阅读说明：本技术 治疗创伤性脑损伤的方法 (Method for treating traumatic brain injury ) 是由 M·C·德维尔德 R·J·J·哈格曼 于 2017-07-12 设计创作，主要内容包括：本发明涉及一种用于在患有创伤性脑损伤或从创伤性脑损伤中恢复的哺乳动物中产生白质、产生髓磷脂和/或减小脑部病变大小的组合物,包括经肠内给予受试者一种包含治疗有效量的以下成分的组合物：(i)尿苷、胞苷或其盐、磷酸酯、酰基衍生物或酯中的一种或多种；(ii)脂质成分,其包含二十二碳六烯酸(22:6；DHA)、二十碳五烯酸(20:5；EPA)和二十二碳五烯酸(22:5；DPA)中的至少一种,优选至少DHA,更优选DHA和EPA,其中脂质成分包含小于2重量％的α-亚麻酸(ALA),按所有脂肪酸的重量计算；(iii)胆碱或其盐或酯,以及(iv)至少一种选自维生素B6、B9和B12的维生素B。(The present invention relates to a composition for producing white matter, producing myelin, and/or reducing the size of brain lesions in a mammal suffering from or recovering from traumatic brain injury comprising enterally administering to a subject a composition comprising a therapeutically effective amount of (i) one or more of uridine, cytidine, or a salt, phosphate, acyl derivative or ester thereof, (ii) a lipid component comprising docosahexaenoic acid (22: 6; DHA), eicosapentaenoic acid (20: 5; EPA) and docosapentaenoic acid (22: 5; DPA), preferably at least DHA, more preferably DHA and EPA, wherein the lipid component comprises less than 2% by weight of α -linolenic acid (ALA), based on the weight of all fatty acids, (iii) choline or a salt or ester thereof, and (iv) at least one vitamin B selected from vitamin B6, B9 and B12.)

1. A composition for producing white matter, producing myelin, and/or reducing the size of a brain lesion in a mammal suffering from or recovering from traumatic brain injury comprising enterally administering to a subject a composition comprising a therapeutically effective amount of:

(i) one or more of uridine, cytidine, or a salt, phosphate, acyl derivative, or ester thereof;

(ii) a lipid fraction comprising at least one of docosahexaenoic acid (22: 6; DHA), eicosapentaenoic acid (20: 5; EPA) and docosapentaenoic acid (22: 5; DPA), preferably at least DHA, more preferably DHA and EPA,

wherein the lipid component comprises less than 2% by weight of α -linolenic acid (ALA), based on the weight of all fatty acids;

(iii) choline or a salt or ester thereof, and

(iv) at least one vitamin B selected from the group consisting of vitamin B6, B9, and B12.

2. The composition for the use according to claim 1, wherein the lipid fraction comprises medium chain fatty acids, wherein the sum of medium chain fatty acids C6:0+ C7:0+ C8:0 is less than 2:1 compared to the sum of C9:0 and C10: 0.

3. The composition for use according to claim 1 or 2, wherein the lipid fraction comprises less than 2 wt.% of fatty acids having less than 14 carbon atoms based on total fatty acids.

4. The composition for use according to any one of the preceding claims, wherein the composition further comprises Linoleic Acid (LA) in an amount of less than 15g per 100g of fatty acids.

5. The composition for use according to any one of the preceding claims, comprising (iv) at least two vitamin bs selected from the group consisting of vitamin B6, B9 and B12.

6. The composition for the use according to claim 5, comprising (iv) vitamins B6, B9 and B12.

7. The composition for use according to any one of the preceding claims, comprising 500-5000mg dha + EPA per day.

8. The composition for use according to any of the preceding claims, wherein composition comprises 100 to 6000mg daily of one or more of uridine, cytidine, or a salt, phosphate, or ester thereof, calculated as uridine and cytidine; preferably 100-6000mg of uridine or salts, phosphates or esters thereof per day, calculated as uridine.

9. The composition for use according to any one of the preceding claims, wherein the composition comprises more than 50mg daily of choline or a salt or ester thereof, calculated as choline.

10. The composition for use according to any of the preceding claims, wherein the composition further comprises a therapeutically effective amount of at least one and more preferably at least two antioxidants vitamin C, vitamin E and selenium.

11. The composition for use according to any one of the preceding claims, wherein the composition further comprises at least one phospholipid.

12. The composition for use according to any one of the preceding claims, wherein the composition comprises per 100ml of liquid:

100-500mg EPA，

1000-1500mg DHA，

80-600mg of a phospholipid,

200-600mg of choline (choline) was added,

400-800mg Uridine Monophosphate (UMP),

20-60mg of α -TE (vitamin E),

60-100mg of vitamin C, and the vitamin C,

40-80 mug of selenium,

1-5 mug of vitamin B12,

0.5-2mg vitamin B6, and

200-600. mu.g folic acid.

13. The composition for use according to any one of the preceding claims, wherein the composition is administered to the mammal starting within 1 month of being diagnosed with TBI.

14. The composition for use according to any one of the preceding claims, for increasing the rate of recovery from traumatic brain injury.

15. Use of a composition for the manufacture of a product for producing white matter, producing myelin, and/or reducing the size of a brain lesion in a mammal suffering from or recovering from traumatic brain injury, wherein the product is enterally administered, wherein the product comprises therapeutically effective amounts of:

(i) one or more of uridine, cytidine, or a salt, phosphate, acyl derivative, or ester thereof;

(ii) a lipid fraction comprising at least one of docosahexaenoic acid (22: 6; DHA), eicosapentaenoic acid (20: 5; EPA) and docosapentaenoic acid (22: 5; DPA), wherein the lipid fraction comprises less than 2 wt.% α -linolenic acid (ALA), by weight of all fatty acids;

(iii) choline or a salt or ester thereof, and

(iv) at least one vitamin B selected from the group consisting of vitamin B6, B9, and B12.

16. Use according to claim 15 for increasing the rate of recovery from traumatic brain injury.

17. A method of producing white matter, producing myelin, and/or reducing the size of a brain lesion in a mammal suffering from or recovering from traumatic brain injury, said method comprising enterally administering a product comprising therapeutically effective amounts of:

(i) one or more of uridine, cytidine, or a salt, phosphate, acyl derivative, or ester thereof;

(ii) a lipid fraction comprising at least one of docosahexaenoic acid (22: 6; DHA), eicosapentaenoic acid (20: 5; EPA) and docosapentaenoic acid (22: 5; DPA), wherein the lipid fraction comprises less than 2 wt.% α -linolenic acid (ALA), by weight of all fatty acids;

(iii) choline or a salt or ester thereof, and

(iv) at least one vitamin B selected from the group consisting of vitamin B6, B9, and B12.

18. A kit for producing white matter, producing myelin, and/or reducing the size of a brain lesion in a mammal suffering from or recovering from traumatic brain injury, the kit comprising a container having therapeutically effective amounts of:

(i) one or more of uridine, cytidine, or a salt, phosphate, acyl derivative, or ester thereof;

(ii) a lipid fraction comprising at least one of docosahexaenoic acid (22: 6; DHA), eicosapentaenoic acid (20: 5; EPA) and docosapentaenoic acid (22: 5; DPA), wherein the lipid fraction comprises less than 2 wt.% α -linolenic acid (ALA), by weight of all fatty acids;

(iii) choline or a salt or ester thereof, and

(iv) at least one vitamin B selected from the group consisting of vitamin B6, B9, and B12.

19. Use of a kit for the manufacture of a product for producing white matter, producing myelin, and/or reducing the size of a brain lesion in a mammal suffering from or recovering from traumatic brain injury, the kit comprising a container having therapeutically effective amounts of:

(i) one or more of uridine, cytidine, or a salt, phosphate, acyl derivative, or ester thereof;

(ii) a lipid fraction comprising at least one of docosahexaenoic acid (22: 6; DHA), eicosapentaenoic acid (20: 5; EPA) and docosapentaenoic acid (22: 5; DPA), wherein the lipid fraction comprises less than 2 wt.% α -linolenic acid (ALA), by weight of all fatty acids;

(iii) choline or a salt or ester thereof, and

(iv) at least one vitamin B selected from the group consisting of vitamin B6, B9, and B12.

Technical Field

The present invention is in the field of medical nutrition and more specifically relates to nutritional compositions for the treatment and recovery of traumatic brain injury and symptoms associated therewith.

Background

Traumatic Brain Injury (TBI) is a form of non-degenerative acquired brain injury. TBI is a serious medical condition that can occur after a major external physical impact to the brain. TBI is the leading cause of disability and death in people under the age of 45, with about 1000 million new cases worldwide each year.

According to the diagnostic criteria detailed in the "diagnostic and statistical handbook for mental disorders (DSM-5)", TBI is associated with a unique combination of one or more of the following features: a change in level of consciousness; memory impairment; confusion associated with orientation defects; neurological signs such as neuro-imagewise observable brain damage, new onset or worsening of epilepsy, visual field defects and hemiparesis. While some symptoms may appear immediately after injury, other symptoms may develop over time, consistent with the anatomical changes of the neural matrix after injury.

The major phase of TBI describes direct damage to brain tissue by contusion or hypoxia caused by the spherical mass effect. Only through improved prevention can primary damage by TBI be alleviated. Secondary injury begins immediately after trauma and underlies the functional deficits associated with TBI. It then occurs through mechanisms such as reperfusion injury, delayed cortical edema, Blood Brain Barrier (BBB) disruption, glutaminergic hyperexcitability, and local electrolyte imbalance. These disorders themselves lead to Reactive Oxygen Species (ROS) -mediated neurodegeneration through calcium release, glutamate toxicity, lipid peroxidation, and mitochondrial dysfunction. This secondary injury may occur in the brain adjacent to the site of the injury originally intended, and may result in an unintended enlargement of the injury area within months after the injury. Damage caused by this complex cascade of cellular, neurochemical, inflammatory and metabolic events may lead to neuronal loss, dendritic changes, axonal and synaptic changes and persistent white matter abnormalities. Currently, no treatment is available to address such adverse consequences. Therefore, the development of effective therapeutic interventions to protect the brain and promote repair after TBI is a particularly urgent task.

WO 2012/125034 relates to improving nerve survival following neurological injury caused by external forces, for example following traumatic brain injury.

One important problem caused by TBI is white matter loss or spread, leading to cognitive dysfunction. Refer to Cristospori et al "White and gray matrix distributions to an executive functional recovery after intake", Neurology (2015) volume 84(14), page 1394-. CN103371993 describes the use of omega-3 fatty acids in the treatment of traumatic brain injury, which has an effect on both lesion size and white matter (by monitoring the fluorescence intensity of MBP), but the effect is still limited. Accordingly, there remains a need in the art for improved treatments for TBI.

Disclosure of Invention

The inventors observed that after TBI, the lesion size was reduced (figure 1) and white matter was produced (figure 2) after administration of a product comprising (i) one or more of uridine and cytidine, or salts, phosphates, acyl derivatives or esters thereof, (ii) a lipid component comprising at least one of docosahexaenoic acid (22: 6; DHA), eicosapentaenoic acid (20: 5; EPA) and docosapentaenoic acid (22: 5; DPA) or esters thereof, wherein the lipid component comprises less than 2 wt.% α -linolenic acid (ALA), calculated on the weight of all fatty acids, (iii) choline or a salt or ester thereof, and (iv) at least one vitamin B selected from the group consisting of vitamin B6, B9 and B12.

Figure 2 herein shows that the intervention of the invention shows a greater increase in myelin production compared to the results obtained in CN103371993 with DHA: the level of CCI-FC with the intervention of the invention was almost the same as that observed in the craniotomy group (Cranio-control), whereas the TBI intervention control group (CCI control) had significantly lower Myelin Basic Protein (MBP); in contrast, in figures 6D and 6E of CN103371993, mean MBP intensity is shown for craniotomy group (sham group, white bands), TBI intervention group (RD-CCI, grey bands) and TBI intervention group treated with fish oil diet containing DHA (FOD-CCI, black bands). When the results of the craniotomy group of the invention (cranio-control group) were set to 1, the CCI-FC was about 0.9 (in contrast, the CCI control group was 0.7), whereas these values in fig. 6 in CN103371993 were 1 and about 0.5 and 0.65, respectively. Thus, the effect obtained by the intervention of the invention showed an almost complete recovery of myelin levels compared to the control group levels, whereas in the FOD-CCI group of CN103371993 there was only a slight improvement compared to the TBI intervention group (RD-CCI) and there was no recovery to the levels detected in the craniotomy group (sham).

Thus, according to one embodiment, the composition comprises:

i) one or more of uridine and cytidine, or salts, phosphates, acyl derivatives or esters thereof;

ii) a lipid fraction comprising at least one of docosahexaenoic acid (22: 6; DHA), eicosapentaenoic acid (20: 5; EPA) and docosapentaenoic acid (22: 5; DPA) or esters thereof, wherein the lipid fraction comprises less than 2 wt.% α -linolenic acid (ALA), based on the weight of all fatty acids;

iii) choline or a salt or ester thereof, and

iv) at least one vitamin B selected from the group consisting of vitamin B6, B9 and B12,

it is useful for the production of white matter, the production of myelin, and the reduction of brain lesion size in mammals suffering from or recovering from traumatic brain injury. The composition is preferably administered enterally (preferably orally).

In this connection, the invention also relates to the use of a composition comprising (i) to (iv) as defined above for the preparation of a product for the production of white matter, the production of myelin and the reduction of the size of brain lesions in a mammal suffering from or recovering from traumatic brain injury. In other words, the present invention also relates to a method for producing white matter, producing myelin and reducing the size of brain lesions in a mammal suffering from or recovering from traumatic brain injury, said method comprising enterally (preferably orally) administering to said mammal a composition comprising (i) - (iv) as defined above.

Although each of the active ingredients (i) - (iv) is suitably administered enterally (preferably orally) in the form of a single composition, it may also be administered in separate dosage units. Thus, the invention also relates to kits of parts comprising (i) - (iv), respectively, together for the production of white matter, the production of myelin and the reduction of brain lesion size in a mammal suffering from or recovering from traumatic brain injury.

Components (i), (ii), (iii), and (iv), as well as other optional components, are described in detail below.

In one aspect, the invention relates to compositions comprising (i), (ii), (iii) and (iv) and other optional ingredients for increasing the recovery rate of TBI, with respect to improved white matter production, improved myelin production, and reduced brain lesion size.

Drawings

Figure 1 shows the effect of dietary intervention on lesion size and white matter in a TBI mouse model. In adult male mice, Controlled Cortical Impingement (CCI) was induced as a TBI model or control craniotomy (sham-lesion) injury. Animals were divided into three experimental groups (craniotomy control group [ white band ], CCI-control group [ dark gray ] and CCI-FC [ light gray ]) treated with either control diet or intervention diet (FC):

(A) representative coronal sections stained with H & E showed lesion size differences between the three groups.

(B) Quantification of lesion size at 70 days post TBI showed a significant reduction in lesion size in CCI-FC mice compared to CCI control mice (one-way anova P < 0.01; Bonferroni multiple comparison post-test;. ＊ P < 0.001.) lesion size was calculated as (contralateral hemisphere-ipsilateral hemisphere)/contralateral hemisphere and expressed as a percentage.

Figure 2 shows the effect of TBI and treatment with compositions effective in treating TBI on myelin content:

(A) representative images of coronary brain tissue sections stained with rockwell Fast blue (LFB) for myelin. Note the differences in staining of the Inner Capsule (IC), Globus Pallidus (GP) -lateral segment, tail-putamen (CP) and Corpus Callosum (CC) regions (rectangular and enlarged specific regions). On the ipsilateral and contralateral sides of the injury site, myelin-stained nerve bundles appeared to be continuous in the CCI-FC group and the craniotomy control group compared to the dashed images seen in the CCI-control group.

(B) Myelin Basic Protein (MBP) levels by western blot MBP expression was significantly higher in the CCI-FC and craniotomy control groups (one-way anova P < 0.001; Bonferroni multiple comparison post test ＊ P <0.001) compared to the CCI-control group mice, legend identical to fig. 1B.

List of embodiments

1. A composition for producing white matter, producing myelin, and/or reducing the size of a brain lesion in a mammal suffering from or recovering from traumatic brain injury comprising enterally administering to a subject a composition comprising a therapeutically effective amount of:

(i) one or more of uridine, cytidine, or a salt, phosphate, acyl derivative, or ester thereof;

(ii) a lipid fraction comprising at least one of docosahexaenoic acid (22: 6; DHA), eicosapentaenoic acid (20: 5; EPA) and docosapentaenoic acid (22: 5; DPA), preferably at least DHA, more preferably DHA and EPA,

wherein the lipid component comprises less than 2% by weight of α -linolenic acid (ALA), based on the weight of all fatty acids;

(iii) choline or a salt or ester thereof, and

(iv) at least one vitamin B selected from the group consisting of vitamin B6, B9, and B12.

2. The composition for use according to embodiment 1, wherein the lipid component comprises medium chain fatty acids, wherein the sum of medium chain fatty acids C6:0+ C7:0+ C8:0 is less than 2:1 compared to the sum of C9:0 and C10: 0.

3. The composition for use according to embodiment 1 or 2, wherein the lipid fraction comprises less than 2 wt.% of fatty acids having less than 14 carbon atoms based on total fatty acids.

4. The composition for use according to any one of the preceding embodiments, wherein the composition further comprises Linoleic Acid (LA) in an amount of less than 15g per 100g of fatty acids.

5. The composition for the use according to any one of the preceding embodiments, comprising (iv) at least two vitamin bs selected from the group consisting of vitamin B6, B9 and B12.

6. The composition for the use according to embodiment 5, comprising (iv) vitamins B6, B9 and B12.

7. The composition for use according to any of the preceding embodiments, comprising 500 + EPA + 5000mg DHA + EPA per day.

8. The composition for use according to any one of the preceding embodiments, wherein the composition comprises 100 to 6000mg daily of one or more of uridine, cytidine, or a salt, phosphate, or ester thereof, calculated as uridine and cytidine; preferably 100-6000mg uridine or a salt, phosphate or ester thereof per day, calculated as uridine.

9. The composition for use according to any one of the preceding embodiments, wherein the composition comprises more than 50mg choline or a salt or ester thereof per day, calculated as choline.

10. The composition for use according to any one of the preceding embodiments, wherein the composition further comprises a therapeutically effective amount of at least one and more preferably at least two antioxidants vitamin C, vitamin E and selenium.

11. The composition for use according to any one of the preceding embodiments, wherein the composition further comprises at least one phospholipid.

12. The composition for use according to any one of the preceding embodiments, wherein the composition comprises per 100ml of liquid:

100-500mg EPA，

1000-1500mg DHA，

80-600mg of a phospholipid,

200-600mg of choline (choline) was added,

400-800mg Uridine Monophosphate (UMP),

20-60mg of α -TE (vitamin E),

60-100mg of vitamin C, and the vitamin C,

40-80 mug of selenium,

1-5 mug of vitamin B12,

0.5-2mg vitamin B6, and

200-600. mu.g folic acid.

13. The composition for use according to any one of the preceding embodiments, wherein the composition is administered to the mammal starting within 1 month of being diagnosed with TBI.

14. The composition for use according to any one of the preceding embodiments, for use in increasing the rate of recovery from traumatic brain injury.

15. Use of a composition for the manufacture of a product for producing white matter, producing myelin, and/or reducing the size of a brain lesion in a mammal suffering from or recovering from traumatic brain injury, wherein the product is enterally administered, wherein the product comprises therapeutically effective amounts of:

(i) one or more of uridine, cytidine, or a salt, phosphate, acyl derivative, or ester thereof;

(ii) a lipid fraction comprising at least one of docosahexaenoic acid (22: 6; DHA), eicosapentaenoic acid (20: 5; EPA) and docosapentaenoic acid (22: 5; DPA), wherein the lipid fraction comprises less than 2 wt.% α -linolenic acid (ALA), by weight of all fatty acids;

(iii) choline or a salt or ester thereof, and

(iv) at least one vitamin B selected from the group consisting of vitamin B6, B9, and B12.

16. The use according to embodiment 15, for increasing the rate of recovery from traumatic brain injury.

17. A method of producing white matter, producing myelin, and/or reducing the size of a brain lesion in a mammal suffering from or recovering from traumatic brain injury, said method comprising enterally administering a product comprising therapeutically effective amounts of:

(i) one or more of uridine, cytidine, or a salt, phosphate, acyl derivative, or ester thereof;

(ii) a lipid fraction comprising at least one of docosahexaenoic acid (22: 6; DHA), eicosapentaenoic acid (20: 5; EPA) and docosapentaenoic acid (22: 5; DPA), wherein the lipid fraction comprises less than 2 wt.% α -linolenic acid (ALA), by weight of all fatty acids;

(iii) choline or a salt or ester thereof, and

(iv) at least one vitamin B selected from the group consisting of vitamin B6, B9, and B12.

18. A kit for producing white matter, producing myelin, and/or reducing the size of a brain lesion in a mammal suffering from or recovering from traumatic brain injury, the kit comprising a container having therapeutically effective amounts of:

(i) one or more of uridine, cytidine, or a salt, phosphate, acyl derivative, or ester thereof;

(ii) a lipid fraction comprising at least one of docosahexaenoic acid (22: 6; DHA), eicosapentaenoic acid (20: 5; EPA) and docosapentaenoic acid (22: 5; DPA), wherein the lipid fraction comprises less than 2 wt.% α -linolenic acid (ALA), by weight of all fatty acids;

(iii) choline or a salt or ester thereof, and

(iv) at least one vitamin B selected from the group consisting of vitamin B6, B9, and B12.

19. Use of a kit for the manufacture of a product for producing white matter, producing myelin, and/or reducing the size of a brain lesion in a mammal suffering from or recovering from traumatic brain injury, the kit comprising a container having therapeutically effective amounts of:

(i) one or more of uridine, cytidine, or a salt, phosphate, acyl derivative, or ester thereof;

(ii) a lipid fraction comprising at least one of docosahexaenoic acid (22: 6; DHA), eicosapentaenoic acid (20: 5; EPA) and docosapentaenoic acid (22: 5; DPA), wherein the lipid fraction comprises less than 2 wt.% α -linolenic acid (ALA), by weight of all fatty acids;

(iii) choline or a salt or ester thereof, and

(iv) at least one vitamin B selected from the group consisting of vitamin B6, B9, and B12.