Preparation method of rivastigmine new-form salt compound and rivastigmine new-form salt compound preparation

Abstract

The invention provides a rivastigmine new-form salt compound and a preparation method of a rivastigmine new-form salt compound preparation. The rivastigmine new-form salt compound is prepared from the following rivastigmine salt and auxiliary materials in percentage by mass: 1.5%-3% of rivastigmine salt, 5%-10% of polysorbate 20, 1%-8% of polyethylene glycol-4000, 0.15%-1.5% of citric acid, 0.5%-1.0% of anhydrous disodium hydrogen phosphate, 0.1%-0.5% of sodium hydroxide and 80%-90% of water for injection. The invention also discloses a method for preparing a preparation by using the compound. The preparation process of the preparation disclosed by the invention is simple, is suitable for large-scale production of enterprises, and has great market development prospects. The preparation disclosed by the invention adopts a new administration mode, and the characteristics of the preparation are utilized, so that the medicine is slowly dissolved out subcutaneously; therefore, the purpose of reducing side effects of intestinal tracts is achieved. The preparation disclosed by the invention is stable in blood concentration and good in tolerance.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and more specifically to a method for preparing a novel salt form of rivastigmine and its formulation. Background Technology

[0002] Alzheimer's disease is a neurological disorder that occurs in old age and pre-old age, characterized by progressive cognitive impairment and behavioral disturbances. Its main manifestations include memory impairment, aphasia, apraxia, agnosia, visuospatial impairment, impairment of abstract thinking and calculation abilities, and personality and behavioral changes. While symptoms can be improved with medication, there is currently no cure. The disease has a long course, leading to a decline in the patient's quality of life and placing a heavy burden on families and society. It is estimated that there are approximately 15 million Alzheimer's patients worldwide. The cause of the disease is not fully understood, and there is currently no cure. Treatment primarily involves medication to manage symptoms and maintain cognitive function for a longer period, delaying the loss of daily living abilities.

[0003] Rosavirin improves cognitive function in Alzheimer's disease patients by inhibiting acetylcholinesterase, thereby increasing the function of cholinergic neurons in the brain. It has highly selective action in the hippocampus and cortex. Furthermore, it slows the formation of amyloid precursor protein (APP) fragments, a major pathological feature of Alzheimer's disease. Its potency is moderate, weaker than physostigmine. It has greater specificity for acetylcholinesterase in the brain compared to cardiac and skeletal muscle. Currently, the main marketed form is an oral capsule, administered as a tartrate bitrate. The initial oral dose is 1.5 mg twice daily. If the patient tolerates this dose well after 4 weeks, the dose can be increased to 3 mg twice daily, taken with breakfast and dinner. The maximum dose is 12 mg / day. However, the biggest problems with oral administration of this drug are nausea, vomiting, diarrhea, abdominal pain, loss of appetite, indigestion, and weight loss. Transdermal patches, on the other hand, have issues with varying drug absorption rates.

[0004] Rosavirin transdermal patches, following capsules and solutions, are a new dosage form and the world's first transdermal patch for the treatment of Alzheimer's disease. Launched by Novartis in July 2007 under the brand name Exelon® Patch, once daily use of Exelon® Patch can improve memory and maintain daily activities in Alzheimer's patients. The low-dose patch group showed comparable therapeutic effects to the oral administration group, but the incidence of nausea and vomiting in the oral administration group was three times higher than in the patch group. The high-dose patch group had slightly higher cognitive scores than the oral administration group, with similar rates of adverse reactions. In particular, the numerous gastrointestinal reactions associated with oral formulations, such as nausea in approximately 47% of patients in clinical studies, and significant weight loss in 26% of women and 18% of men, significantly impacted patient tolerability and acceptability of the medication. Other common side effects included vomiting, loss of appetite, indigestion, and weakness, greatly affecting patient tolerance and the overall quality of treatment. Summary of the Invention

[0005] To address the issue of significant gastrointestinal side effects in the aforementioned oral formulations, the present invention aims to disclose a novel salt form of rivastigmine and a method for preparing the formulation. This formulation is convenient to use, exhibits minimal individual differences in drug absorption, and has few side effects.

[0006] To achieve the above objectives, the present invention adopts the following technical solution: On one hand, the present invention discloses a novel salt form of rivastigmine, which is prepared from rivastigmine salt and excipients in the following mass ratios: 1.5%-3% rivastigmine salt, 5%-10% polysorbate 20, 1%-8% polyethylene glycol-4000, 0.15-1.5% citric acid, 0.5%-1.0% anhydrous disodium hydrogen phosphate, 0.1-0.5% sodium hydroxide, and 80-90% water for injection.

[0007] Preferably, the carbamate salt is one of palmitate, dipalmitate, hexanoate, adipic acid salt, heptanate, pimecrolate, octanoate, and octanoate.

[0008] The preferred method for preparing rivastigmine salt is as follows: 1) Take an appropriate amount of organic acid, add it to a solvent, and heat and stir to dissolve it; 2) Then add the yellow liquid rivastigmine and stir; 3) Slowly add ethyl acetate while stirring, until white crystals precipitate out; 4) Let stand for 1-3 hours, filter, dry the solid at 40-60℃, and crush it for the first time using a hammer mill to obtain carbaryl salt; 5) The chapatidin salt was pulverized a second time using an ultra-fine pulverizer, and the particle size was controlled to be D90≤10μm.

[0009] On the other hand, the present invention also discloses a method for preparing formulations using the above-mentioned compounds, the method comprising the following steps: S1. Under sterile conditions, rivastigmine salt is first air-jet milled to control the particle size D10: 0.1-1.0μm, D50: 0.5-2.5μm, D90: 1.0-8.5μm; S2. Under sterile conditions, take an appropriate amount of water, add surfactants polysorbate 20, polyethylene glycol-4000, citric acid, anhydrous disodium hydrogen phosphate, and sodium hydroxide, stir to dissolve, then filter using a filter membrane, and add the sample from step S1 under sterile conditions, and stir to mix evenly. S3. Under sterile conditions, use a grinder, fill it with 30-80% sterile zirconium beads of 0.2-0.8 mm, add the sample from step S2 into the grinder, turn on the peristaltic pump and grinder, and circulate and grind to control the sample particle size at the nanometer level. Finally, control the rivastigmine salt particle size to: D10: 0.01-0.1 μm, D50: 0.15-0.25 μm, D90: 1.2-5.5 μm; S4. Under aseptic conditions, the nanocrystal suspension obtained in step S3 is encapsulated in an injection bottle.

[0010] Preferably, in step S1, the airflow temperature is controlled at 121°C, the feed pressure is set at 0.5-0.8 MPa, and the pulverizing pressure is set at 0.5-0.8 MPa for airflow pulverization.

[0011] Preferably, the formulation is a long-acting injectable for the treatment of Alzheimer's disease, administered via subcutaneous or intramuscular injection.

[0012] Compared with the prior art, the beneficial effects of the present invention are: The preparation process of the formulation disclosed in this invention is simple, suitable for large-scale production by enterprises, and has great market development potential.

[0013] The formulation disclosed in this invention employs a novel administration method, utilizing the characteristics of the formulation itself to allow the drug to slowly dissolve under the skin; it can enter the bloodstream uniformly and slowly, thereby reducing intestinal side effects.

[0014] The formulation disclosed in this invention has stable blood drug concentrations and is well tolerated. Detailed Implementation

[0015] The technical solution will now be clearly and completely described in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments.

[0016] This invention discloses a novel salt form of rivastigmine, which is prepared from rivastigmine salt and excipients in the following mass ratios: 1.5%-3% rivastigmine salt, 5%-10% polysorbate 20, 1%-8% polyethylene glycol-4000, 0.15-1.5% citric acid, 0.5%-1.0% anhydrous disodium hydrogen phosphate, 0.1-0.5% sodium hydroxide, and 80-90% water for injection.

[0017] The carbamate salt is one of palmitate (Formula 1), dipalmitate (Formula 2), hexanoate (Formula 3), adipicate (Formula 4), heptanate (Formula 5), ​​pimecronate (Formula 6), octanoate (Formula 7), and octanoate (Formula 8).

[0018] Formula 1: Formula 2: ; Formula 3: Formula 4: ; Formula 5: Formula 6: ; Formula 7: Formula 8: .

[0019] The preparation method of rivastigmine salt is as follows: 1) Take an appropriate amount of organic acid, add it to a solvent, and heat and stir to dissolve it; 2) Then add the yellow liquid rivastigmine and stir; 3) Slowly add ethyl acetate while stirring, until white crystals precipitate out; 4) Let stand for 1-3 hours, filter, dry the solid at 40-60℃, and crush it for the first time using a hammer mill to obtain carbaryl salt; 5) The chapatidin salt was pulverized a second time using an ultra-fine pulverizer, and the particle size was controlled to be D90≤10μm.

[0020] The following detailed examples illustrate the method for preparing formulations using the novel salt form of rivastigmine.

[0021] Example 1 The formulation of the preparation disclosed in this embodiment is as follows: Preparation method of the formulation: S1. Under sterile conditions, first perform air jet milling on rivastigmine salt, control the dry air temperature at 121℃, set the feed pressure at 0.5-0.8 MPa, and the milling pressure at 0.5-0.8 MPa to perform air jet milling, and control the particle size D10: 0.1-1.0 μm, D50: 0.5-2.5 μm, D90: 1.0-8.5 μm; S2. Under sterile conditions, take an appropriate amount of water for injection, add surfactants polysorbate 20, polyethylene glycol-4000, citric acid, anhydrous disodium hydrogen phosphate, and sodium hydroxide, stir to dissolve, then filter using a 0.22-micron filter membrane, and then add the sample from step S1 (after calculating the amount according to the formulation prescription) under sterile conditions, and stir to mix evenly. S3. Under sterile conditions, use a grinder to fill with 45% 0.3mm sterile zirconium beads. Add the sample from step S2 to the grinder, turn on the peristaltic pump, adjust the grinder speed, and start circulating and grinding the sample to control the sample particle size at the nanometer level. Finally, control the rivastigmine salt particle size within a suitable range: D10: 0.01-0.1μm, D50: 0.15-0.25μm, D90: 1.2-5.5μm, thus obtaining a sterile nanocrystal suspension. S4. Under aseptic conditions, the nanocrystal suspension obtained in step S3 is encapsulated in an injection bottle to obtain dipalmitoate rivastigmine long-acting injection.

[0022] Example 2 The formulation of the preparation disclosed in this embodiment is as follows: The preparation method of the formulation in this embodiment is the same as that in Example 1, except that the raw materials for preparing rivastigmine are different, which will not be described in detail here. Long-acting dipalmitate rivastigmine salt injection is obtained.

[0023] Example 3 The formulation of the preparation disclosed in this embodiment is as follows: The preparation method of the formulation in this embodiment is the same as that in Example 1, except that the raw materials for preparing rivastigmine are different, which will not be described in detail here. Long-acting rivastigmine succinate salt injection is obtained.

[0024] Experimental Example 1 In vivo pharmacokinetic experiments were conducted on the long-acting dipalmitate rivastigmine salt injection (subcutaneous injection) prepared in Example 1 and commercially available ordinary capsules (rivastigmine bitartrate capsules, 3 mg, manufacturer: Novartis Farmaceutica SA, oral administration).

[0025] Eighteen beagle dogs (weighing between 7 kg and 10 kg) were randomly divided into two groups of nine each. One group received a whole tablet of the long-acting dipalmitoate rivastigmine salt injection prepared in Example 1 (subcutaneous injection), while the other group received 3 mg of a commercially available ordinary capsule (rivastigmine bitartrate capsule, 3 mg, manufacturer: Novartis Farmaceutica SA, oral administration). Sampling was performed at 15 min, 30 min, 45 min, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 10 h, 12 h, 18 h, 24 h, 2 d, 3 d, 4 d, 5 d, 6 d, and 7 d (sampling of the commercially available tablet group was stopped at 24 h). 0.50 mL of methanol was added to the radial vein of the hind leg, vortexed for 1 min, centrifuged, and 20 μL of the supernatant was collected for content determination. The pharmacokinetic parameters of each formulation in vivo are shown in Table 1.

[0026] Table 1: The results in the table above show that, compared with commercially available ordinary tablets, Example 1 has significant differences in Tmax and AUC, and Example 1 can basically be administered once every 7-10 days.

[0027] Therefore, the long-acting rivastigmine salt injection prepared according to Example 1 has a further extended time to peak concentration compared with commercially available formulations, achieving an effect of 7-10 doses per day. At the same time, its AUC SD value is smaller than that of commercially available formulations, showing a significant difference, indicating that there are fewer changes in vivo and fewer side effects. It can be considered that the present invention has the effect of reducing side effects.

[0028] The above descriptions are merely some embodiments of the present invention. It should be noted that those skilled in the art can make other modifications and improvements without departing from the inventive concept of the present invention, and these all fall within the protection scope of the present invention.

Claims

1. A new form of salt of rivastigmine characterized in that, The compound is prepared from the following mass ratio of rivastigmine salt and adjuvant: 1.5%-3% of rivastigmine salt, 5%-10% of polysorbate 20, 1%-8% of polyethylene glycol-4000, 0.15-1.5% of citric acid, 0.5%-1.0% of anhydrous disodium hydrogen phosphate, 0.1-0.5% of sodium hydroxide, and 80-90% of water for injection.

2. The compound of claim 1, wherein The rivastigmine salt is one of palmitate, dipalmitate, hexanoate, adipate, heptanoate, pimelate, octanoate, and suberate.

3. The compound of claim 2, wherein The preparation method of the rivastigmine salt is as follows: 1) Take a proper amount of organic acid, add a solvent, and heat and stir to dissolve; 2) Then add the yellow liquid rivastigmine, and stir; 3) Slowly add ethyl acetate while stirring, and then until white crystals are precipitated; 4) Stand for 1-3 hours, filter, dry the solid at 40-60℃, and use a hammer stone crusher for the first time to crush, to obtain the rivastigmine salt; 5) Use a super micro pulverizer for the second time to crush the rivastigmine salt, and control the particle size to be D90≤10 μm.

4. Process for the preparation of a formulation using a compound according to any one of claims 1 to 3, characterized in that, The method comprises the following steps: S1, in a sterile environment, first perform airflow pulverization on the rivastigmine salt, and control the particle size to be D10: 0.1-1.0 μm, D50: 0.5-2.5 μm, and D90: 1.0-8.5 μm; S2, in a sterile environment, take a proper amount of water, add the surfactants polysorbate 20, polyethylene glycol-4000, citric acid, anhydrous disodium hydrogen phosphate, and sodium hydroxide, stir and dissolve, filter using a filter membrane, use sterile operation, add the sample of step S1, and stir and mix uniformly; S3, in a sterile environment, use a grinder, fill 30-80% of 0.2-0.8 mm sterile zirconium beads, add the sample of step S2 to the grinder, start the peristaltic pump and the grinder, and perform cyclic grinding to control the particle size of the sample to be in the nanometer level, and finally control the particle size of the rivastigmine salt to be D10: 0.01-0.1 μm, D50: 0.15-0.25 μm, and D90: 1.2-5.5 μm; S4, under sterile conditions, package the nanocrystal suspension obtained in step S3 in an injection bottle.

5. The method of claim 4, wherein, In step S1, control the airflow temperature to be 121℃, set the feeding pressure to be 0.5-0.8 Mpa, and perform airflow pulverization at a pulverization pressure of 0.5-0.8 Mpa.

6. The method of claim 5, wherein, The preparation is a long-acting injection for the treatment of Alzheimer's disease, and is administered by subcutaneous or intramuscular injection.

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