of emulsifier, co-emulsifier, 60-90 parts of freeze-dried binder, 50-80 parts of freeze-dried skeleton agent, and 2-20 parts of flavoring agent.

[0007] Preferably, the oil phase described in the present invention comprises most non-polar solvents, including but not limited to one or more of natural vegetable oils such as sesame oil, soybean oil, peanut oil, olive oil, aromatic volatile oils, polyoxyethylene castor oil, cod liver oil, liquid paraffin, stearic acid, isopropyl myristate, isopropyl palmitate, medium chain (C8-C10) triglycerides, etc.

[0008] Preferably, the emulsifier described in the present invention includes gum arabic, tragacanth gum, apricot gum, egg yolk, and most surfactants such as higher fatty acid salts such as oleic acid and palmitic acid, sulfates or sulfonates such as sodium dodecyl sulfate, sodium dodecylbenzene sulfonate, sodium octadecyl sulfate, lecithin, betaine, glyceryl monostearate, sorbitan fatty acid, polysorbates, polyoxyethylene type, polyoxyethylene-polyoxypropylene copolymer (poloxamer), etc. One or more thereof.

[0009] Preferably, the auxiliary emulsifiers described in the present invention include medium-chain and short-chain alcohols and amines, glycerides, sorbitan esters and polyethylene glycols.

[0010] Preferably, the freeze-dried adhesive of the present invention includes one or more of gelatin, xanthan gum, pectin, sodium alginate, methyl cellulose, sodium carboxymethyl cellulose, agar, hydroxypropyl cellulose and the like.

[0011] Preferably, the freeze-dried matrix agent of the present invention includes one or more of mannitol, sorbitol, erythritol, xylitol, glucose, lactose, glycine and the like.

[0012] Preferably, the flavor corrector of the present invention includes one or more of sucralose, sucrose, fructose, stevioside, aspartame and the like.

[0013] Preferably, it comprises the following raw material and auxiliary material components by weight: 100 parts of olanzapine, 20-50 parts of oil phase, 1-10 parts of emulsifier, 1-10 parts of emulsifier, 80 parts of freeze-dried binder, 60 parts of freeze-dried skeleton agent, and 10 parts of flavoring agent.

[0014] Preferably, the ratio of the oil phase to the water phase in the emulsion system is 1:3 to 1:10.

[0015] Another object of the present invention is to provide a method for preparing the olanzapine orally disintegrating tablets, the preparation steps of which are as follows:

[0016] (1) dissolving olanzapine in the oil phase and adding an emulsifier to obtain an oil phase solution. Adding the mannitol and sucralose to water to dissolve to obtain an aqueous phase solution, adding the oil phase solution to the aqueous phase solution, and emulsifying with a high-speed homogenizer to obtain an emulsion;

[0017] (2) Dissolve the gelatin in hot water and cool to room temperature to obtain a gelatin solution. Add the emulsion obtained in step (1) to the gelatin solution, adjust the volume, stir and mix evenly, defoam, fill, and transfer to a freeze dryer after quick freezing and freeze drying, and pack out of the box to obtain the olanzapine orally disintegrating tablets.

[0018] Preferably, in step (1), the control parameters of the homogenization and emulsification are a homogenization speed of 8-14 kr / min and a homogenization time of 3-5 min.

[0019] Preferably, in step (2), the temperature of the hot water for dissolving the gelatin is 50-70°C.

[0020] Preferably, in step (2), the constant volume ratio is 1:1-1:1.06.

[0021] Preferably, in step (2), the defoaming step uses a vacuum pump for defoaming.

[0022] Preferably, in step (2), the quick freezing is performed by using a tunnel quick freezing technology, the quick freezing tunnel is about 4 m long, the speed is 0.06-0.07 m / s, and it is divided into a quick freezing tunnel and a temporary storage tunnel. The quick freezing tunnel is set at a temperature below -30°C, and the temporary storage tunnel is set at a temperature below -10°C.

[0023] Preferably, in step (2), freeze drying is performed using a vacuum freeze dryer, and the parameters are set as follows: in the pre-freezing stage, the plate temperature is lowered to -30°C for 10-30 minutes; the condenser temperature is lowered to below -45°C, the vacuum pump and the diaphragm valve are turned on, the front box is evacuated, and the sublimation operation is started; the temperature is set to 15-35°C, and the temperature is maintained for 0.5-1.5 hours after reaching the set value, and the freeze drying is completed and the product is packaged.

[0024] Preferably, in step (2), after freeze-drying, a packaging machine is used for heat-sealing packaging, and the packaging material is a cold-stamped solid medicinal composite hard sheet of polyvinyl chloride / polyamide / aluminum / polyamide / polyvinyl chloride as the bottom aluminum and a paper / polyester / aluminum medicinal covering film as the cover film, to make a peel-back package.

[0025] Therefore, the present invention has the following beneficial effects:

[0026] The raw material of olanzapine is a BCS II compound, i.e., low solubility and high permeability. The emulsion system preparation method of the present invention improves the solubility of olanzapine in water and improves the bioavailability. The olanzapine orally disintegrating tablet prepared by the present invention can be rapidly dissolved and has higher patient compliance.

[0027] The orodisintegrating tablet prepared by the present invention can be rapidly disintegrated and dispersed within a few seconds after encountering saliva, and the patient can smoothly take the medicine without or with a small amount of water. It is particularly suitable for children, the elderly, patients with difficulty in swallowing and specific water-free conditions, and is convenient for some patients (such as those who are bedridden for a long time or work outdoors and have difficulty in getting water). Description of the drawings:

[0028] Figure 1 Olanzapine orally disintegrating tablets prepared in Examples 1-3

[0029] Figure 2 Comparative diagram of the dissolution of the orally disintegrating tablet prepared in Example 2 and Zyprexa in aqueous medium Specific implementation method:

[0030] In order to better understand the essence of the present invention, the present invention is further described below in conjunction with specific embodiments.

[0031] Example 1

[0032] Prescription composition:

[0033] Olanzapine 10g, polyoxyethylene castor oil 20g, 1,2-propylene glycol 1g, poloxamer 5g, gelatin 8g, mannitol 6g, sucralose 1g, water 300g.

[0034] Preparation process:

[0035] (1) Olanzapine was dissolved in polyoxyethylene castor oil, and 1,2-propylene glycol was added to obtain an oil phase. Mannitol, sucralose, and poloxamer were added to 100 ml of water and stirred to dissolve into an aqueous solution to obtain an aqueous phase. The oil phase was added to the aqueous phase, and emulsified using a high-speed homogenizer at a homogenization speed of 10 kr / min and a homogenization time of 3 min to obtain an emulsion.

[0036] (2) Dissolve gelatin in hot water and cool to room temperature to obtain a gelatin solution, add the liquid medicine obtained in step (1) to the gelatin solution, stir to mix thoroughly, and adjust the volume. Then use a vacuum pump to defoam, fill, and quickly freeze in a tunnel. The temperature of the quick-freezing tunnel is set below -30°C, and the temperature of the temporary storage tunnel is set below -10°C.

[0037] (3) Transfer to freeze dryer for freeze drying: pre-freeze, lower the plate temperature to -30°C for 10 minutes; after the temperature is maintained, evacuate and start sublimation operation, then set the heat transfer oil inlet temperature to 35°C, maintain the temperature for 0.5 hours after reaching the set value, sublimation is completed, and the machine is taken out of the box.

[0038] Example 2

[0039] Prescription composition:

[0040] Olanzapine 100g, cod liver oil 25g, 1,2-propylene glycol 5g, Tween 80 5g, gelatin 80g, mannitol 60g, aspartame 0.5g, water 300g.

[0041] Preparation process:

[0042] (1) Olanzapine was dissolved in cod liver oil, and 1,2-propylene glycol was added to obtain an oil phase. Mannitol, aspartame, and Tween 80 were added to 150 ml of water and stirred to dissolve into an aqueous solution to obtain an aqueous phase. The oil phase was added to the aqueous phase, and emulsified using a high-speed homogenizer at a homogenization speed of 14 kr / min and a homogenization time of 3 min to obtain an emulsion.

[0043] (2) Dissolve gelatin in hot water and cool to room temperature to obtain a gelatin solution, add the liquid medicine obtained in step (1) to the gelatin solution, stir to mix thoroughly, and adjust the volume. Then use a vacuum pump to defoam, fill, and quickly freeze in a tunnel. The temperature of the quick-freezing tunnel is set below -30°C, and the temperature of the temporary storage tunnel is set below -10°C.

[0044] (3) Transfer to freeze dryer for freeze drying: pre-freeze, lower the plate temperature to -30°C for 10 minutes; after the temperature is maintained, evacuate and start sublimation operation, then set the heat transfer oil inlet temperature to 35°C, maintain the temperature for 0.5 hours after reaching the set value, sublimation is completed, and the machine is taken out of the box.

[0045] Example 3

[0046] Prescription composition:

[0047] Olanzapine 100g, ethyl oleate 30g, polyethylene glycol PEG400 10g, Tween 80 1g, gelatin 80g, mannitol 60g, sucralose 1g, water 300g.

[0048] Preparation process:

[0049] (1) Olanzapine was dissolved in ethyl oleate, and polyethylene glycol PEG400 was added to obtain an oil phase. Mannitol, sucralose, and Tween 80 were added to 200 ml of water and stirred to dissolve into an aqueous solution to obtain an aqueous phase. The oil phase was added to the aqueous phase, and emulsified using a high-speed homogenizer at a homogenization speed of 10 kr / min and a homogenization time of 3 min to obtain an emulsion.

[0050] (2) Dissolve gelatin in hot water and cool to room temperature to obtain a gelatin solution, add the emulsion obtained in step (1) to the gelatin solution, stir to mix thoroughly, and adjust the volume. Then use a vacuum pump to defoam, fill, and quickly freeze in a tunnel. The quick-freezing tunnel is set at a temperature below -30°C, and the temporary storage tunnel is set at a temperature below -10°C.

[0051] (3) Transfer to freeze dryer for freeze drying: pre-freeze, lower the plate temperature to -30°C for 10 minutes; after the temperature is maintained, evacuate and start sublimation operation, then set the heat transfer oil inlet temperature to 35°C, maintain the temperature for 0.5 hours after reaching the set value, sublimation is completed, and the machine is taken out of the box.

[0052] The orally disintegrating tablets prepared in Examples 1-3 are as follows Figure 1 As shown, all of them are light yellow round freeze-dried tablets, the tablets are complete and smooth, and they can disintegrate quickly. The orodisintegrating tablets prepared in Example 1 are compared with the orodisintegrating tablets of olanzapine (Zyprexa) produced by Catalent UK Swindon Zydis Limited (the original manufacturer) for dissolution. Figure 2 As shown, it is found that the orally disintegrating tablet prepared in Example 2 dissolves faster, which further illustrates that the orally disintegrating tablet of the present invention can exert its drug effect more quickly.

Claims

1. A freeze-dried olanzapine orally disintegrating tablet, characterized in that: The components include olanzapine, an oil phase, an emulsifier, an emulsifier aid, a freeze-dried adhesive, a freeze-dried skeleton agent, and a flavoring agent.

2. The olanzapine orally disintegrating tablet according to claim 1, characterized in that The composition ratio is preferably 100 parts of olanzapine, 20-50 parts of oil phase, 1-10 parts of emulsifier, co-emulsifier, 60-90 parts of freeze-dried binder, 50-80 parts of freeze-dried skeleton agent, and 2-20 parts of flavoring agent.

3. The olanzapine orally disintegrating tablet according to claim 1, characterized in that The oil phase includes most non-polar solvents, including but not limited to natural vegetable oils such as sesame oil, soybean oil, peanut oil, olive oil, aromatic volatile oils, polyoxyethylene castor oil, cod liver oil, liquid paraffin, stearic acid, isopropyl myristate, isopropyl palmitate, medium chain (C8-C10) triglycerides, etc. One or more thereof.

4. The olanzapine orally disintegrating tablet according to claim 1, characterized in that The emulsifier includes gum arabic, tragacanth gum, apricot gum, egg yolk, and most surfactants such as higher fatty acid salts such as oleic acid and palmitic acid, sulfates or sulfonates such as sodium dodecyl sulfate, sodium dodecylbenzene sulfonate, sodium octadecyl sulfate, lecithin, betaine, glyceryl monostearate, sorbitan fatty acid, polysorbates, polyoxyethylene type, polyoxyethylene-polyoxypropylene copolymer (poloxamer), etc. One or more thereof.

5. The olanzapine orally disintegrating tablet according to claim 1, characterized in that The auxiliary emulsifiers include medium-chain and short-chain alcohols and amines, glycerides, sorbitan esters and polyethylene glycols.

6. The olanzapine orally disintegrating tablet according to claim 1, characterized in that The freeze-dried adhesive includes one or more of gelatin, xanthan gum, pectin, sodium alginate, methyl cellulose, sodium carboxymethyl cellulose, agar, hydroxypropyl cellulose and the like.

7. The olanzapine orally disintegrating tablet according to claim 1, characterized in that The freeze-dried skeleton agent includes one or more of mannitol, sorbitol, erythritol, xylitol, glucose, lactose, glycine and the like.

8. The olanzapine orally disintegrating tablet according to claim 1, characterized in that The flavor corrector includes one or more of sucralose, sucrose, fructose, stevioside, aspartame and the like.

9. The olanzapine orally disintegrating tablet according to claim 1, wherein the ratio of the oil phase to the water phase in the emulsion system is 1:3 to 1:

10.

10. A method for preparing the olanzapine orally disintegrating tablet according to any one of claims 1 to 9, the method comprising the following steps: (1) dissolving olanzapine in the oil phase and adding an emulsifier to obtain an oil phase solution. Adding the mannitol and sucralose to water to dissolve to obtain an aqueous phase solution, adding the oil phase solution to the aqueous phase solution, and emulsifying with a high-speed homogenizer to obtain an emulsion; (2) Dissolve the gelatin in hot water and cool to room temperature to obtain a gelatin solution. Add the emulsion obtained in step (1) to the gelatin solution, adjust the volume, stir and mix evenly, defoam, fill, and transfer to a freeze dryer after quick freezing and freeze drying, and pack out of the box to obtain the olanzapine orally disintegrating tablets.

11. The method according to claim 10, characterized in that The control parameters of the homogenization and emulsification are a homogenization speed of 8-14 kr / min and a homogenization time of 3-5 min.

12. The method according to claim 10, characterized in that The use of a freezing tunnel for quick freezing can achieve continuous quick freezing and improve production efficiency. It is preferred to set the actual temperature of the quick freezing tunnel to no higher than -30°C and the actual temperature of the temporary storage tunnel to no higher than -10°C.

13. The method according to claim 10, characterized in that During the pre-freezing stage, the plate temperature is lowered to -30°C for 10-30 minutes; the condenser temperature is cooled to below -45°C, the vacuum pump and diaphragm valve are turned on, the front box is evacuated, and the sublimation operation is started; the temperature is set to 15-35°C, and the temperature is maintained for 0.5-1.5 hours after reaching the set value, and the freeze-drying is completed and the products are packed out of the box.

14. The method according to claim 10, characterized in that The packaging material is a cold-stamped solid medicinal composite hard sheet of polyvinyl chloride / polyamide / aluminum / polyamide / polyvinyl chloride as the bottom aluminum, and a paper / polyester / aluminum medicinal covering film as the cover film, and is heat-sealed and packaged using a pharmaceutical packaging machine.

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