Pharmaceutical composition for treating postpartum depression of pregnant and lying-in women

Abstract

The invention discloses a pharmaceutical composition for treating or preventing postpartum depression of pregnant and lactating women, which is characterized by comprising a vitamin K2 compound or a pharmaceutically acceptable salt thereof and an optional pharmaceutically acceptable carrier, diluent or excipient. In particular, the pharmaceutical composition can also promote the development of the offspring brain and / or improve the learning ability.

Description

[0001] This application is a divisional application of the patent application with the application number 201811435423.0 filed on November 28, 2018. Technical Field

[0002] The present invention relates to the field of pharmaceutical technology, and more particularly to a pharmaceutical composition for treating postpartum depression in pregnant and lactating women and / or promoting the brain development and / or learning ability of offspring. Background Art

[0003] Depression has become one of the top ten diseases causing death and disability in work and life. Postpartum depression not only seriously endangers the health of the mother, but also affects the physical and mental health of the baby, the mother-child relationship and the quality of family life. At present, the cause of postpartum depression is unknown and the treatment is not satisfactory. Infantile mental retardation is abnormal brain function during the development period caused by various reasons. Mental retardation not only affects the physical and mental health of children, but also brings a heavy social and economic burden, seriously affecting the national quality, and is a social problem that cannot be ignored. Pregnancy and lactation diseases are caused by the joint participation of various internal and external factors, resulting in abnormalities in the physiological functions of the mother and fetus, and can cause a series of related diseases, such as Pregnancy and Lactation-associated Osteoporosis (PLO), Postpartum depression (PPD), premature birth and pregnancy-induced hypertension, etc., and even affect the brain development and intelligence level of the newborn, resulting in mental retardation in infants. Summary of the Invention

[0004] The inventors of the present invention surprisingly found that a vitamin, vitamin K2, can treat postpartum depression and can also promote the neural development and learning ability of offspring.

[0005] An object of the present invention is to provide a pharmaceutical composition for treating or preventing postpartum depression in pregnant and lactating women, which is achieved by the following technical solutions:

[0006] A pharmaceutical composition for treating or preventing postpartum depression in pregnant and lactating women, characterized by comprising a vitamin K2 compound or a pharmaceutically acceptable salt thereof and an optional pharmaceutically acceptable carrier, diluent or excipient.

[0007] Vitamin K2 is a general term for a series of terpene side chain compounds containing a 2-methyl-1,4-naphthoquinone nucleus and an isoprene structural unit with varying numbers at the C3 position. According to the number of carbon elements on the terpene side chain, it can be divided into K2(5), K2(15), K2(25), K2(35), etc. The number of isoprene structural units carried at the C3 position of vitamin K2 in the present invention is not particularly limited.

[0008] The pharmaceutical composition may optionally include other antidepressant drugs, such as, monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs), selective serotonin (5-HT) reuptake inhibitors.

[0009] In a specific embodiment of the present invention, the pharmaceutical composition can also promote the brain development of the offspring and / or improve the learning ability of the offspring.

[0010] In a specific embodiment of the present invention, the vitamin K2 is K2(10), K2(20), K2(35) or K2(40).

[0011] In a specific embodiment of the present invention, the vitamin K2 is natural, synthetic, or vitamin K2 converted from vitamin K1 and vitamin K3 in the liver.

[0012] In a specific embodiment of the present invention, the dosage of the vitamin K2 compound or its pharmaceutically acceptable salt is determined by a physician according to various factors such as the patient's condition, weight, etc. The general content range is: calculated as vitamin K2, 5 μg to 300 mg per person per day; preferably, 40 μg to 100 mg per person per day; more preferably, 80 μg to 50 mg per person per day.

[0013] The pharmaceutical composition can be administered in various conventional ways, preferably by oral administration.

[0014] Another object of the present invention is to provide a pharmaceutical composition for promoting the brain development of the offspring of a parturient and / or improving the learning ability of the offspring, which is achieved by the following technical solution:

[0015] A pharmaceutical composition for promoting the brain development of the offspring of a parturient and / or improving the learning ability of the offspring, characterized in that it comprises a vitamin K2 compound or its pharmaceutically acceptable salt and an optional pharmaceutically acceptable carrier, diluent or excipient.

[0016] In a specific embodiment of the present invention, it is characterized in that the vitamin K2, the administration method and the dosage are as described above.

[0017] Another object of the present invention is to provide an application of a vitamin K2 compound or its pharmaceutically acceptable salt in the preparation of a drug for treating or preventing postpartum depression in pregnant and lactating women, and / or promoting the brain development of the offspring and / or improving the learning ability of the offspring, which is achieved by the following technical solution:

[0018] An application of a vitamin K2 compound or its pharmaceutically acceptable salt in the preparation of a drug for treating or preventing postpartum depression in pregnant and lactating women, and / or promoting the brain development of the offspring and / or improving the learning ability of the offspring.

[0019] In a specific embodiment of the present invention, it is characterized in that the vitamin K2, the administration method, and the administration dosage are as described above.

[0020] In a specific embodiment of the present invention, the vitamin K2 compound or its pharmaceutically acceptable salt is used in combination with other antidepressant drugs. The other antidepressant drugs are as described above.

[0021] In a specific embodiment of the present invention, the pharmaceutically acceptable carrier, diluent or excipient in the pharmaceutical composition is selected from one or more of water-soluble solvents or oily solvents, dispersants, isotonic agents, preservatives, solubilizers or stabilizers. Among them, the water-soluble solvent can be selected from distilled water, physiological saline, Ringer's solution or phosphate buffer solution (PBS), etc.; the oil-soluble solvent can be selected from vegetable oils, such as olive oil, castor oil, sesame oil, cottonseed oil or corn oil, etc.; the dispersant can be selected from Tween 20 or Tween 80, polyethylene glycol, carboxymethyl cellulose, or sodium alginate, etc.; the isotonic agent can be selected from sodium chloride, glycerol, sorbitol, or glucose, etc.; the solubilizer can be selected from sodium salicylate, poloxamer or sodium acetate, etc.; the preservative can be selected from methyl paraben, propyl paraben, benzyl alcohol, chlorobutanol, sodium benzoate, or phenol, etc.; the stabilizer can be selected from albumin, such as human serum albumin, bovine serum albumin, etc. In addition, the pharmaceutically acceptable carrier, diluent or excipient can also be selected from biodegradable materials, such as polylactic acid, poly(lactic-co-glycolic acid), polyaspartic acid, etc. For those skilled in the art, known formulation techniques can be applied to prepare the pharmaceutical composition of the present invention. For example, the vitamin K2 compound or its pharmaceutically acceptable salt is dissolved, suspended or emulsified in a water-soluble solvent or an oily solvent together with a dispersant, and / or an isotonic agent, and / or a preservative, and / or a solubilizer, and / or a stabilizer (here, Remington: the science and practice of pharmacy, 21st edition, Lippincott Williams & Wilkins, 2005 is introduced as a reference).

[0022] For clinicians, under the teachings of the present invention, they can adjust or modify the frequency and dosage of daily administration according to the needs of clinical treatment effects.

[0023] It has been experimentally proven that the vitamin K2 compound or its pharmaceutically acceptable salt of the present invention can inhibit the uptake of serotonin by synapses, increase the content of serotonin between synapses, and increase synaptic excitability, thereby treating maternal depression; at the same time, it can also promote the neural development and learning ability of offspring. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1It was shown that the residence time of the parental generation in the open arms of the normal diet and vitamin K2 treatment group was significantly longer than that of the low-calcium diet group (P < 0.05).

[0025] Figure 2 It was shown that the immobility time of the parental generation in the normal diet and vitamin K2 treatment group was significantly shorter than that of the low-calcium diet group (P < 0.05).

[0026] Figure 3 It was shown that the escape latency of the offspring in the water maze experiment of the normal diet and vitamin K2 treatment group was significantly lower than that of the low-calcium diet group.

[0027] Figure 4 It was shown that the movement trajectory of the offspring in the water maze of the normal diet and vitamin K2 treatment group was significantly better than that of the offspring in the low-calcium group (P < 0.05), *P < 0.05, low-calcium + vitamin K2 treatment group vs low-calcium + solvent group, #P < 0.05, normal group vs low-calcium + solvent group.

[0028] Figure 5 It was shown that the expression of DCX in the dentate gyrus of the brain of the offspring in the normal diet and vitamin K2 treatment group was significantly better than that of the offspring in the low-calcium group. Detailed implementation mode

[0029] The feasibility of the present invention will be further illustrated by the following examples. For those skilled in the art, according to the teachings of the prior art and under the guidance of the embodiments of the present invention, it is obvious to make equivalent modifications or substitutions to the technical features therein, and it still falls within the scope of protection of the present invention.

[0030] Example

[0031] Materials and methods:

[0032] 1.1 Main reagents and instruments

[0033] Vitamin K2 (Sigma, USA); low-calcium rat feed (Beijing Keao Xieli Feed Co., Ltd., China); maintenance rat feed (Beijing Keao Xieli Feed Co., Ltd., China); doublecortin DCX primary antibody (abcom, China); dual-energy X-ray bone densitometer (Hologic, USA); dual-energy optical microscope (Nikon, Japan); Micro-CT machine (Siemens, Germany).

[0034] 1.2 Animal grouping and administration

[0035] The vitamin K2 raw material drug was dissolved in a solvent (edible oil) to prepare a solution with a drug concentration of 10 mg / ml. The treatment group was orally administered according to the vitamin K2 dosage (2 mg / kg / d) every day, and the other two groups were orally administered the solvent every day.

[0036] Twenty-four SPF-grade female SD rats at 3 months of age and weighing 280 - 350 g were provided by the Laboratory Animal Science Department of Peking University Health Science Center [SCXK(Beijing) 2011 - 0012]. After conception, the 24 SD rats were randomly divided into 3 groups (n = 8) using a random number table method: a normal group (rats were given maintenance feed + solvent by gavage), a low-calcium diet group (rats were given low-calcium feed + solvent by gavage), and a vitamin K2 treatment group (rats were given low-calcium feed + vitamin K2 by gavage, 2 mg / kg / d). After parturition, 6 pups per litter in each group were retained for lactation. After lactation, 2 pups per litter were randomly selected from each group (n = 16) for testing the cognitive learning ability of the offspring.

[0037] Experimental example

[0038] 1.3 Elevated plus maze experiment:

[0039] After pregnancy and lactation, the maternal rats were subjected to the elevated plus maze experiment to detect their degree of depression and anxiety. The maternal rats were slowly placed in the middle rock area facing the open arms, and the residence time of the rats in the open arms and closed arms within 5 min was recorded. By calculating the residence time in the open arms, the anxiety and depression-like behaviors of the rats were evaluated. A decrease in the residence time in the open arms indicated the emergence of anxiety and depression-like behaviors. The experimental results are shown in Figure 1 。

[0040] 1.4 Forced swim test:

[0041] After pregnancy and lactation, the maternal rats were subjected to the forced swim test to detect their degree of postpartum depression. The maternal rats were placed in a transparent glass cylinder filled with water. The diameter of the cylinder was 20 cm, the height was 30 cm, the water surface was 10 cm from the upper edge of the cylinder, and the water temperature was 22 ± 1°C. The swimming time was 10 minutes, and the time of obvious movement and non-obvious movement (simple floating) of the mice's limbs in the first 5 minutes was recorded. The floating time (immobility) of the mice was used as one of the indicators to judge the severity of depression. The experimental results are shown in Figure 2 。

[0042] 1.5 Morris water maze test:

[0043] After pregnancy and lactation, the Morris water maze test was conducted on the offspring pups to detect their learning and cognitive abilities. The Morris water maze consisted of a circular iron reservoir with a diameter of 130 cm and a height of 55 cm and an escape platform, and the water temperature was maintained at 25 °C. The pool was evenly divided into 4 quadrants, and the platform was located in the center of the second quadrant and could rotate in any direction. The circular pool was located in a well-lit laboratory, including relatively fixed extra-maze visual cues. A camera with a display system was installed above the maze to synchronously record the movement trajectory of the rats. One day before the water maze test, each rat was allowed to swim freely in the water maze pool without an escape platform for 60 s to exclude rats with swimming ability defects. The experiment lasted for 5 days, with 4 training sessions per day, and each session was separated by 15 min. During training, the experimenter randomly selected 1 quadrant as the entry point and put the rats into the water. The experiment was stopped when the rats climbed onto the hidden platform or reached 60 s. After the rats climbed onto the hidden platform, they were allowed to stay for 10 s; if the rats did not find the platform within 60 s, they were guided to climb onto the hidden platform and allowed to stay for 10 s. The escape latency (EL) behavior of the rats searching for the platform during the experiment was recorded by an image tracking system, and the EL was recorded. The experimental results are shown in Figure 3 and Figure 4 .

[0044] 1.6 Doublecortin (DCX) immunohistochemical staining of the dentate gyrus of the brain

[0045] After the water maze test, the three groups of offspring pups were anesthetized and sacrificed, fixed by cardiac perfusion, decapitated to remove the brain, placed in 4% paraformaldehyde for fixation, left overnight at 4 °C, dehydrated, embedded in paraffin, and the brain tissue was continuously sectioned by a microtome with a section thickness of 5 μm. Rabbit anti-DCX diluted at a volume ratio of 1:500 was used as the primary antibody, and goat anti-rabbit IgG was used as the secondary antibody. DAB staining solution was used to stain the cells and tissues, and immunohistochemical staining was performed on the brain tissue sections. Then, the number and morphology of DCX(+) cells in the hippocampal dentate gyrus were observed using an optical microscope. The experimental results are shown in Figure 5 .

[0046] 1.7 Statistical analysis:

[0047] SPSS 21.0 was used for statistical analysis. Measurement data were expressed as mean ± standard deviation. One-way ANOVA was used for comparison among the 3 groups, and LSD was used for pairwise comparison. P < 0.05 was considered statistically significant.

[0048] Experimental results:

[0049] The experimental results are shown in Appendix Figures 1-5 and its description.

[0050] Conclusion: Osteoporosis during pregnancy and lactation not only leads to an increase in postpartum depressive-like behaviors in maternal rats, but also causes impairments in the hippocampal development, cognition, and spatial learning ability of offspring. Supplementing vitamin K2 can effectively treat postpartum depression and improve the cognitive learning ability of offspring.

[0051] The above are only some embodiments of the present invention. For those of ordinary skill in the art, without departing from the inventive concept of the present invention, several modifications and improvements can still be made, and these all fall within the protection scope of the present invention.

Claims

1. Use of vitamin K2 compound or its pharmaceutically acceptable salt in the preparation of a drug for treating or preventing postpartum depression in pregnant and lactating women and promoting the brain development of offspring and improving the learning ability of offspring.

2. The use according to claim 1, wherein, The drug contains a vitamin K2 compound or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier, diluent or excipient, and optionally contains other antidepressant drugs.

3. The use according to claim 2, wherein, The other antidepressant drugs are selected from monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs) or selective serotonin (5-HT) reuptake inhibitors.

4. The use according to claim 1 or claim 2, wherein, Wherein the vitamin K2 is K2(10), K2(20), K2(35) or K2(40).

5. The use according to claim 1 or claim 2, wherein, Wherein the vitamin K2 is natural, synthetic, or vitamin K2 converted from vitamin K1 and vitamin K3 in the liver.

6. The use according to claim 1 or claim 2, wherein, Wherein, The content range of the vitamin K2 compound or its pharmaceutically acceptable salt is: calculated as vitamin K2, 5 μg to 300 mg per person per day; preferably, 40 μg to 100 mg per person per day; more preferably, 80 μg to 50 mg per person per day.

7. The use according to claim 1, wherein, The drug is administered orally.

8. The use according to claim 1, wherein, The vitamin K2 compound or its pharmaceutically acceptable salt inhibits the uptake of serotonin by synapses, increases the content of serotonin between synapses, increases synaptic excitability, thereby treating maternal depression; and at the same time promotes the neurodevelopment and learning ability of offspring.

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