CN115068617A - Brain-targeted pharmaceutical composition, drug delivery preparation and preparation method thereof - Google Patents
Brain-targeted pharmaceutical composition, drug delivery preparation and preparation method thereof Download PDFInfo
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- CN115068617A CN115068617A CN202210734628.9A CN202210734628A CN115068617A CN 115068617 A CN115068617 A CN 115068617A CN 202210734628 A CN202210734628 A CN 202210734628A CN 115068617 A CN115068617 A CN 115068617A
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- levodopa
- nasal
- preparation
- gel
- formulation
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Abstract
The invention provides a brain-targeted pharmaceutical composition, a drug delivery preparation and a preparation method thereof. The composition is prepared by compounding levodopa and aromatic resuscitation inducing medicine. The developed nasal mucosa administration preparation comprises 5-50% of levodopa and aromatic resuscitation drugs, wherein the mass ratio of the levodopa to the aromatic resuscitation drugs is (1-120): 1. can also be developed into a levodopa suspension preparation, which comprises the following components according to final concentration: 0.02g/mL of levodopa, 1.9-2.86 mg/mL of sodium carboxymethylcellulose, 0.095mg/mL of sodium metabisulfite, 2.86mg/mL of levoborneol, ethanol and water as solvents in a volume ratio of 1: 20 are combined. The drug delivery preparation can improve the solubility, the transdermal rate and the targeting effect, can reduce the irritation of the drug and has good effect on the Parkinson disease.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a brain-targeted pharmaceutical composition, a drug delivery preparation and a preparation method thereof.
Background
Parkinson Disease (PD) is a common neurodegenerative disease of middle-aged and old people, the average disease age is about 60 years old, reports show that the prevalence rate of PD of people over 65 years old in China is about 1.7%, PD can cause the dopaminergic neurons of substantia nigra to be deformed and lost, the striatal dopamine content is obviously reduced, and because dopamine can not penetrate through a blood brain barrier, the precursor levodopa of the dopamine is the most effective medicament for treating the Parkinson disease, enters the center through the blood brain barrier, and is converted into the dopamine through the action of dopa decarboxylase to play a pharmacological action. However, clinical studies have found that about 95% of levodopa absorbed is decarboxylated to dopamine peripherally and only 1% penetrates the blood-brain barrier into the brain. In order to reduce the content of dopamine in peripheral tissues and peripheral adverse reactions and enhance the curative effect, more levodopa needs to enter the brain, so that the dose of the levodopa is reduced and the bioavailability of the levodopa is increased.
The dosage form of levodopa is mostly tablet at present, but the main problems of the tablet are that: dopamine generated by levodopa can stimulate a medullary extending and emetic chemosensory area, so that adverse reactions such as anorexia, nausea, vomiting and the like can occur in the early period of taking medicine, part of patients can also have postural hypotension with unknown reasons, arrhythmia can be caused because dopamine can excite the heart, transient transaminase can also be increased, and meanwhile unstable gastrointestinal tract absorption can cause fluctuation of symptoms of PD patients, namely the on period and the off period alternately occur, and the symptoms comprise types such as curative effect decline, unpredictable off period, frozen gait and the like. Various dosage forms improved on tablets are also presented in succession, for example, CN102755310B discloses a solid oral sustained-release preparation which provides sustained-release levodopa and amantadine, and belongs to the technical field of sustained-release preparations of tablets, capsules and pellets, wherein the drug release is sustained-release or dual-release. As another example, the CN104918607A patent discloses the invention of a powder composition containing inhalable levodopa, Dipalmitoylphosphatidylcholine (DPPC) and a salt for high dose levodopa capsules for pulmonary use. In order to solve the compliance of patients, CN108553416A improves the dosage form into a suspension, and discloses a sustained-release suspension preparation containing levodopa and benserazide hydrochloride and a preparation method thereof. Although the above patent improves the dosage form of levodopa, it is difficult to solve the problems of brain targeting and first pass effect, etc., and it cannot effectively prevent the side effects caused by the conversion of levodopa into dopamine in peripheral tissues.
In addition, the clinical use of subcutaneously injected apomorphine as a means of reducing adverse effects is a remedy for the sudden "off" phase, but is associated with cutaneous nodules, lethargy, dyskinesias and neuropsychiatric symptoms. The half-life period of the levodopa is short, the levodopa is not absorbed by the whole intestinal tract and is only limited to the upper section of the gastrointestinal tract, the retention time is about 3-4 hours, the problem of short retention time at the upper end of the gastrointestinal tract can be expected to be solved by changing a dosage form such as a gastric retention agent, and the levodopa is metabolized into 3-O-methyldopa to reduce the curative effect, cause serious adverse reaction and can not remarkably shorten the 'closing' time of a patient. A novel subcutaneous patch ND0611 capable of continuously releasing carbidopa can improve the pharmacokinetics of levodopa, and although transdermal administration is considered to be an ideal administration route, the transdermal patch can reduce the difference of individual administration, provide a long-term slow release effect, and can reduce the complications of levodopa. However, levodopa itself has strong hydrophilicity and poor stability, and is difficult to penetrate through the stratum corneum of the skin, so that absorption of levodopa is limited, and at present, levodopa is technically difficult and unsatisfactory in effect, and has strong irritation to the skin, so that the progress of transdermal administration of levodopa is not great. In addition, the first levodopa inhalant Inbrija on the market in the United states can bypass the gastrointestinal tract and be quickly absorbed, so that a patient in the off-stage can recover the motor function as soon as possible to treat the symptoms in the off-stage, but dry powder needs to enter the body through the own suction of the patient, depends on the own breathing capacity of the patient, is severely limited and is not suitable for the patient to use, has high requirements on physicochemical parameters such as powder particle size and the like, and if the breathing coordination of the patient is poor, the medicine is easily adhered to the throat, the airway and other parts and cannot completely enter the lung, so that the clinical effect is poor, the dry powder inhalant has the highest difficulty in the development process of the inhalant, and the manufacturing cost of the device is high. The levodopa-carbidopa gel can be directly conveyed to the jejunum through a gastrostomy tube, is regulated and controlled by a portable infusion pump, has better effects of reducing the time of the off period and reducing the dyskinesia, can reduce the motor fluctuation of a Parkinson patient, but has adverse reactions such as easy infusion pump displacement, gastrostomy infection, skin irritation, peripheral neuropathy, pain and the like. In addition, in order to reduce the side effect of levodopa, the levodopa is often prepared into a compound preparation with a peripheral decarboxylase inhibitor, but the serious peripheral side effect is not obviously improved.
How to develop a new brain-targeted drug while avoiding some obstacles on its physiological structure and function is a hot spot of current research, but no progress has been made yet.
Disclosure of Invention
Aiming at the problems in the prior art, the invention provides a brain-targeted pharmaceutical composition, a drug delivery preparation and a preparation method thereof, the composition combines levodopa and aromatic resuscitation drugs, and is further developed into a nasal mucosa drug delivery preparation and a suspension preparation, so that the solubility and the targeting effect of the preparation can be improved, the irritation of the drugs can be reduced, and the brain-targeted pharmaceutical composition has a good effect on Parkinson's disease. The technical scheme of the invention is as follows:
in a first aspect, the invention provides a brain-targeted pharmaceutical composition, which comprises levodopa and an aromatic resuscitation drug.
Further, the aromatic resuscitation inducing medicine is selected from one or more of terpenes menthol, limonene, eucalyptus oil, peppermint oil, wintergreen oil, caraway oil, clove oil, turpentine, borneol, musk, storax, benzoin and grassleaf sweelflag rhizome.
In a second aspect, the invention provides a nasal mucosa drug delivery preparation, which comprises the pharmaceutical composition, wherein the mass percentage of levodopa in the nasal mucosa drug delivery preparation is 5-50%, and the mass ratio of levodopa to aromatic resuscitation inducing traditional Chinese medicines is (1-120): 1.
further, the aromatic resuscitation inducing medicine is selected from one or more of terpenes menthol, limonene, eucalyptus oil, peppermint oil, wintergreen oil, caraway oil, clove oil, turpentine, borneol, musk, storax, benzoin and grassleaf sweelflag rhizome.
Optionally, the aromatic resuscitation inducing medicine comprises the following components in percentage by weight in the nasal mucosa administration preparation: 0.25 percent of raw musk, 0.25 percent of levorotatory borneol, 0.25 percent of storax, 0.25 percent of benzoin gum and 0.25 percent of menthol.
Optionally, the aromatic resuscitation inducing medicine comprises the following components in percentage by weight in the nasal mucosa administration preparation: menthol 0.25%, storax 0.25%, benzoin gum 0.25%, dry calamus 0.25%, L-borneol 1.5%.
Optionally, the aromatic resuscitation inducing drug comprises the following components in percentage by weight in the nasal mucosa administration preparation: 0.25 percent of raw musk, 0.25 percent of menthol, 0.25 percent of storax, 0.25 percent of benzoin gum and 1 percent of levo-borneol.
Preferably, the aromatic resuscitation inducing medicine comprises the following components in percentage by weight in the nasal mucosa administration preparation: 2 percent of raw musk.
Preferably, the aromatic resuscitation inducing medicine comprises the following components in percentage by weight in the nasal mucosa administration preparation: 2 percent of menthol.
Preferably, the aromatic resuscitation inducing medicine comprises the following components in percentage by weight in the nasal mucosa administration preparation: 2 percent of levo-borneol.
Preferably, the aromatic resuscitation inducing medicine comprises the following components in percentage by weight in the nasal mucosa administration preparation: 1% of levo-borneol and 2% of menthol.
Further preferably, the aromatic resuscitation inducing medicine comprises the following components in percentage by weight in the nasal mucosa administration preparation: 3 percent of levo-borneol.
Further preferably, the aromatic resuscitation inducing medicine comprises the following components in percentage by weight in the nasal mucosa administration preparation: 3% of levo-borneol and 3% of menthol.
Further, the nasal mucosa administration preparation also comprises: gel matrix, penetration enhancer, humectant, pH regulator and water.
Further, the gel matrix comprises one of polyacrylic acid, polyvinyl alcohol, carbomer and cellulose matrix, and the mass percentage of the gel matrix in the nasal mucosa administration preparation is 0.4-2%.
Further, the cellulose matrix comprises one or more of methylcellulose, sodium carboxymethylcellulose and hydroxypropyl cellulose.
Preferably, the gel matrix is carbomer.
Further, the penetration enhancer comprises one or more of squalane, propylene glycol, oleic acid, lauric acid, laurocapram and cocoa butter, and the mass percentage of the penetration enhancer in the nasal mucosa administration preparation is 0.5-3%.
Further, the humectant comprises glycerin or propylene glycol, and the mass percentage of the humectant in the nasal mucosa administration preparation is 5-20%.
Further, the pH regulator comprises one or more of triethanolamine, sodium hydroxide and potassium hydroxide, and the pH of the nasal mucosa administration preparation is regulated to be 5-6.
Further, the water is one of distilled water, deionized water, pure water and ultrapure water.
Furthermore, the nasal mucosa drug administration preparation also comprises a bacteriostatic agent and an antioxidant, wherein the bacteriostatic agent comprises one or more of ethylparaben, potassium sorbate, propyl p-hydroxybenzoate and benzyl alcohol, and the mass percentage of the bacteriostatic agent in the nasal mucosa drug administration preparation is 0.05-0.2%; the antioxidant comprises one or more of vitamin C, ethylene diamine tetraacetic acid disodium and sodium bisulfite, and the mass percentage of the antioxidant in the nasal mucosa administration preparation is 0.1-0.3%.
In a third aspect, the present invention provides a method for preparing a nasal mucosal delivery formulation, comprising the steps of:
step 1, adding part of water into a gel matrix, uniformly mixing, and adjusting the pH of a system to 5-6 to obtain a gel solution;
step 2, mixing the aromatic resuscitation inducing medicine, the penetration enhancer and the humectant with the gel solution after ultrasonic treatment;
step 3, further adding levodopa into the mixed gel liquid, adding the rest water, and uniformly mixing to obtain nasal gel;
and 4, directly preparing the nasal gel or further preparing the nasal gel into aerosol, nasal drops, spray or freeze-dried powder, quantitatively filling, sealing, checking the weight, detecting leakage and packaging.
Further, when the nasal mucosa drug delivery preparation further comprises a bacteriostatic agent and an antioxidant, the preparation method further comprises the following steps: and (3) after the levodopa is added in the step (3), further adding a bacteriostatic agent and an antioxidant, adding the rest water, and uniformly mixing to obtain the levodopa-containing antibacterial agent.
In a fourth aspect, the present invention provides a levodopa suspension formulation, the composition of the components according to final concentration being: 0.02g/mL of levodopa, 1.9-2.86 mg/mL of sodium carboxymethylcellulose, 0.095mg/mL of sodium metabisulfite, 2.86mg/mL of levoborneol, ethanol and water as solvents in a volume ratio of 1: 20 are combined.
In a fifth aspect, the present invention provides a method for preparing the levodopa suspension preparation, comprising: dissolving levo-borneol in ethanol, dissolving sodium carboxymethylcellulose in water, mixing the two solutions with levodopa to obtain a solution, and adding sodium pyrosulfite to dissolve.
The invention has the beneficial effects that:
1. the composition formed by the levodopa and the aromatic resuscitation inducing medicine can promote the levodopa to penetrate through a blood brain barrier, improve the brain targeting of the levodopa, and reduce peripheral adverse reactions.
2. The preparation for administration is a specially-made nasal mucosa preparation, the nasal administration can bypass the blood brain barrier to enter the central nerve by passing through the blood brain barrier, and meanwhile, the first pass effect is avoided, the bioavailability is improved, and the targeting effect is further improved.
3. The other type of the drug delivery preparation of the invention is oral suspension solution, wherein the drug can be absorbed in the gastrointestinal tract immediately, the absorption is faster and more efficient than that of tablets or capsules of the same dose of the drug, and the aromatic resuscitation inducing drug can increase the targeting function of the suspension.
Drawings
FIG. 1 is a graph showing the cumulative amount of levodopa that permeates transdermally in vitro in the nasal formulations of examples 1-9 of the present invention.
FIG. 2 is a bar graph showing the drug retention in the skin of the nasal preparations of examples 1 to 9 of the present invention.
FIG. 3 is a bar graph showing the effect of residence time on the rods in the MPTP model mouse rod rotation experiment in example 15 of the present invention.
Detailed Description
In the description of the present invention, it is to be noted that those whose specific conditions are not specified in the examples are carried out according to the conventional conditions or the conditions recommended by the manufacturers. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
The present invention will be described in further detail with reference to the drawings and detailed description, so as to enable those skilled in the art to more fully, accurately and deeply understand the concept and technical solution of the present invention, and the scope of the present invention includes but is not limited to the following examples, and any modifications made to the details and form of the technical solution of the present invention can be made within the scope of the present invention without departing from the spirit and scope of the present application.
The specific embodiment of the invention provides a brain targeting drug composition, which is prepared by compounding levodopa and aromatic resuscitation drugs, wherein the aromatic resuscitation drugs are selected from one or more than two of terpenes, menthol, limonene, eucalyptus oil, peppermint oil, wintergreen oil, caraway oil, clove oil, turpentine, borneol, musk, storax, benzoin and grassleaf sweelflag rhizome. The aromatic resuscitation inducing medicine can promote levodopa to penetrate blood brain barrier, improve levodopa brain targeting and reduce peripheral adverse reactions. The composition is prepared into various nasal mucosa administration preparations, the nasal administration can bypass the blood brain barrier to enter the central nerve by passing through the blood brain barrier, and simultaneously, the first pass effect is avoided, the bioavailability is improved, and the targeting effect is further improved. See the following detailed description of the examples.
Example 1
The embodiment provides a nasal mucosa administration gel, which comprises the following components in percentage by weight in the gel: 20% of levodopa, 0.25% of raw musk, 0.25% of levoborneol, 0.25% of storax, 0.25% of benzoin gum, 0.25% of menthol, 9400.4% of carbomer, 15% of propylene glycol (penetration enhancer and humectant), 0.1% of sodium bisulfite, 0.2% of ethylparaben and the balance of purified water. The preparation method comprises the following steps:
the method comprises the following steps: adding carbomer 940 into purified water to enable the carbomer to be fully swelled, and adjusting the pH value to 5-6 by triethanolamine to form a gel solution; in addition, the pH value can be adjusted by adopting sodium hydroxide and potassium hydroxide, and the pH value can be adjusted to 5-6 as long as the pH value is a pH adjusting agent for food.
Step two: mixing Moschus, levo-Borneolum, storax, benzoin gum, menthol, and propylene glycol, ultrasonic processing, and mixing with the above gel solution;
step three: further adding levodopa, sodium bisulfite and ethylparaben into the mixed gel solution, adding the rest purified water, mixing to obtain nasal gel, quantitatively filling, sealing, checking weight, detecting leakage, and packaging to obtain nasal mucosa administration gel.
The nasal gel can be further prepared into aerosol, nasal drops, spray or freeze-dried powder, and the preparation process is conventional in the art and is not described in detail herein.
Example 2
The embodiment provides a nasal mucosa administration gel, which comprises the following components in percentage by weight in the gel: 20% of levodopa, 0.25% of menthol, 0.25% of storax oil, 0.25% of benzoin gum, 0.25% of dry calamus, 1.5% of levoborneol, 9400.4% of carbomer, 15% of propylene glycol (penetration enhancer and humectant), 0.2% of sodium bisulfite, 0.1% of ethylparaben and the balance of purified water. The preparation method is the same as example 1.
Example 3
The embodiment provides a nasal mucosa administration gel, which comprises the following components in percentage by weight in the gel: 20% of levodopa, 0.25% of musk, 0.25% of menthol, 0.25% of storax oil, 0.25% of benzoin gum, 1% of levoborneol, 9400.4% of carbomer, 15% of propylene glycol (penetration enhancer and humectant), 0.1% of sodium bisulfite, 0.2% of ethylparaben and the balance of purified water. The preparation method is the same as example 1.
Example 4
The embodiment provides a nasal mucosa administration gel, which comprises the following components in percentage by weight in the gel: 21% of levodopa, 2% of musk, 9400.5% of carbomer, 10% of propylene glycol (penetration enhancer and humectant), 0.3% of sodium bisulfite, 0.2% of ethylparaben and the balance of purified water. The preparation method is the same as example 1.
Example 5
The embodiment provides a nasal mucosa administration gel, which comprises the following components in percentage by weight in the gel: 21% of levodopa, 2% of menthol, 9400.5% of carbomer, 10% of propylene glycol (penetration enhancer and humectant), 0.3% of sodium bisulfite, 0.2% of ethylparaben and the balance of purified water. The preparation method is the same as example 1.
Example 6
The embodiment provides a nasal mucosa administration gel, which comprises the following components in percentage by weight in the gel: 21% of levodopa, 2% of levoborneol, 9400.5% of carbomer, 10% of propylene glycol (penetration enhancer and humectant), 0.3% of sodium bisulfite, 0.2% of ethylparaben and the balance of purified water. The preparation method is the same as example 1.
Example 7
The embodiment provides a nasal mucosa administration gel, which comprises the following components in percentage by weight in the gel: 21% of levodopa, 3% of levoborneol, 9400.6% of carbomer, 15% of propylene glycol (penetration enhancer and humectant), 0.3% of sodium bisulfite, 0.2% of ethylparaben and the balance of purified water. The preparation method is the same as example 1.
Example 8
The embodiment provides a nasal mucosa administration gel, which comprises the following components in percentage by weight in the gel: 21% of levodopa, 1% of levoborneol, 2% of menthol, 9400.5% of carbomer, 10% of propylene glycol (a penetration enhancer and a humectant), 0.3% of sodium bisulfite, 0.2% of ethylparaben and the balance of purified water. The preparation method is the same as example 1.
Example 9
The embodiment provides a nasal mucosa administration gel, which comprises the following components in percentage by weight in the gel: 21% of levodopa, 3% of levoborneol, 3% of menthol, 9400.6% of carbomer, 15% of propylene glycol (penetration enhancer and humectant), 0.3% of sodium bisulfite, 0.2% of ethylparaben and the balance of purified water. The preparation method is the same as example 1.
Example 10
Further examine the effect of the nasal gel obtained in examples 1-9 on the cilia of the nasal mucosa of a toad:
the toxicity of the nasal mucociliary is examined by in vivo methods. The negative control group and the positive control group are respectively treated by normal saline and 1% sodium deoxycholate solution. The toad is fixed on the back, the hemostatic forceps is pulled to open the mouth, and the physiological saline, 1 percent sodium deoxycholate solution and 0.5mL nasal gel are respectively dripped on the mucous membrane of the upper palate. So that the upper jaw is completely submerged. Washing the medicine with normal saline after 30min, separating toad palatal mucosa with size of about 3mm x 3mm, washing attached blood clot with normal saline, spreading the mucosa on a glass slide with the mucosa facing upwards, wetting with normal saline, covering with a cover glass, discharging air bubbles, and observing ciliary movement under an optical microscope (10 × 40 times). And then placing the glass slide in a closed container with a small amount of normal saline at room temperature, taking out the glass slide at intervals of 30min, observing the glass slide under a microscope, and recording the ciliary continuous movement time. The cilia movement stop time of each experimental group was recorded and the percentage of cilia movement duration time was calculated. Higher this percentage indicates less cilia toxicity of the formulation and higher safety of the formulation. Generally, the percentage of time that cilia continue moving is greater than 85% is taken as the safety threshold of the preparation.
Percent exercise time is defined as administration exercise time/negative control exercise time multiplied by 100%
The sustained movement time table of the cilia toxicity test is shown in table 1, and the percentage of the sustained movement time of cilia in each group is calculated according to the formula by taking the sustained movement time of the cilia in the normal saline group as 100%. The result shows that the percentage of the sustained movement time of cilia in the positive control group is 8.33 percent, and the cilia have obvious toxicity; the cilia of the nasal gel group are clear and intact under a microscope and the cilia move actively, the percentage of the cilia moving duration time is 96.67% (> 85%), which shows that the nasal gel has no influence on the nasal mucociliary movement basically, has no obvious toxicity and is basically safe for nasal administration.
Table 1 effect of 3 groups of drugs in examples 1 to 9 on duration of mucociliary motility of toads nose (n ═ 3)
Skin irritation test:
rabbits were raised for 1 week before the start of the experiment, observed for ingestion and behavior, and randomly divided into single-dose groups and multiple-dose groups after complete absence of abnormalities, each group containing 5 intact skin groups. Single administration: 24h before administration, both sides of the dorsal spine were clipped and depilated with 8% sodium sulfide solution, approximately 5cm x 5cm on each side of the depilatory range. The experiment adopts the same body and left and right self control, the right hair removal area of the rabbit is coated with 0.5mL of nasal gel, the left hair removal area is coated with 0.5mL of distilled water as the control, the control is covered by 2 layers of sterile gauze, then the control is covered by a polyethylene film, and the rabbit is wrapped by a rabbit sleeve to be fixed in a single cage for feeding. After 6h, removing the covering, washing the medicine with warm water, and observing the local conditions 1, 24, 48 and 72h after removing the test object by naked eyes under natural light, and observing whether the medicine application part is red and swollen. Multiple administration: the experimental procedure was the same as single administration, 1 time daily for 7 consecutive times. After each removal of the test substance, the local skin was observed for redness and swelling, and the local conditions were recorded at 1, 24, 48, and 72h after the 7 th administration.
The results of the nasal gel on skin irritation are shown in table 2, single dose: at each time point after the tested medicine is removed, the skin irritation reaction is observed by naked eyes, obvious reactions such as erythema, edema and the like are not found, and the left side and the right side have no obvious difference. Multiple administration: no irritation reaction such as erythema and edema is seen on the skin. The experimental result shows that the nasal gel has no irritation to the skin of the rabbit.
Table 2 nasal gel results for rabbit skin irritation (n ═ 5)
In vitro transdermal experiments:
the receiving cell was filled with 7mL of ethanol-physiological saline (3: 7) as a receiving medium, and air bubbles were discharged to bring the liquid surface into contact with the inner layer of the skin. Adjusting the temperature of the diffusion cell to (32 +/-1) ° C, stirring at a constant speed (about 200r/min), sucking 1mL of receiving solution from the sample receiving cell 0.5, 1,2, 4, 6, 8, 10, 12 and 24 hours after the start of the experiment, and simultaneously adding the receiving solution with the same temperature and volume. The absorbed receiving solution is filtered by a 0.22 mu m microporous filter membrane, and the cumulative permeation amount (Q) and the permeation rate constant (J) are calculated according to the following formula, and the result is shown in figure 1, which shows that the gel of example 9 has the highest drug cumulative permeation amount and the best effect in the skin, and secondly, the gels of example 7 and example 8, and the levoborneol and the menthol have obvious effect of promoting the nasal gel permeation of the levodopa.
Q＝[C n ×V 0 +∑C i ×V]S, wherein C n : the concentration in the receiving solution at the time of the nth sampling; c i : the concentration in the receiving solution at the time of the ith sampling; v 0 : the volume of the diffusion cell is 7 mL; v: sampling volume is 1 mL; s: diffusion area 1.3267cm 2 。
The nasal gel was fitted to the Higuchi model, Q J · t1/2+ a, where Q is the cumulative permeation, J is the transdermal rate constant, t is the time, a is the integration constant, and the results of the fit are shown in table 3.
TABLE 3 nasal formulations Higuchi fitting equation
Drug retention in skin experiment:
after the transdermal experiment is terminated, the drug layer attached to the skin is washed by distilled water to clean the drug on the surface of the skin, the filter paper absorbs water, the skin is weighed, the skin is cut into pieces, a proper amount of normal saline is added to be ground into chyle, and the chyle is ultrasonically homogenized. Centrifuging at 4000r/min for 10min, collecting supernatant, filtering, and adding filtrate into 10mL volumetric flask. The retention of the drug per unit area of the skin was calculated and the data was plotted as a histogram to visually represent the comparison of the two, the results are shown in fig. 2, which indicates that the gel of example 9 has the highest retention of the drug in the skin and the best effect, and that the gels of examples 7 and 8, levoborneol and menthol, have significant synergy.
Example 11
This example provides a levodopa suspension formulation, and the formulation for preparing 100mL of suspension comprises: 2.1g levodopa, 0.2% (g/mL) sodium carboxymethylcellulose, 0.01% (g/mL) sodium metabisulfite, 5mL ethanol, 0.3g levoborneol, and the balance purified water.
The preparation method comprises the following steps: 2.1g of levodopa is precisely weighed and placed in a penicillin bottle. Accurately weighing 0.3g of levo-borneol and dissolving the levo-borneol in 5mL of ethanol, accurately weighing 0.2g of sodium carboxymethylcellulose and dissolving the sodium carboxymethylcellulose in 100mL of water, adding the two solutions into a penicillin bottle, and magnetically stirring the two solutions until the two solutions are completely dissolved. 10mg of sodium metabisulfite was precisely weighed and dissolved in the above solution.
Example 12
This example provides a levodopa suspension formulation, the formulation for preparing 100mL of suspension comprising: 2.1g levodopa, 0.3% (g/mL) sodium carboxymethylcellulose, 0.01% (g/mL) sodium metabisulfite, 5mL ethanol, 0.3g levoborneol, and the balance purified water. The preparation method is the same as example 11.
Example 13
This example provides a levodopa suspension formulation, and the formulation for preparing 100mL of suspension comprises: 2.1g levodopa, 0.5% (g/mL) sodium carboxymethylcellulose, 0.01% (g/mL) sodium metabisulfite, 5mL ethanol, 0.3g levoborneol, and the balance purified water. The preparation method is the same as example 11.
Example 14
The stability of the suspensions obtained in examples 11 to 13 was further investigated:
determination of sedimentation volume ratio: the prepared suspension was stoppered and the level H recorded 0 Shaking for 10 times, standing for 30min, recording the height of the sediment, and calculating the sedimentation volume ratio F ═ H/H 0 Results between 0 and 1, and greater than 0.9, demonstrate that the suspension is stable, the greater the number.
Redispersion testing: the prepared suspension was filled into a stoppered cylinder and allowed to settle for 48h, then the stoppered cylinder was inverted (once for each inversion) and the number of inversions required to redisperse the bottom sediment was noted. The fewer number of flips required, the better the redispersion.
The experimental results are as follows
TABLE 4 results of the measurement of the sedimentation volume ratio of levodopa suspension
| Examples | H 0 (cm) | H(cm) | F |
| 11 | 8.9 | 8.7 | 0.98 |
| 12 | 8.9 | 8.8 | 0.99 |
| 13 | 8.9 | 8.8 | 0.99 |
TABLE 5 Levodopa suspension redispersion test results
As can be seen from the sedimentation volume ratio measurements and the redispersion test results in tables 4 and 5, the greater the concentration of the suspending agent sodium carboxymethylcellulose, the more stable the suspension and the less effective the redispersion. When the ratio of sodium carboxymethylcellulose is 1.9mg/mL (i.e., 0.2% (g/mL)), the suspension is relatively stable, suspending is relatively effective, and redispersion is good. Therefore, the amount of sodium carboxymethylcellulose is preferably controlled to 1.9 to 2.86mg/mL, more preferably 1.9 mg/mL.
Example 15
The nasal gel formulations and suspension formulations obtained in example 9 and example 11 were subjected to the following mouse pharmacodynamic experiments.
Animal molding: an SPF (specific pathogen free) grade male c57B/6 mouse 8-10 weeks old is selected to construct an acute Parkinson model, 1-methyl-4-phenyl 1,2,3, 6-tetrahydropyridine (MPTP) is intraperitoneally injected at a dose of 18mg/kg, 4 times a day and 2h intervals every time, and a control group of mice is injected with physiological saline with the same volume.
The experimental animals were divided into six groups and the administration was started 1 week before molding while continuing the administration for 2 weeks.
Group A, nasal administration of levodopa to nasal gel (without aromatic resuscitation inducing drug) at a dose of 0.21g/kg (corresponding to MPTP + levodopa nasal gel (without L-borneol) in figure 3);
group B, nasal administration of the nasal gel of example 9 at 0.21g/kg (corresponding to MPTP + levodopa nasal gel (containing levoborneol) in FIG. 3);
group C, the levodopa suspension of example 11 was administered by intragastric administration at 44.1mg/kg, and the dose of levodopa in the four groups was the same (corresponding to the levodopa suspension in FIG. 3);
d, administrating commercial levodopa tablet by intragastric administration according to 44.1mg/kg, wherein the administration dose of the four groups of levodopa is the same (corresponding to levodopa in figure 3);
group E: control mice were injected with an equal volume of saline without MPTP molding (corresponding to the blank control in fig. 3);
and F group: MPTP mice were molded without administration after molding (corresponding to MPTP in fig. 3).
And (3) behavioral testing: the limb movement conditions of the mice after the model making and the drug administration are observed by a rotating rod experiment respectively on the 1 st, 3 th and 5 th days after the model making.
Rod turning experiment: the mouse was placed on a bar which was rotated continuously, allowed to move in the opposite direction to the bar, and the time when the mouse first dropped from the bar was recorded, the results being shown in fig. 3.
Compared with the normal control group, the time of the mice in the MPTP model group on the rods at the 1 st, 3 th and 5 th days after the MPTP injection is obviously prolonged, and the movement coordination capability of the mice after the model is reduced. The influence of retention time of commercial levodopa on the rod in intragastric administration is minimal, the nasal gel group of example 9 and the nasal gel containing only levodopa (without aromatic resuscitation drugs) in nasal cavity are obviously shortened on the rod compared with the MPTP injection group on 3 rd and 5 th days after MPTP injection, and the retention time is especially more obvious on 5 th day after injection compared with the nasal gel containing only levodopa (without aromatic resuscitation drugs) in nasal cavity.
In addition, the levodopa suspension group of example 11 significantly reduced the time on the rod on both days 3 and 5 after MPTP injection compared to the gavage administration of commercially available levodopa tablets.
Example 16
The nasal gel formulation obtained in example 9 and the levodopa suspension obtained in example 11 were subjected to the following rat pharmacokinetic experiments.
Experimental animals: SD rats, body weight about 200 g.
The experimental method comprises the following steps: healthy rats, half male and female, were fasted for 12h before the experiment and had free access to water.
Experimental animals were divided into four groups:
in group A, levodopa nasal gel (without aromatic resuscitation medicine) is administered via nasal cavity at a dose of 0.21 g/kg;
group B, nasal administration of the nasal gel of example 9 at 0.21 g/kg;
group C, the levodopa suspension of example 11 was administered by gavage at 44.1mg/kg, and the dose of levodopa in four groups was the same.
And D, gavage the stomach of a commercial levodopa tablet, and administering the levodopa tablet at 44.1mg/kg, wherein the dose of the levodopa in four groups is the same.
Rats were sampled at the following sampling time points: performing orbital bleeding for 10min, 30min, 45min, 1h, 1.5h, 2h, 3h, 4h, 8h and 12 h.
When the drug is administrated through the nasal cavity, a rat is anesthetized by 25% urethane solution, a 1mL syringe with a needle is used, and a hose with the diameter of about 1mm is connected to the needle. The device is used for sucking the liquid medicine, the hose is inserted into the nostril of the rat by about 5-10mm, and the liquid medicine can be pushed in, and the result is shown in table 4.
TABLE 6 mean T of pharmacokinetic experiments in rats for nasal gels of levodopa compositions max 、T 1/2 、C max And AUC 0-t (n＝6)
AUC for administration of levodopa via nasal route and levodopa tablet available for intragastric administration 0-∞ For comparison, the relative bioavailability of the levodopa nasal gel in rats was calculated (F) r )。
(Note: in stands for nasal administration; po stands for intragastric administration)
The relative bioavailability of the nasal gel without levo-borneol to the intragastric administration preparation is 542.58%, and the relative bioavailability of the nasal gel of example 9 to the intragastric commercially available levodopa tablet administration preparation is 1086.17%. The relative bioavailability of the levodopa suspension of example 11 to the intragastric commercial levodopa tablet dosage formulation was 128.32%.
The pharmacokinetics of levodopa in vivo is researched by adopting nasal cavity and intragastric levodopa suspension and a commercially available levodopa tablet, various parameters of the pharmacokinetics of nasal cavity and intragastric administration are compared, and statistical analysis is carried out. In the research, T of nasal gel is found max Significantly less than the time to peak of the nasal gel of the commercial levodopa tablet, example 90.55 for the gavage group, C for the gel max The value is obviously different from that of the gavage group, which shows that the absorption of the medicine in the body is obviously accelerated; the relative bioavailability of the nasal gel containing levodopa alone was about 5 times that of the commercial levodopa tablet, and the relative bioavailability of the nasal gel of example 9 was about 11 times that of the commercial levodopa tablet. It can be seen that the nasal gel of example 9, administered nasally, is rapidly absorbed and has significantly improved bioavailability compared to commercially available levodopa tablets.
Additionally, T of levodopa suspension max Significantly less than the commercial levodopa tablet, the peak time of the suspension of example 11 was 0.72 of the commercial dosing group, suspension C max The value is obviously different from the value of the commercial group, which shows that the absorption of the medicine in the body is obviously accelerated; the relative bioavailability of the levodopa suspension group of example 11 is about 1.3 times that of the commercially available levodopa tablet. It can be seen that the levodopa suspension of example 11 is absorbed rapidly and the bioavailability is significantly improved compared to commercially available levodopa tablets.
Example 17
The nasal gel preparation obtained in example 9 and the levodopa suspension obtained in example 11 were subjected to the following rat brain tissue distribution experiment.
Experimental animals: SD rats, weighing about 200 g.
The experimental method comprises the following steps: healthy rats, half male and female, were fasted for 12h before the experiment and had free access to water.
Experimental animals were divided into four groups:
in group A, levodopa nasal gel (without aromatic resuscitation medicine) is administered via nasal cavity at a dose of 0.21 g/kg;
group B, nasal administration of the nasal gel of example 9 at 0.21 g/kg;
group C, the levodopa suspension of example 11 was administered by gavage at 44.1mg/kg, and the dose of levodopa was the same for the four groups.
And D, gavage the stomach of a commercial levodopa tablet, and administering the levodopa tablet at 44.1mg/kg, wherein the dose of the levodopa in four groups is the same.
Brain tissue distribution experiments: the experimental animals were sacrificed at 30min, 1h, and 5h, respectively, and brain, heart, liver, spleen, lung, and kidney tissues were taken out and stored in a refrigerator at-20 deg.C for assay.
When the nasal administration is carried out, a rat is anesthetized by using a 25% urethane solution, and a 1mL syringe with a needle is connected with a hose with the diameter of about 1mm at the position of the needle. The device is used for sucking the liquid medicine, the hose is inserted into the nostril of the rat by about 5-10mm, and the liquid medicine can be pushed in, and the result is shown in table 5.
Table 7 rat brain tissue content of levodopa compositions (n ═ 6)
According to the determination result of the brain tissue sample, compared with the levodopa tablet administration group sold in the stomach filling market, the nasal gel administration group has higher concentration of the nasal gel drug reaching the brain tissue of a rat within 0.5h, and the treatment effect is obviously good, probably because the drug can partially penetrate through the nasal cavity olfactory nerve path and directly reach the brain tissue. The nasal gel of example 9 has better therapeutic effect than the nasal gel containing only levodopa, and probably because the aromatic resuscitation inducing Chinese medicine has the effect of promoting permeation, the levodopa can easily permeate the blood brain barrier, and the content of the levodopa in the brain is higher.
In addition, the levodopa suspension administration group of example 11 reached a higher concentration of rat brain tissue at 0.5h and the therapeutic effect was significantly better, probably because the levodopa suspension was more easily absorbed, making the levodopa content in the brain higher, compared to the levodopa tablet administration group sold in the gavage market.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the present invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.
Claims (10)
1. A brain-targeted pharmaceutical composition, characterized by: comprises levodopa and aromatic resuscitation inducing medicine.
2. A formulation for nasal mucosal delivery, comprising: the pharmaceutical composition of claim 1, wherein the mass percentage of the levodopa in the nasal mucosa administration preparation is 5-50%, and the mass ratio of the levodopa to the aromatic resuscitation inducing traditional Chinese medicine is (1-120): 1.
3. a formulation for nasal mucosal delivery according to claim 2, wherein: the aromatic resuscitation inducing medicine is selected from one or more of terpenes such as menthol, limonene, eucalyptus oil, oleum Menthae Dementholatum, wintergreen oil, Carum Carvi oil, oleum Caryophylli, oleum Terebinthinae, Borneolum Syntheticum, Moschus, storax, Benzonum, and rhizoma Acori Graminei.
4. A formulation for nasal mucosal delivery according to claim 3, wherein: the aromatic resuscitation inducing medicine comprises the following components in percentage by weight in the nasal mucosa administration preparation: 3 percent of levo-borneol.
5. A formulation for nasal mucosal delivery according to claim 3, wherein: the aromatic resuscitation inducing medicine comprises the following components in percentage by weight in the nasal mucosa administration preparation: 3% of levo-borneol and 3% of menthol.
6. A formulation for nasal mucosal delivery according to any one of claims 2 to 5, wherein: the nasal mucosal delivery formulation further comprises: gel matrix, penetration enhancer, humectant, pH regulator and water.
7. A formulation for nasal mucosal delivery according to claim 6, wherein: the nasal mucosa administration preparation also comprises a bacteriostatic agent and an antioxidant, wherein the bacteriostatic agent comprises one or more of ethylparaben, potassium sorbate, propyl p-hydroxybenzoate and benzyl alcohol, and the mass percentage of the bacteriostatic agent in the nasal mucosa administration preparation is 0.05-0.2%; the antioxidant comprises one or more of vitamin C, ethylene diamine tetraacetic acid disodium and sodium bisulfite, and the mass percentage of the antioxidant in the nasal mucosa administration preparation is 0.1-0.3%.
8. A process for the preparation of a formulation for nasal mucosal delivery according to any of claims 2 to 7, wherein: the method comprises the following steps:
step 1, adding part of water into a gel matrix, uniformly mixing, and adjusting the pH of a system to 5-6 to obtain a gel solution;
step 2, mixing the aromatic resuscitation inducing medicine, the penetration enhancer and the humectant with the gel solution after ultrasonic treatment;
step 3, further adding levodopa into the mixed gel liquid, adding the rest water, and uniformly mixing to obtain nasal gel;
and 4, directly preparing the nasal gel or further preparing the nasal gel into aerosol, nasal drops, spray or freeze-dried powder, quantitatively filling, sealing, checking the weight, detecting leakage and packaging.
9. A levodopa suspension formulation characterized by: the components of the composition according to final concentration are as follows: 0.02g/mL of levodopa, 1.9-2.86 mg/mL of sodium carboxymethylcellulose, 0.095mg/mL of sodium metabisulfite, 2.86mg/mL of levoborneol, ethanol and water as solvents in a volume ratio of 1: 20 are combined.
10. A method of preparing a levodopa suspension formulation according to claim 9, wherein: the method comprises the following steps: dissolving levo-borneol in ethanol, dissolving sodium carboxymethylcellulose in water, mixing the two solutions with levodopa to obtain a solution, and adding sodium pyrosulfite to dissolve.
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| JP2000038338A (en) * | 1998-07-23 | 2000-02-08 | Junichi Sudo | Composition for percutaneous absorption |
| CN101053550A (en) * | 2007-04-25 | 2007-10-17 | 昆明制药集团股份有限公司 | Rhizoma Gastrodiae nasal gel preparation |
| CN101797243A (en) * | 2010-03-23 | 2010-08-11 | 广东药学院 | Composition containing levodopa and borneol, and application thereof |
| CN115707462A (en) * | 2021-08-19 | 2023-02-21 | 沈阳药科大学 | Levodopa composition for improving brain targeting and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JP2000038338A (en) * | 1998-07-23 | 2000-02-08 | Junichi Sudo | Composition for percutaneous absorption |
| CN101053550A (en) * | 2007-04-25 | 2007-10-17 | 昆明制药集团股份有限公司 | Rhizoma Gastrodiae nasal gel preparation |
| CN101797243A (en) * | 2010-03-23 | 2010-08-11 | 广东药学院 | Composition containing levodopa and borneol, and application thereof |
| CN115707462A (en) * | 2021-08-19 | 2023-02-21 | 沈阳药科大学 | Levodopa composition for improving brain targeting and application thereof |
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