CN107050428A - FGF20 medicines and its treatment use to cerebral trauma - Google Patents

Abstract

The invention belongs to the technical field of protein/polypeptide drugs, and provides a pharmaceutical composition for treating brain trauma, which includes fibroblast growth factor 20, and can be used for repairing the blood-brain barrier of the traumatic brain. In addition, the present invention also provides pharmaceutical preparations and applications including the pharmaceutical composition.

Description

FGF20 Drugs and Its Therapeutic Application to Brain Trauma

technical field

The invention belongs to the technical field of protein/polypeptide drugs, in particular, the invention relates to a pharmaceutical composition containing FGF20, which is used for treating brain trauma, especially for repairing the blood-brain barrier of the traumatic brain. In addition, the present invention also relates to therapeutic uses and the like including the pharmaceutical composition.

Background technique

Brain trauma, also known as traumatic brain injury (TBI), refers to the impact or impact of external mechanical force on the head, rapid acceleration or deceleration, foreign objects penetrating into the brain, etc., causing brain tissue damage, resulting in temporary or Permanent cognitive, physical and psychological dysfunction, etc. Brain trauma is not a single pathophysiological mechanism, but a complex disease process, and there is currently no effective treatment.

The blood brain barrier is composed of brain microvascular endothelial cells, astrocyte terminal feet, pericytes and basement membrane. It is not a simple physical barrier. effect. Among these, the first line of defense is the endothelium, which presents a dynamic, highly regulated interface between the blood and the central nervous system. The endothelial cells of the blood-brain barrier are distinguished from peripheral endothelial cells by their lack of fenestration, minimal pinocytosis and the presence of tight junctions between endothelial cells. The main role of the blood-brain barrier is to strictly regulate cell permeability. This is primarily mediated by tight junctions between capillary endothelial cells that restrict the movement of cytosols, ions, and water.

The protein drugs (also known as active growth factor groups and nutritional ingredients) in the prior art are not only complex in composition, but also large in dosage, very difficult to produce stably, and difficult to popularize and apply in practice. In particular, the functions and structures of different members of the existing fibroblast growth factor (FGF) family are different. There are currently 23 types, and it is not easy to confirm and choose one of them.

In summary, although there is no effective treatment for brain trauma at present, the inventor has not shrunk in the face of the difficulties of the prior art. After long-term arduous research, especially in combination with the inventor's experience, he has discovered a FGF (namely FGF20) can effectively treat brain trauma, especially it can repair the blood-brain barrier of traumatic brain.

Contents of the invention

The object of the present invention is to provide a pharmaceutical composition for treating brain trauma, especially for repairing the blood-brain barrier of traumatic brain. In addition, the present invention also provides pharmaceutical preparations and applications including the pharmaceutical composition.

Specifically, in a first aspect, the present invention provides a pharmaceutical composition for treating brain trauma, which includes fibroblast growth factor 20 (FGF20).

FGF20 is known in the prior art, and prior art is keen on studying the non-natural mutant of FGF20, but the inventors found that the effect of using human natural FGF20 (that is, FGF20 without mutation) is better, so in the present invention In a specific embodiment, FGF20 is human natural FGF20, and its preparation method can refer to Chinese patent application CN104293821A.

Preferably, in the pharmaceutical composition of the first aspect of the present invention, the pharmaceutically active ingredient only includes FGF20. That is, except for FGF20, the pharmaceutical composition of the first aspect of the present invention does not contain other pharmaceutically active ingredients for treating brain trauma.

Preferably, in the pharmaceutical composition of the first aspect of the present invention, the treatment of brain trauma is repairing the blood-brain barrier of the traumatic brain.

Also preferably in the pharmaceutical composition of the first aspect of the invention the wound is hydraulic trauma.

In the second aspect, the present invention provides a pharmaceutical preparation for treating brain trauma, which includes the pharmaceutical composition of the first aspect of the present invention and pharmaceutically acceptable auxiliary materials. Herein, pharmaceutically acceptable auxiliary materials refer to non-toxic fillers, stabilizers, diluents, carriers, solvents or other preparation auxiliary materials. For example, diluents, excipients, such as microcrystalline cellulose, mannitol, etc.; fillers, such as starch, sucrose, etc.; binders, such as starch, cellulose derivatives, alginate, gelatin, and/or polyethylene Pyrrolidone; disintegrants, such as calcium carbonate and/or sodium bicarbonate; absorption enhancers, such as quaternary ammonium compounds; surfactants, such as cetyl alcohol; carriers, solvents, such as water, saline, kaolin, bentonite, etc.; Lubricants such as talc, calcium/magnesium stearate, polyethylene glycol, etc.

Preferably, in the pharmaceutical preparation according to the second aspect of the present invention, the pharmaceutically acceptable auxiliary material is an injection pharmaceutical preparation auxiliary material. That is, the pharmaceutical preparation of the second aspect of the present invention is an injectable (drug) preparation. For example, the pharmaceutical composition of the first aspect of the present invention can be dissolved or diluted with physiological saline to make water for injection; it can also be mixed with mannitol and human serum albumin and freeze-dried to make injection (freeze) dry powder.

Preferably in the pharmaceutical formulation of the second aspect of the invention, the pharmaceutically active ingredient is brought only by the pharmaceutical composition of the first aspect of the invention. That is, the pharmaceutical preparation of the second aspect of the present invention consists of the pharmaceutical composition of the first aspect of the present invention and pharmaceutically acceptable excipients.

The present inventors found that only one injection of an effective amount of FGF20 is required for the effect to be effective. Therefore, the pharmaceutical preparation of the second aspect of the present invention preferably contains an effective amount of FGF20. For rats, the inventors found that the dose is 0.6-2.4 mg/kg, preferably 1.2-1.8 mg/kg, most preferably 1.5 mg/kg, and the effective dose for rats can be converted according to the weight of the rats. Herein, according to the context, unless otherwise specified, an effective amount refers to an effective amount for an adult. According to the equivalent dose conversion relationship between experimental animals and people known to those of ordinary skill in the art (usually refer to the guidance opinions of drug regulatory agencies such as FDA and SFDA, and also refer to: Huang Jihan et al. Between animals and between animals and humans in pharmacological tests Equivalent dose conversion between. Chinese Clinical Pharmacology and Therapeutics, 2004, 9 (9): 1069-1072) can be derived from the dose of experimental animals to adult dose. Specifically, for rats, the experimental animals used in the specific embodiments of the present invention, according to the above-mentioned literature, the conversion relationship between them and adults is generally 6:1, so for adults, the converted adult dose is 0.1- 0.4 mg/kg, preferably 0.2-0.3 mg/kg, most preferably 0.25 mg/kg. According to the normal adult body weight of 60Kg, it can be deduced that the pharmaceutical preparation according to the second aspect of the present invention preferably contains 6-24 mg FGF20, preferably 12-18 mg FGF20, most preferably 15 mg FGF20.

Preferably, in the pharmaceutical preparation of the second aspect of the present invention, the treatment of brain trauma is repairing the blood-brain barrier of the traumatic brain.

Also preferably in the pharmaceutical formulation of the second aspect of the invention the wound is hydraulic trauma.

In a third aspect, the present invention provides the use of FGF20 in the preparation of a medicament for treating brain trauma.

Preferably, in the application of the third aspect of the present invention, FGF20 is used alone as the active ingredient of the medicine. That is, the third aspect of the present invention preferably provides the use of FGF20 alone as an active ingredient in the preparation of a medicament for treating brain trauma.

Preferably in the use of the third aspect of the invention, the medicament comprises 6-24 mg FGF20, preferably 12-18 mg FGF20, most preferably 15 mg FGF20.

Preferably, in the application of the third aspect of the present invention, the treatment of brain trauma is repairing the blood-brain barrier of the traumatized brain.

Also preferably in the use of the third aspect of the invention the trauma is hydraulic trauma.

Preferably in the application of the third aspect of the invention, the drug is an injectable drug, such as the pharmaceutical formulation of the second aspect of the invention.

The beneficial effects obtained by the present invention are: the medicament of the present invention can be used to treat brain trauma, especially to repair the blood-brain barrier of traumatic brain; The efficacy is beneficial to its practical promotion and application; the drug has a remarkable therapeutic effect, especially it can improve the decline of behavioral function caused by brain trauma.

The present invention will be described in detail below through specific embodiments and accompanying drawings. It should be pointed out that these descriptions are only exemplary descriptions and do not limit the scope of the present invention. Many variations and modifications of the present invention will be obvious to those skilled in the art from the discussion of this specification.

Description of drawings

Figure 1 shows the staining photos of the permeability changes of the blood-brain barrier detected by Evans Blue (Evans Blue) staining.

Figure 2 shows the quantitative results of the blood-brain barrier permeability changes detected by Evans blue staining, where the ordinate represents the amount (ng) of Evans blue extracted per mg of brain tissue, where the sign of difference is: **P< 0.01, compared with the sham operation group (Sham); #P<0.05, compared with the model group (TBI).

Figure 3 shows the results of the Cylinder behavior score, where the sign of significant difference: **P<0.01, compared with the sham operation group (Sham); #P<0.05, compared with the model group (TBI).

detailed description

Specific embodiments of the present invention will be described in detail below. It should be noted that the technical features or combinations of technical features described in the following embodiments should not be considered isolated, and they can be combined with each other to achieve better technical effects.

The establishment of embodiment 1 hydraulic brain trauma rat model

The treatment of embodiment 2FGF20 to rats with hydraulic brain injury

Rats were randomly divided into three groups: 1, sham operation group (Sham): except that the hydraulic impact injury was not carried out, all the other treatments were the same as the model group; 2, model group (TBI): the right brain of the rat was established as in Example 1 Trauma model; 3. FGF20-administered group (TBI+FGF20): 0.5 hours after establishing the rat right brain trauma model as in Example 1, FGF20 was injected intraperitoneally at a dose of 1.5 mg/kg.

After 24 hours in the right brain injury model of rats in each group, Evans blue (4%, 3mL/kg) was injected through the tail vein, and the whole brain was taken 3 hours after the injection, and the staining situation of Evans blue in the injured area was photographed ( figure 1). Then the brain was immersed in an equal volume of trichloroacetyl overnight, and the supernatant was collected by centrifugation to measure the content of Evans blue at 620 nm (Figure 2). The results are shown in Figure 1 and Figure 2, indicating that FGF20 can significantly reduce the amount of Evans blue passing through the blood-brain barrier, indicating that FGF20 has a repairing effect on the integrity of the blood-brain barrier.

The rest of the rats were subjected to Cylinder neurological scoring, and the brain damage of the rats was detected from the behavior (Fig. 3). Behavioral scores found that the model group scored 32±2.2, and the FGF20-administered group was 18.7±2.1, indicating that FGF20 can significantly improve the decline in behavioral function caused by hydraulic brain trauma.

Claims (10)

CLAIMS 1. A pharmaceutical composition for treating brain trauma, preferably for repairing the blood-brain barrier of the traumatized brain, comprising fibroblast growth factor 20 (FGF20). 2. The pharmaceutical composition of claim 1, wherein the pharmaceutically active ingredient comprises only FGF20. 3. A pharmaceutical preparation for treating brain trauma (preferably for repairing the blood-brain barrier of the traumatic brain), comprising the pharmaceutical composition according to claim 1 or 2 and pharmaceutically acceptable auxiliary materials. 4. The pharmaceutical formulation as claimed in claim 3, comprising 6-24 mg FGF20, preferably 12-18 mg FGF20, most preferably 15 mg FGF20. 5. The pharmaceutical preparation according to claim 3, wherein the pharmaceutically acceptable auxiliary material is an injection pharmaceutical preparation auxiliary material. 6. Application of FGF20 in the preparation of medicines for treating brain trauma. 7. The application according to claim 6, wherein the treatment of brain trauma is to repair the blood-brain barrier of the traumatic brain. 8. The use of claim 6, wherein the trauma is hydraulic trauma. 9. The use as claimed in claim 6, wherein the drug is an injectable drug. 10. The application according to claim 6, wherein FGF20 is used alone as the active ingredient of the medicine.