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CN115554297A - New medical application of cytisine and pharmaceutical preparation thereof - Google Patents

New medical application of cytisine and pharmaceutical preparation thereof Download PDF

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CN115554297A
CN115554297A CN202211393734.1A CN202211393734A CN115554297A CN 115554297 A CN115554297 A CN 115554297A CN 202211393734 A CN202211393734 A CN 202211393734A CN 115554297 A CN115554297 A CN 115554297A
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CN115554297B (en
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吴祥根
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Beijing Boxin Kemei Biotechnology Co ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A61K9/00—Medicinal preparations characterised by special physical form
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    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A61K9/00—Medicinal preparations characterised by special physical form
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

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Abstract

The invention relates to a new medical application of cytisine, in particular to a new application of cytisine in treating corneal injury and related eye diseases and a pharmaceutical preparation thereof. The cytisine ophthalmic medicinal preparation provided by the invention can effectively promote the repair of corneal epithelial injury, and particularly has an especially obvious effect on the corneal epithelial injury which is difficult to heal and is caused by other factors (such as diabetes and other basic diseases); has significant clinical and commercial application value.

Description

New medical application of cytisine and pharmaceutical preparation thereof
Technical Field
The invention relates to a new medical application of cytisine, in particular to a new application of cytisine in treating corneal injury and related eye diseases, and a pharmaceutical preparation thereof.
Background
In the conventional ophthalmic operations such as cataract superfulsive operation, fundus operation and the like, the cornea is damaged in the operation process, and particularly, the corneal epithelium is obviously damaged. In addition, damage to the corneal epithelium may be caused by a number of factors, including, but not limited to, corneal nerve dysfunction, infection, trauma, inflammatory response, ocular disorders (including eyelid disorders, corneal disorders, etc.), surgical injury, drug use, and the like. Patients with basic diseases such as diabetes mellitus often have clinical problems such as difficult corneal epithelium healing.
After the corneal epithelium is damaged, the patient may experience eye abrasion, blindness, tearing, eye pain, and the like. The common recognition of clinical diagnosis and treatment experts of corneal epithelial injury issued by China is clearly proposed, and the treatment principle aiming at patients with corneal epithelial injury is to find possible causes or pathogenic factors and remove the causes; local treatment is the main treatment, and patients with related general disease history combine with general treatment to cause primary disease; promoting the repair of corneal epithelial damage; preventing infection. Specifically, the commonly used drugs after clinical corneal epithelial injury are levofloxacin eye drops, recombinant bovine basic fibroblast growth factor eye drops, sodium hyaluronate eye drops and the like. The levofloxacin eye drops can prevent keratitis and infection; sodium hyaluronate eye drops and the like can promote the regeneration of corneal epithelium, promote the healing of injured parts, make patients feel comfortable and reduce eye pain symptoms. Although the above drugs have a certain therapeutic effect on corneal epithelial injury, the above drugs are not effective and often have poor therapeutic effects for some patients with basic diseases such as diabetes.
Therefore, the study of drugs for the effective prevention and treatment of corneal injuries, especially refractory corneal epithelial injuries, remains challenging and of great clinical significance. The invention aims to provide a medicament for effectively promoting the repair of corneal injury, in particular to the repair of corneal epithelial injury which is difficult to heal due to basic diseases such as diabetes and the like.
Disclosure of Invention
The inventor of the application discovers that the cytisine has pharmacological activity of promoting the restoration of the damaged cornea for the first time, and through deep research, the cytisine can remarkably promote the restoration of the damaged cornea epithelium by eye drop administration and can be used for restoring the damaged cornea epithelium; in particular, the cytisine can remarkably promote the repair of the corneal injury of a diabetes model mouse, and the specific action mechanism of the cytisine needs to be further researched.
Cytisine, also called glaucine or cytisine, CAS number 485-35-8, molecular formula C 11 H 14 N 2 O, molecular weight 234.38, is a quinolizidine alkaloid extracted from Sophora alopecuroides L of Sophora of Leguminosae; the structural formula is shown as the following formula I:
Figure BDA0003932417100000021
the cytisine has certain toxicity, and the clinical use of 0.15% aqueous solution of cytisine for intramuscular or intravenous injection can rescue patients with symptoms of reflex apnea, shock, neonatal asphyxia and the like caused by operation and various wounds. In addition, cytisine can be used for producing smoking stopping medicine, emergency medicine, and antitussive.
In addition to the above known clinical uses, the clinical use of cytisine is severely limited and rarely used for other purposes due to its toxicity. Therefore, at present, no study report of the sparteine for repairing the corneal injury exists, and no pharmaceutical preparation for repairing the corneal injury is researched and marketed. . The invention relates to application of cytisine in preparing a medicine for treating and repairing corneal injury, belonging to the first disclosure. The present invention is also the unexpected discovery of the applicant that the administration of cytisine to the eye at a concentration not only does not produce its toxic effects, but also is effective in promoting healing of corneal epithelial injuries.
Therefore, the invention firstly provides a new medical application of the cytisine in repairing the corneal injury, and based on the application discovery, a corresponding ophthalmic medicine preparation is designed, so that the cytisine is used for treating the corneal injury and treating diseases related to the corneal injury.
Further, the present invention provides a use of cytisine in the preparation of a pharmaceutical composition for the treatment of corneal injury, preferably corneal epithelial injury.
In another aspect, the present invention provides a pharmaceutical composition for treating and/or preventing corneal injury, comprising cytisine; preferably, the corneal injury is corneal epithelial injury.
As a preferable embodiment of the new medical application or the pharmaceutical composition, the pharmaceutical concentration of the cytisine is 1-8 mg/ml; preferably, the concentration of cytisine is 2-8 mg/ml, 3-6 mg/ml, 3-5 mg/ml, 3mg/ml, 4mg/ml or 5mg/ml.
As a preferred mode of the present invention, the pharmaceutical composition of the present invention further comprises one or more other auxiliary ingredients selected from one or more of sodium hyaluronate, levofloxacin, recombinant bovine basic fibroblast growth factor. Preferably, the auxiliary ingredient is sodium hyaluronate.
Preferably, the auxiliary ingredient in the pharmaceutical composition of the present invention is sodium hyaluronate. In the pharmaceutical composition, the mass ratio of the cytisine to the sodium hyaluronate is 1:0.2 to 1:5; more preferably, the mass ratio of the cytisine to the sodium hyaluronate is 1:0.5 to 1: 2. 1:0.8 to 1:1.2, most preferably the mass ratio of the two is 1:1.
Further, the pharmaceutical composition further comprises pharmaceutically acceptable auxiliary materials; preferably, the pharmaceutically acceptable excipients include, but are not limited to, gel matrix, preservatives, pH adjusting agents, isotonic adjusting agents, and the like. Preferably, the pharmaceutically acceptable auxiliary materials are gel matrix, preservative, pH regulator and/or isotonic regulator; preferably, the isotonicity adjusting agent is sodium chloride; the gel matrix can be any gel matrix suitable for ocular use, including but not limited to carbomers, poloxamers, and the like.
Preferably, the pharmaceutical composition further comprises a pH regulator, and the pH value of the pharmaceutical composition is regulated to 5-9; more preferably 5.5 to 8, 6 to 7.5, 6.5 to 7.5, 7.0 to 7.5, such as 6.0, 6.5, 7.0, 7.4 or 7.5.
Preferably, the pharmaceutical composition further comprises an isoosmotic adjusting agent, and the osmotic pressure is adjusted to be 220-380 mmol/L; more preferably, the osmotic pressure is adjusted to 280 to 310mmol/L.
Further, the pharmaceutical composition of the present invention is an ophthalmic pharmaceutical composition, preferably an eye drop formulation or an ophthalmic gel formulation.
On the other hand, the invention provides a preparation method of the pharmaceutical composition, and particularly relates to a preparation method of an eye drop preparation, which comprises the following steps: dissolving main drug cytisine in water, adding other auxiliary components, antiseptic, pH regulator and/or isotonic regulator, sterile filtering, and packaging. Wherein the antiseptic, pH regulator, and isotonic regulator can be added according to the prior art. Preferably, the water is water for injection, and the isotonic regulator is sodium chloride.
Further, the invention provides a preparation method of the laburnine ophthalmic gel preparation, which comprises the following specific steps: swelling the hydrogel matrix, dissolving main drug laburnine in appropriate amount of water, adding the laburnine solution into the swollen hydrogel matrix, stirring, adding other auxiliary components, antiseptic, pH regulator and/or isotonic regulator, stirring, sterilizing, and packaging. Wherein the antiseptic, pH regulator, and isotonic regulator can be added according to the prior art. Preferably, the hydrogel matrix is carbomer 940 and is swollen with dilute hydrochloric acid; the water is water for injection, and the isotonic regulator is sodium chloride.
The invention has the beneficial effects that:
the cytisine ophthalmic medicinal preparation can effectively promote the corneal epithelial injury repair, and particularly has an obvious effect on the corneal epithelial injury difficult to heal caused by other factors (such as diabetes and other basic diseases).
Drawings
FIG. 1: a fluorescence staining map for repairing the corneal epithelial injury of a diabetes model mouse;
FIG. 2: quantitatively analyzing the defect area of the diabetic mouse after corneal epithelium damage;
FIG. 3: graph of blink frequency change after eye drop of experimental drug.
Detailed Description
The invention is explained in further detail below by means of specific embodiments in conjunction with the figures.
Example 1: preparation of the ophthalmic pharmaceutical composition of the present invention
Specifically, the present example provides specific examples of cytisine-based ophthalmic pharmaceutical compositions, including eye drop formulations and ophthalmic gel formulations, the following specific example drugs and their preparation are as follows:
experimental drug 1: dissolving 10mg cytisine in 10mL of water for injection, adding isotonic regulator sodium chloride, adjusting pH to 7.4, filtering the solution with 0.22 μm microporous membrane, and packaging under sterile condition.
Experimental drug 2: dissolving 30mg of cytisine in 10mL of water for injection, adding isotonic regulator sodium chloride, adjusting pH to 7.4, filtering the solution with 0.22 μm microporous membrane, and packaging under sterile condition.
Experimental drug 3: dissolving cytisine 60mg in 10mL of water for injection, adding isotonic regulator sodium chloride, adjusting pH to 7.4, filtering the solution with 0.22 μm microporous membrane, and packaging under aseptic condition.
Control drugs: 0.3% sodium hyaluronate eye drops (trade name: ali).
Example 2: diabetic model mouse corneal epithelium injury repair test
Experimental animals: since the STZ-induced diabetic mouse is a well-recognized model similar to human diabetes, this example was studied using this model. C57BL/6 mice, male, 6-8 weeks old, and 18-25 g in body weight (purchased from Jinan Pengyue laboratory animal technology Co., ltd.). Animals were randomly divided into two groups, one group was injected intraperitoneally with freshly prepared citrate buffer (pH 4.5) to prepare STZ solution, 5 days of continuous injection, blood glucose was measured per mouse on day 8 (after one week) after the last (fifth injection) for 3 days, and blood glucose values of STZ-injected groups of more than 300mg/dL (16.7 mmol/L) were considered successful in type i diabetes model. At the 12-week test, the same body weight and blood glucose monitoring was performed on the mice, and the mice meeting the respective parameter indexes and the condition of taking tissue material were used for the test. The other group was injected with citrate buffer without STZ as a normal control. The experimental results show that the STZ intraperitoneal injection modeled mice gradually show typical symptoms of diabetes such as polydipsia, polyphagia, polyuria, weight loss and the like, the blood sugar is stably maintained at a higher level, and the weight is lower than that of normal mice (table 1), which indicates that the modeling is successful.
TABLE 1 weight and blood glucose measurements at sample points in normal and diabetic model mice: (
Figure BDA0003932417100000051
n＝50～60)
Figure BDA0003932417100000052
The experimental method comprises the following steps: performing corneal epithelium scraping after the mice are modeled for 12 weeks in diabetes, establishing a diabetic keratopathy model, namely a corneal epithelium and corneal nerve injury model, and then randomly dividing the diabetic keratopathy model mice into: a normal saline eye drop group, a 0.3% sodium hyaluronate eye drop group, an example 1 (0.1% cytisine) eye drop group, an example 2 (0.3% cytisine) eye drop group, and an example 3 (0.6% cytisine) eye drop group. After grouping, the test groups were applied by eye drop, and each group was applied with 5. Mu.l/eye solution each time, 3 times per day for 3 consecutive days. After the treatment is finished, the corneal epithelial defect percentage of each group of mice is detected.
The experimental results are as follows: after corneal epithelium curettage was performed on diabetic mice, eye drop treatment was performed on each group of diabetic mice at each time point, and the corneas were stained with a fluorescein sodium solution at 0h, 24h, 36h, 48h, 60h, and 72h after curettage. The results of the eye-drop experiments in each group are shown in fig. 1, at 24h after corneal injury, the fluorescein sodium staining areas of the three groups of cytisine eye-drop groups are obviously smaller than those of the normal saline eye-drop group and the sodium hyaluronate eye-drop group, while the fluorescein sodium staining areas of the experimental drug 2 (0.3% cytisine) eye-drop group and the experimental drug 3 (0.6% cytisine) eye-drop group are equivalent and superior to those of the experimental drug 1 (0.1% cytisine) eye-drop group; at 48h after corneal injury, the fluorescein sodium staining area of the experimental drug 3 (0.6% cytisine) eye drop group is almost not existed, and the fluorescein sodium staining of the experimental drug 2 (0.3% cytisine) eye drop group and the experimental drug 1 (0.1% cytisine) eye drop group shows that a certain injury area exists, but the staining areas are smaller than that of the sodium hyaluronate eye drop group; at 60h after corneal injury, the fluorescein sodium staining areas of the experimental drug 3 (0.6% cytisine) eye drop group and the experimental drug 2 (0.3% cytisine) eye drop group are almost not existed, which indicates that the corneal epithelium of the two groups is completely repaired, the corneal repair of the sodium hyaluronate eye drop group and the corneal repair of the experimental drug 1 (0.1% cytisine) eye drop group are also obvious, but the experimental drug 1 eye drop group is obviously superior to the sodium hyaluronate eye drop group; the normal saline group also has a certain fluorescent sodium staining area; at 72h after corneal injury, the experimental drug 1 (0.1% cytisine) eye drop group also basically repaired, but the sodium hyaluronate eye drop group and the normal saline group cornea are not completely repaired.
The fluorescence area was quantitatively analyzed using the software imageJ, resulting in fig. 2. As can be seen from FIGS. 1 and 2, the laburnine eye drops can effectively improve the speed of repairing the cornea of the diabetic mouse after the injury, and the effect is better than that of the sodium hyaluronate eye drops.
Example 3: eye irritation test of cytisine eye drops
Experimental animals: referring to the experimental drug 1 in example 1, cytisine eye drops with concentrations of 1, 3, 5, 8 and 10mg/mL were prepared, and sodium chloride as an isotonic adjusting agent was added to all eye drops, and the pH was adjusted to 7.4.
The experimental method comprises the following steps: new Zealand rabbits (male) with the weight of 2.0-2.5 kg (purchased from Qingdao Kangda Rabbit industry Co., ltd.) are selected. Animals were randomly divided into 8 groups of 1, 3, 5, 8, 10mg/mL cytisine eye drops, physiological saline, 0.01% benzalkonium chloride solution, 0.5% sodium dodecyl sulfate solution (0.5% SDS), and 5 animals per group. All rabbits were left without any treatment in the right eye and used as controls, and the left eye was dropped with the above solutions, respectively, and the number of blinks within two minutes after dropping was recorded.
The experimental results are as follows: as shown in figure 3, the groups of 1mg/mL, 3mg/mL and 5mg/mL cytisine eye drops do not cause the change of the rabbit blinking frequency, while the group of 8mg/mL cytisine eye drops slightly causes the change of the blinking frequency, and is equivalent to 0.01% benzalkonium chloride eye drops which are commonly used as preservatives in eye drops (P is more than 0.05 after eye dropping), which indicates that the eye irritation of the 8mg/mL cytisine eye drops is within an acceptable range, and the blinking frequency of the group of 10mg/mL cytisine eye drops is preferentially obviously increased, thus indicating that the 10mg/mL cytisine eye drops have certain eye local irritation.
In conclusion, the laburnine eye drops can remarkably promote the repair of diabetic mice after corneal epithelium injury, the curative effect evaluation is superior to that of sodium hyaluronate eye drops, and the laburnine eye drops have good ocular tolerance when the concentration is not higher than 8mg/mL.

Claims (15)

1. A pharmaceutical composition for treating and/or preventing corneal damage, wherein the pharmaceutical composition comprises cytisine.
2. The pharmaceutical composition of claim 1, wherein the corneal injury is corneal epithelial injury.
3. The pharmaceutical composition of claim 2, wherein: the medicine concentration of the cytisine is 1-8 mg/ml.
4. The pharmaceutical composition of claim 3, wherein: the medicine concentration of the cytisine is 3-8 mg/ml.
5. The pharmaceutical composition of claim 4, wherein: the medicine concentration of the cytisine is 3-6 mg/ml.
6. The pharmaceutical composition of claim 5, wherein: the medicine concentration of the cytisine is 5mg/ml or 6mg/ml.
7. The pharmaceutical composition of any one of claims 1-6, wherein: the pharmaceutical composition is an ophthalmic pharmaceutical composition.
8. The pharmaceutical composition of claim 7, wherein: the pharmaceutical composition is an eye drop preparation or an ophthalmic gel preparation.
9. The pharmaceutical composition of claim 8, wherein: the pharmaceutical composition further comprises pharmaceutically acceptable auxiliary materials.
10. The pharmaceutical composition of claim 9, wherein: the pharmaceutical composition further comprises one or more accessory ingredients.
11. The pharmaceutical composition of claim 10, wherein: the auxiliary components are selected from one or more of sodium hyaluronate, levofloxacin and recombinant bovine basic fibroblast growth factor.
12. The pharmaceutical composition of claim 11, wherein: the auxiliary component in the pharmaceutical composition is sodium hyaluronate, and the mass ratio of the cytisine to the sodium hyaluronate is 1:0.2 to 1:5.
13. the pharmaceutical composition of claim 12, wherein: the mass ratio of the laburnine to the sodium hyaluronate is 1:1.
14. use of cytisine in the preparation of an ophthalmic pharmaceutical composition for the treatment and/or prevention of corneal damage.
15. Use according to claim 14, characterized in that the corneal damage is corneal epithelial damage.
CN202211393734.1A 2022-09-30 2022-11-08 Novel medical application of cytisine and pharmaceutical preparation thereof Active CN115554297B (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN119015278A (en) * 2024-09-20 2024-11-26 广州医科大学 New use of cytisine, cytisine-polypeptide coupling compound and preparation method and use thereof

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101428021A (en) * 2007-11-09 2009-05-13 江苏中康药物科技有限公司 Externally used medicament preparation for kicking craving for tobacco and wine
CN103284319A (en) * 2013-06-20 2013-09-11 昌宁德康生物科技有限公司 Oral cavity atomized liquid with cytosine replacing nicotine and preparation method thereof
CN104473924A (en) * 2014-12-04 2015-04-01 宁夏医科大学 Application of cytisine in medicines for treating cerebral arterial thrombosis
CN113440487A (en) * 2020-03-27 2021-09-28 北京万全德众医药生物技术有限公司 Caragana tablets and preparation method thereof
US20210369744A1 (en) * 2020-05-29 2021-12-02 The Regents Of The University Of California Compositions and methods for enhancing visual function

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101428021A (en) * 2007-11-09 2009-05-13 江苏中康药物科技有限公司 Externally used medicament preparation for kicking craving for tobacco and wine
CN103284319A (en) * 2013-06-20 2013-09-11 昌宁德康生物科技有限公司 Oral cavity atomized liquid with cytosine replacing nicotine and preparation method thereof
CN104473924A (en) * 2014-12-04 2015-04-01 宁夏医科大学 Application of cytisine in medicines for treating cerebral arterial thrombosis
CN113440487A (en) * 2020-03-27 2021-09-28 北京万全德众医药生物技术有限公司 Caragana tablets and preparation method thereof
US20210369744A1 (en) * 2020-05-29 2021-12-02 The Regents Of The University Of California Compositions and methods for enhancing visual function

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN119015278A (en) * 2024-09-20 2024-11-26 广州医科大学 New use of cytisine, cytisine-polypeptide coupling compound and preparation method and use thereof
CN119015278B (en) * 2024-09-20 2025-03-14 广州医科大学 Cymosine-polypeptide coupled compound, and preparation method and application thereof

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