TWI796023B - Pharmaceutical compositions and uses thereof - Google Patents

Abstract

The present invention provides a pharmaceutical composition containing a herbal mixture of at least two of the following ingredients: zingiber officinale; codonopsis pilosula; wolfiporia extensa; citrus reticulate blanco; and atractylodes macrocephala. Also provided uses of treating or reducing alcohol hangover, liver, kidney and gastrointestinal tract injuries, by administering an effective amount of the pharmaceutical composition disclosed herein.

Description

Pharmaceutical composition and its use

The invention relates to a novel pharmaceutical composition for treating or reducing alcohol hangover, liver, kidney and gastrointestinal tract damage.

Alcohol-induced hangover is the most commonly reported adverse effect of excessive alcohol consumption and occurs when the blood alcohol concentration (BAC) returns to almost zero. Since ethanol is miscible with water, it will target water-rich tissues, such as the brain, where it will cause familiar symptoms such as generalized pain, headache, tiredness, concentration problems, thirst, dizziness , nausea, cognitive impairment, and mood changes. Alcohol hangovers can lead to workplace absenteeism, impaired job performance, decreased productivity, poor academic performance, and can jeopardize potentially dangerous everyday activities, such as driving a car or operating heavy machinery. These socioeconomic consequences and health risks of alcohol hangovers are much higher when compared to various common diseases and other health risk factors.

The search for a cure for alcohol-induced damage and side effects, including hangovers, is as old as alcohol itself. There are many cures and preventatives available, but scientific evidence of their effectiveness is generally lacking.

Therefore, there is a need for methods and compositions that can rapidly reduce the symptoms of elevated blood alcohol concentration (BAC) or quickly regain sobriety after drinking, or reduce or prevent the symptoms of drinking. The present invention addresses this need and others.

In one embodiment, the present invention discloses a pharmaceutical composition comprising (1) a herbal mixture comprising at least two herbs selected from the group consisting of: dried ginger; Codonopsis pilosula; Poria cocos; tangerine peel and Atractylodes macrocephala; and ( 2) A pharmaceutically acceptable carrier.

In another embodiment, there is provided a pharmaceutical composition comprising: (1) a herbal mixture comprising Codonopsis pilosula; Poria cocos and tangerine peel; and (2) a pharmaceutically acceptable carrier.

In another embodiment, there is provided a pharmaceutical composition comprising: (1) a herbal mixture comprising dried ginger; Codonopsis pilosula; Poria cocos; tangerine peel and Atractylodes macrocephala; and (2) a pharmaceutically acceptable carrier.

Also included is the use of a pharmaceutical composition described herein for the manufacture of a medicament for treating or reducing the effects of alcohol consumption.

It also includes the use of the pharmaceutical composition described herein in the preparation of medicines for treating or reducing liver cell inflammation and fat accumulation.

It also includes the use of the pharmaceutical composition described herein in the preparation of medicines for treating or reducing small intestinal mucosal or intestinal function damage.

It also includes the use of the pharmaceutical composition described herein in the preparation of medicines for treating or reducing glomerular damage or renal function damage.

Also provided are methods of treating or reducing the effects of alcohol consumption in a subject in need thereof by administering a pharmaceutical composition described herein.

The terms "invention" and "present invention" used in this patent are intended to refer broadly to all subject matter of this patent and the claims of the following patent applications. Statements containing these terms should be understood not to limit the subject matter described herein or to limit the meaning or scope of the claims of the following patent applications. Embodiments of the invention covered by this patent are defined by the following claims, not this summary. This Summary is a high-level overview of various aspects of the invention, and introduces some that are further described in the following Embodiments section. concept. This Summary is not intended to identify key or essential features of the claimed subject matter, nor is it intended to be used in isolation to determine the scope of the claimed subject matter. The subject matter should be understood by reference to appropriate portions of the entire specification, any or all drawings and each claim.

When reading the following drawings and embodiments, the present invention will become more clear.

Fig. 1 is a line graph illustrating the effect of the pharmaceutical composition of the present invention on the body weight of mice.

2 and 3 are histograms illustrating the effects of the pharmaceutical composition of the present invention on the liver/body weight ratio and kidney/body weight ratio of mice.

Figure 4 and Figure 5 are histograms illustrating the effect of the pharmaceutical composition of the present invention on serum liver function (AST and ALT) levels in mice.

6 and 7 are histograms illustrating the effects of the pharmaceutical composition of the present invention on serum levels of total cholesterol (T-CHO) and triglyceride (TG) in mice.

Figure 8 is a histogram illustrating the effect of the pharmaceutical composition of the present invention on serum glucose levels in mice.

9 and 10 are histograms illustrating the effects of the pharmaceutical composition of the present invention on the levels of total cholesterol (T-CHO) and triglyceride (TG) in the liver of mice.

Fig. 11 is a histogram illustrating the steatosis score of mice with alcoholic liver disease treated by the pharmaceutical composition of the present invention.

Figure 12 is a histogram illustrating the effect of one embodiment of a pharmaceutical composition of the present invention on field sobriety test performance.

Figure 13 is a histogram illustrating the effect of one embodiment of the pharmaceutical composition of the present invention on alcohol-induced symptoms 1 hour after drinking alcohol.

Figure 14 is a histogram illustrating the effect of one embodiment of the pharmaceutical composition of the present invention on alcohol-induced symptoms 2 hours after drinking alcohol.

Figure 15 is a histogram illustrating the effect of one embodiment of the pharmaceutical composition of the present invention on alcohol-induced symptoms 24 hours after drinking alcohol.

16A to 16C are histograms illustrating the effect of one embodiment of the pharmaceutical composition of the present invention on liver function tests (AST, ALT, and γ-GT).

Figures 17A and 17B are histograms illustrating the effect of one embodiment of a pharmaceutical composition of the present invention on renal function tests (aldosterone and creatinine).

Figure 18 is a histogram illustrating the effect of one embodiment of the pharmaceutical composition of the present invention on glucose-6-phosphate dehydrogenase (G6PD).

Figure 19 is a collection of images of hematoxylin and eosin staining (H and E), showing alcohol-induced damage to the jejunal villi (Panel B) and an embodiment of the pharmaceutical composition of the present invention reduces alcohol-induced damage to the small intestinal capsule damage (C to E).

Figure 20 is a collection of H and E images showing alcohol-induced glomerular damage (Panel B) and an embodiment of the pharmaceutical composition of the present invention reduces alcohol-induced glomerular damage (Panel C to E) .

definition

As employed above and throughout this disclosure, unless otherwise indicated, the following terms shall be understood to have the following meanings.

As used herein, the singular terms "a" and "the" include plural referents unless the context clearly dictates otherwise.

As used herein, "effective amount" includes sufficient to treat or ameliorate at least one Or the dosage of the pharmaceutical composition of the symptom caused by BAC elevation.

As used herein, the term "treatment" refers to palliative purposes or results, and/or slowing or inhibiting the development of alcohol-induced symptoms or signs.

As used herein, the term "individual" generally refers to a human or animal having or suspected of having symptoms due to alcohol consumption or elevated BAC. Individuals who are about to consume alcohol, whether or not they have symptoms or signs of alcohol consumption or elevated BAC, are also included within the term "individual".

All numbers herein are understood to be modified by "about". As used herein, the term "about" is meant to encompass a variation of ±10%.

In one embodiment, the present invention discloses a pharmaceutical composition comprising (1) a herbal mixture comprising at least two herbs selected from the group consisting of: dried ginger; Codonopsis pilosula; Poria cocos; tangerine peel and Atractylodes macrocephala; and ( 2) A pharmaceutically acceptable carrier.

In an exemplary embodiment, the herbal mixture includes dried ginger and Codonopsis pilosula. In an exemplary embodiment, the herbal mixture comprises Codonopsis Codonopsis and Poria cocos. In an exemplary embodiment, the herbal mixture includes Poria and Tangerine Peel. In an exemplary embodiment, the herbal mixture comprises tangerine peel and atractylodes macrocephala. In an exemplary embodiment, the herbal mixture includes dried ginger and Poria cocos. In an exemplary embodiment, the herbal mixture includes dried ginger and tangerine peel. In an exemplary embodiment, the herbal mixture includes dried ginger and Atractylodes macrocephala. In an exemplary embodiment, the herbal mixture includes Codonopsis Codonopsis and Tangerine Peel. In an exemplary embodiment, the herbal mixture comprises Codonopsis Codonopsis and Atractylodes macrocephala. In an exemplary embodiment, the herbal mixture comprises Poria cocos and Atractylodes macrocephala.

In another embodiment, the present invention discloses a pharmaceutical composition comprising (1) a mixture of herbs, the mixture comprising at least three herbs selected from the group consisting of: dried ginger; Codonopsis pilosula; Poria cocos; Tangerine peel and Atractylodes macrocephala; and ( 2) A pharmaceutically acceptable carrier.

In an exemplary embodiment, the herbal mixture includes dried ginger, Codonopsis pilosula, and Poria cocos. In an exemplary embodiment, the herbal mixture comprises Codonopsis Codonopsis, Poria cocos and Tangerine peel. In an exemplary embodiment, the herbal mixture comprises Poria cocos, Tangerine peel and Atractylodes macrocephala. In an exemplary embodiment, the herbal mixture includes tangerine peel, atractylodes macrocephala and dried ginger. In an exemplary embodiment, the herbal mixture includes dried ginger, tangerine peel and Atractylodes macrocephala. In an exemplary embodiment, the herbal mixture includes dried ginger, Codonopsis pilosula and Tangerine peel. In an exemplary embodiment, the herbal mixture includes dried ginger, Poria cocos and Atractylodes macrocephala. In an exemplary embodiment, the weight ratio of Codonopsis pilosula : Tangerine peel : Poria cocos in the herbal mixture is about 25-35%: 25-35%: 30-50%.

In an exemplary embodiment, the herbal mixture comprises dried ginger, Codonopsis pilosula and Atractylodes macrocephala. In an exemplary embodiment, the herbal mixture includes dried ginger, Poria cocos and Atractylodes macrocephala.

In an exemplary embodiment, the herbal mixture includes Codonopsis Codonopsis, Tangerine Peel, and Atractylodes Rhizome. In an exemplary embodiment, the herbal mixture comprises Codonopsis Codonopsis, Poria cocos and Atractylodes macrocephala.

In another embodiment, the present invention discloses a pharmaceutical composition, which comprises (1) a herbal mixture comprising dried ginger; Codonopsis pilosula; Poria cocos; tangerine peel and Atractylodes macrocephala; and (2) a pharmaceutically acceptable carrier.

In an exemplary embodiment, the herbal extract comprises about 5-15% by weight dried ginger. In an exemplary embodiment, the herbal extract comprises about 15-25% Codonopsis pilosula by weight. In an exemplary embodiment, the herbal extract comprises about 25-35% by weight Poria cocos. In an exemplary embodiment, the herbal extract comprises about 15-25% by weight of tangerine peel. In an exemplary embodiment, the herbal extract comprises about 10-20% by weight Atractylodes macrocephala. In an exemplary embodiment, the herbal extract comprises about 20-25% by weight Codonopsis pilosula; about 30-35% by weight Poria cocos; about 20-25% by weight tangerine peel; about 15-18% by weight Atractylodes macrocephala and Contains about 6-12% by weight of dried ginger.

In an exemplary embodiment, the herbal mixture is dry powder or lyophilized powder of at least two of the listed herbs (ie, dried ginger; Codonopsis pilosula; Poria cocos; Tangerine peel and Atractylodes macrocephala). In an exemplary embodiment, the herbal mixture is an aqueous or alcoholic extract of at least two of the listed herbs (ie, dried ginger; Codonopsis pilosula; Poria cocos; Tangerine peel and Atractylodes macrocephala).

The herbal medicine in the herbal medicine mixture can be the original herbal medicine, dry powder, freeze-dried powder, ground powder, decoction, water or alcohol crude extract or extract granule of the original herbal medicine. In an exemplary embodiment, the herbal mixture is prepared by aqueous extraction, wherein the raw herbs (optionally ground prior to extraction for optimal extraction results) are heated in water or a solvent, followed by filtration, concentration (wherein the liquid extraction The material is condensed by vacuum or low pressure concentration).

The National Institute on Alcohol Abuse and Alcoholism lists varying degrees of impairment as blood alcohol concentration (BAC) increases:

Mild impairment (BAC between 0.0-0.05%): mild impairment of speech, memory, attention, coordination and balance, relaxation and drowsiness.

Moderate impairment (BAC level between 0.06-0.15%): increased risk of aggression, further impairment of speech, memory, attention, coordination, balance, and driving skills.

Severe impairment (BAC level between 0.16-0.30%): significant impairment of speech, memory, attention, coordination, balance, judgment and decision-making, confusion, fainting, nausea and vomiting, loss of consciousness, mood changes, irregular breathing

Life-threatening (alcohol overdose, BAC 0.31-0.45%): confusion, loss of consciousness, seizures, and hypothermia.

A hangover refers to a group of symptoms that occur as a result of excessive alcohol consumption. Typical symptoms include fatigue, weakness, thirst, headache, muscle aches, nausea, stomach pain, dizziness, sensitivity to light and sound, anxiety, irritability, sweating, and increased blood pressure.

For example, it is desirable to administer the pharmaceutical composition before, during, or shortly after social drinking of any amount of alcohol to reduce symptoms and signs of elevated BAC and to enable rapid sobriety in the drinker. It is also desirable to administer pharmaceutical compositions for the treatment and prevention of gastrointestinal and urinary system damage, such as liver, kidney or intestinal damage.

The present invention provides methods of reducing or treating the effects of alcohol consumption in a subject in need thereof by administering a pharmaceutical composition described herein.

Non-limiting examples of the effects of alcohol consumption include symptoms, signs of elevated blood alcohol levels, or alcohol hangovers.

Pharmaceutical compositions can be formulated or prepared readily using a mixture of herbs and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers may contain physiologically acceptable compounds, which serve, for example, to stabilize or increase or decrease the rate of absorption or clearance of the pharmaceutical composition of the invention. Physiologically acceptable compounds may include, for example, carbohydrates, such as glucose, sucrose, or polydextrose; antioxidants, such as ascorbic acid or glutathione; chelating agents; low molecular weight proteins; detergents; liposomal vehicles; or other stabilizers and / or buffer. Such preparations can be prepared by various techniques, including combining herbal mixtures with appropriate A pharmaceutically acceptable carrier (such as a liquid carrier, a solid carrier or both) is combined.

The pharmaceutical compositions provided herein optionally include antioxidants, buffers, bacteriostats, suspending agents, thickeners, preservatives, co-solvents, and thickeners or other therapeutic ingredients for the treatment of alcohol disorders, such as calcium acamprosate ( acamprosate), gabapentin (trade name NEURONTIN) or topiramate (trade name topamax). The carrier and other therapeutic ingredients must be acceptable in the sense of being compatible with the pharmaceutical composition and not injurious to the subject.

The pharmaceutical composition is administered in an amount effective to reduce symptoms or signs of elevated BAC in a subject. The dosage of the pharmaceutical composition administered will depend on the amount of alcohol consumed and other clinical factors such as the weight and general condition of the individual and the route of administration. Useful dosages of the pharmaceutical compositions provided herein are determined by comparing their in vitro activity and in vivo activity in animal models. Methods for extrapolating effective doses in mice and other animals to humans are known in the art; see, eg, US Patent No. 4,938,949, which is incorporated herein by reference.

According to the methods provided herein, the pharmaceutical compositions are delivered by any of a variety of routes, including but not limited to injection (e.g., subcutaneous, intramuscular, intravenous, intraarterial, intraperitoneal, intradermal, intravitreal); dermal ; Transdermal; Transdermal; Oral (e.g., lozenge, powder, pill, lozenge, capsule, liquid, edible film strip, or any dosage form suitable for herbal medicine); Implantable osmotic pump; Suppository; Aerosol Spray; topical; eyes; nasal inhalation; lung inhalation or inhalation into skin. In one embodiment, the pharmaceutical composition of the present invention may be administered orally in the form of an aqueous extract.

Pharmaceutical compositions can be administered as a single dose treatment or as multiple dose treatments over a period of time. The pharmaceutical composition may conveniently be administered at appropriate intervals, for example once a day, twice a day, three times a day, four times a day, six times a day, every other day, every three days.

The methods described herein also encompass research methods and uses, including in vitro and in vivo methods of treating or reducing the effects of alcohol consumption in a subject after consuming any amount of alcohol.

Embodiments of the invention are illustrated by the following examples, which should not be construed in any way as limiting the scope of the invention. During the studies described in the following examples, conventional procedures were followed unless otherwise stated. For illustrative purposes, some procedures are described below.

example

Example 1: A case study on the effects of a pharmaceutical composition on mice

The purpose of this study is to study the protective effect of pharmaceutical compositions S1~S11 on improving alcoholic liver injury in a mouse model of alcoholic liver disease. The ingredients of pharmaceutical compositions S1~S11 are shown in Table 1 below ("○" means that the ingredients exist) .

1. Alcoholic liver disease in mice

Fifty-two eight-week-old C57BL/6 male mice were adapted to a pair-fed liquid diet (the control diet contained no alcohol) for one week, and then the mice were divided into alcohol-fed group and pair-fed group (normal control group); the mice in the alcohol-fed group received Lieber-DeCarli liquid diet (high-fat alcohol liquid feed) every day, the alcohol concentration was 1-5% (increased by 1-5% per day), and the mice in the liquid diet The mice were fed with 5% alcohol ad libitum for 5 weeks; the pair-fed mice received a calorie-matched liquid diet (liquid carrier was redistilled water (ddH ₂ O)) as a normal control group for 5 weeks.

2. Treatment

At the beginning of the disease induction period, the vehicle (ddH ₂ O) or the pharmaceutical composition was administered orally (PO) to the mice once a day (QD), and the mice were treated for 35 days or 5 weeks. The dose volume was 12.3 mL/kg (body weight), and day 1 of treatment was denoted as day 0. The experimental design is shown in Table 2 below.

11 groups of pharmaceutical compositions such as S1~S11 were tested on mice with alcoholic liver disease to evaluate the protective effect on alcoholic liver injury. Animals in the first group received a pair-fed liquid diet, while the vehicle (ddH ₂ O) served as the normal control group; animals in the second group received Lieber-DeCarli liquid diet, and the vehicle (ddH ₂ O) served as the disease control group; Animals in group 13 received Lieber-DeCarli liquid diet and pharmaceutical compositions S1-S11 respectively.

Referring to FIG. 1 , a significant decrease in body weight was observed in the alcohol-fed mice; whereas no significant body weight change was observed in the treatment group compared to the vehicle control group (group 2).

With reference to Figure 2 and Figure 3, at the end of the study (the 34th day), the average liver/body weight ratio was 5.78%, while the normal control group (group 1) was 3.55% (p<0.05); and the kidney/body weight ratio The average value was 1.35%, while that of the normal control group (group 1) was 1.01% (p<0.05). It can be seen that the liver/body weight ratio and kidney/body weight ratio of mice fed alcohol were significantly increased.

In addition, with reference to Figure 2, treatment groups S1 (Group 3), S2 (Group 4), S3 (Group 5), S5 (Group 7), S6 (Group 8) or S10 (Group 12) After treatment, the liver/body weight ratio was significantly decreased (p<0.05) compared to the vehicle control group (group 2).

3. Serum Chemistry Measurements

Mice were fasted overnight before blood collection on days 0 and 34, and blood samples were collected 4 hours after the last administration for serum chemistry analysis. Serum chemical parameters include AST (Aspartate aminotransferase, Aspartate aminotransferase), ALT (Alanine aminotransferase, Alanine aminotransferase), total cholesterol (T-CHO), triglyceride (TG) and blood sugar ( GLU), wherein AST, ALT, CHO and TG are measured using a Hitachi 7180 analyzer, and GLU is measured using a blood glucose meter.

Referring to Figure 4 and Figure 5, the blood chemical analysis on the 34th day showed that compared with the normal control group (Group 1), the serum AST and ALT levels of mice fed alcohol were significantly increased, and the AST value was 122.5±29.6U /L, while the normal control group (group 1) was 80.8±3.5U/L; the ALT value was 49.7±6.3U/L, while the normal control group (group 1) was 33.9±3.0U/L (p<0.05 ). However, no significant differences in serum AST and ALT were observed in the treatment group when compared to the vehicle control group (group 2).

Referring to Figure 6, at the beginning of treatment (the 0th day), treatment groups S1 (the 3rd group), S3 (the 5th group), S5 (the 7th group), S7 (the 9th group) or S9 (the 11th group) Serum total cholesterol (T-CHO) levels compared to vehicle controls group (Group 2) was significantly increased (p<0.05); and at the end of the study (Day 34), compared with the normal control group (Group 1), the serum T-CHO level of mice fed alcohol was significantly increased ( p<0.05). However, no significant increase in serum T-CHO was found in the treated group compared to the vehicle control group (group 2).

With reference to Fig. 7, compare with vehicle control group (the 2nd group), treatment group S2 (the 4th group), S3 (the 5th group), S5 (the 7th group), S6 (the 8th group) and S9 (the 11th group) The serum triglyceride (TG) level of the group) was significantly reduced (p<0.05); and at the end of the study (day 34), compared with the normal control group (group 1), serum TG levels of mice fed alcohol The levels were significantly lower (p<0.05); however, no significant changes in serum TG were found in the treated group compared to the vehicle control group (Group 2).

Referring to Figure 8, at the beginning of treatment (Day 0), serum glucose levels in treatment groups S1 (Group 3), S2 (Group 4) or S5 (Group 7) were comparable to those in the vehicle control group (Group 2). at the end of the study (day 34), compared with the vehicle control group (group 2), the serum glucose levels of mice fed alcohol in treatment group S8 (group 10) were significantly decreased (p<0.05).

4. Measurement of liver total cholesterol (T-CHO) and triglyceride levels

At the end of the study on day 34, liver tissues were collected and extracted with PBS; the tissues were analyzed for total cholesterol (T-CHO) and triglycerides (TG) by using a Hitachi 7180 analyzer.

Referring to FIG. 9 and FIG. 10 , the levels of total cholesterol (T-CHO) and triglyceride (TG) in the liver of mice fed alcohol increased. Compared with the vehicle control group (group 2), the hepatic T-CHO levels in the treatment groups S7 (group 9), S8 (group 10), S9 (group 11) and S11 (group 13) were significantly reduced ( p<0.05); while compared with the vehicle control group (group 2), the liver TG level in the treatment group S8 (group 10) was significantly reduced (p<0.05).

5. Liver Enzyme Measurement

The level of glutathione peroxidase (GPx) in the liver was measured by ELISA, and the results are shown in Table 3 below.

6. Microscopic Evaluation

When mice were dissected, tissue samples were collected and preserved in 10% neutral buffered formalin (NBF); (Eosin) staining and microscopic (Leica DM2700M) examination by a veterinary pathologist blinded to the nature of the treatment.

6.1 Semi-quantitative scoring of hepatic steatosis lesions

The severity grading system of hepatic fatty degeneration lesions under the microscope is shown in Table 4 below, and the scores of each group after treatment are shown in Table 5 and Figure 11 below.

Referring to Figure 11, compared with the vehicle control group (group 2), the liver steatosis lesion score of mice fed with the Lieber-DeCarli liquid diet treated by the treatment group S5 (group 7) was significantly reduced (p<0.05; one-way ANOVA); therefore, the results showed that the treatment group S5 (group 7) could protect mice from alcohol-induced liver steatosis and improve liver pathology in the alcoholic liver disease mouse model.

6.2 Semi-quantitative scoring of histopathological observations

According to the reference materials published in Toxicologic Pathology (Shackelfold et al., 2002), the severity grading system criteria for other microscopic lesions (liver, kidney and intestinal tract) are shown in Table 6 below, and the scores of each group after treatment are shown in the table below 7.

As can be seen from Table 7, in the liver, local minimal mononuclear cell infiltration was observed (2/4 male animals in group 1, 3/4 male animals in group 2, 1/4 male animals in group 4 , 3/4 male animals in group 5, 1/4 male animals in group 6, 1/4 male animals in group 7, 3/4 male animals in group 8, 1/4 male animals in group 9 , 1/4 male animals in group 10, 2/4 male animals in group 11, 2/4 male animals in group 12, and 2/4 male animals in group 13). There was no statistical difference in the severity of microscopic changes between the treatment group and the vehicle control group (group 2) (p>0.05; one-way ANOVA).

As can be seen from Table 7, in the kidneys, focal mild chronic progressive nephropathy in the cortex (1/4 male animals in the 4th group), minimal hyperplasia of eosinophils in the cortical renal tubules (1/4 in the 3rd group) were observed in the kidney. /4 male animals), localized minimal eosinophilic hyperplasia in cortical tubules (1/4 male animals in group 5), localized minimal to slight casts in renal tubules (1/4 male animals in group 5 and 1/4 male animals in group 7 male animals), focal minimal dilation of renal tubules (1/4 male animals in group 5 and 1/4 male animals in group 9), and localized minimal mineralization of papillary tubules (1/4 male animals in group 7 animal). There was no statistical difference in the severity of microscopic changes between the treatment group and the vehicle control group (group 2) (p>0.05; one-way ANOVA).

As can be seen from Table 7, in the intestinal tract, focal minimal to slight degeneration/necrosis was observed (1/4 male animals in group 5 and 1/4 male animals in group 10). There was no statistical difference in the severity of microscopic changes between the treatment group and the vehicle control group (group 2) (p>0.05; one-way ANOVA).

Taken together, the overall results indicate that the pharmaceutical composition S5 can protect mice from alcohol-induced increase in hepatic steatosis and improve liver pathology in the aforementioned mouse models.

7. Statistical analysis

All values are expressed as mean ± standard deviation (S.D.) or standard error of the mean (SEM); unpaired Student's t-test (unpaired Student's t-test) was used in the normal group (group 1) and the vehicle group (group 2 groups) were compared, and one-way ANOVA (one-way ANOVA) and Dunnett's test (Dunnett's test) were used to compare the vehicle group (group 2) and other treatment groups (groups 3 to 13) for Statistical Analysis. Differences were considered statistically significant when the p-value was less than 0.05 (p<0.05).

Example 2: Case study on the effects of pharmaceutical compositions on humans

A study involving 25 individual volunteers was carried out to evaluate the effect of the pharmaceutical composition of the invention on elevated BAC. Included in the study were 21 men and 4 women, aged between 31 and 50 years. Table 8 shows the basic demographic details of the selected individuals.

The pharmaceutical composition (hereinafter referred to as "CGW3 formulation") comprises an extract of a herbal mixture comprising about 5-15% by weight of dried ginger; about 15-25% by weight of Codonopsis pilosula; about 25-35% by weight of Poria cocos; about 15-25% by weight of tangerine peel; and about 10-20% by weight of Atractylodes macrocephala.

Each individual was examined under each of the following 3 conditions:

1) Drinking alcohol without taking CGW3 formulation (control setting)

2) Ingest 120ml of CGW3 formulation 30 minutes before drinking and 30 minutes after drinking.

3) Take 120ml of CGW3 formulation once a day 15 days before drinking, and 30 minutes before and 30 minutes after drinking.

Each male subject drank 147ml of alcohol, and each female drank 73.5ml of alcohol. After drinking alcohol, the following examinations and assessments are performed by a neurologist:

(a) Field sobriety tests, including finger-nose test, counting test (counting with eyes closed), and Romberg balance test.

(b) Self-administered questionnaires 1 hour, 2 hours and 24 hours after drinking alcohol. The 1-hour post-drinking questionnaire addresses alcohol-induced hangover symptoms, such as dizziness, fever, sweating, headache, abdominal pain, diarrhea, skin itching and rash, and abdominal pain. The 2-hour post-drinking questionnaire addresses alcohol-induced hangover symptoms, including incoherent speech, altered level of consciousness, confusion, unsteady gait, blurred vision, and hand tremors. The 24-hour alcohol consumption questionnaire addresses the following alcohol-induced hangover symptoms: work performance, decreased concentration or memory, nausea, vomiting, abdominal discomfort, back pain, head and neck pain, dry eyes and discomfort, insomnia, and lethargy.

(c) Serological tests: glucose-6-phosphate dehydrogenase (G6PD), alanine aminotransferase (ALT), aspartate aminotransferase (AST), γ-glutamate aminotransferase ( γ-GT), creatinine and aldosterone.

As shown in Figure 12 and Table 9, subjects who took the CGW3 formulation 15 times before drinking performed significantly better on the finger-nose test, counting test, and maintained better balance compared to the control setting. In addition, subjects who took the CGW3 formulation once before drinking alcohol also had significantly more correct count tests and maintained better balance compared to the control setting. The results showed that ingestion of the CGW3 formulation at least once prior to alcohol consumption significantly improved performance on non-standardized field sobriety tests (finger-nose test, counting test and balance test).

Table 10 and Figures 13 to 15 show that ingestion of the CGW3 formulation once or 15 times before drinking reduces all alcohol-induced hangover symptoms. Specifically, taking the CGW3 formulation 15 times before alcohol consumption significantly reduced dizziness, confusion and improved next-day concentration or memory compared to a control setting. A single dose of the CGW3 formulation before alcohol consumption significantly reduced incoherent speech, altered levels of consciousness and improved next day work performance compared to the control setting.

Table 11 and Figures 16-18 show the effects of CGW3 formulations on liver function tests, kidney function tests and G6PD. Compared with the control setting, taking the CGW3 formulation once before drinking significantly reduced the serum levels of G6PD and γ-GT, and taking the CGW3 formulation 15 times before drinking significantly reduced the serum levels of ALT and AST, and noted a significant increase in serum creatinine levels. downward trend.

Example 3: In vivo studies on the effects of pharmaceutical compositions

The effects of CGW3 formulations on the intestinal envelope and glomeruli of mice were evaluated.

Male C57BL/6 mice, 8-10 weeks old, weighing about 20 grams (purchased from Taiwan National Animal Center and bred at Chang Gung University Animal Center, IACUC number CGU108-009) were used in the study. The study included the following 5 study groups with 10 mice in each group.

1. Conventional control diet: Mice were fed Lieber-DeCarli diet (221.78 g Lieber-DeCarli standard diet powder stirred in 1 liter of distilled water) by oral gavage for 4 weeks. 12.3 ml/kg body weight/day of distilled water was administered by oral gavage one week before and throughout the regular control diet.

2. Liquid alcohol diet: According to the "Evaluation Method of Liver Health Care Efficacy of Healthy Food" published by the Taiwan Food and Drug Administration in 2016, the mice were fed by oral gavage Lieber-DeCarli alcohol diet (132.18g Lieber-DeCarli standard diet powder and 67ml 95% alcohol in 933ml distilled water) for 4 weeks to induce intestinal and kidney damage. One week before and throughout the liquid alcohol diet, 12.3 ml/kg body weight/day of distilled water was administered by oral gavage.

3. Liquid alcohol diet + 4.1 ml/kg body weight/day of CGW3 formulation: Mice were fed a Lieber-DeCarli alcohol diet by oral gavage for 4 weeks. One week before and throughout the liquid alcohol diet, 4.1 ml/kg body weight/day of the CGW3 formulation (equivalent to 0.33 mg/kg body weight/day for humans) was administered by oral gavage once a day for a total of 5 days. week).

4. Liquid alcohol diet + 12.3 ml/kg body weight/day of CGW3 formulation: Mice were fed a Lieber-DeCarli alcohol diet by oral gavage for 4 weeks. One week before and throughout the liquid alcohol diet, 12.3 ml/kg body weight/day of the CGW3 formulation (equivalent to 1 mg/kg body weight/day in humans) was administered by oral gavage once a day for a total of 5 weeks .

5. Liquid alcohol diet + 36.9 ml/kg body weight/day of CGW3 formulation: Mice were fed a Lieber-DeCarli alcohol diet by oral gavage for 4 weeks. During the week before and throughout the liquid alcohol diet, borrow 36.9 ml/kg body weight/day of the CGW3 formulation (equivalent to 3 mg/kg body weight/day for humans) was administered by oral gavage once a day for a total of 5 weeks.

The protective effects of the CGW3 formulations on the intestinal envelope and glomeruli were assessed after 5 weeks of administration of the CGW3 formulations.

Pathological examination

After sacrifice of mice, jejunum and kidney tissues were fixed in 10% formalin and stained according to the hematoxylin and eosin protocol. Staining results: the nucleus is blue, and the cytoplasm and interstitial tissue are red.

result:

Figure 19, Panel B, shows that mice fed a liquid alcohol diet had impaired jejunal villi compared to mice on a regular control diet (Figure 19, Panel A). Jejunal villi damage was reversed or attenuated by regular feeding of CGW3 formulations (Figure 19, panels C-E).

Figure 20, Panel B, shows glomerular injury in mice consuming a liquid alcohol diet compared to mice on a regular control diet (Figure 20, Panel A). The glomerulus is a kidney tissue that filters raw urine that is enclosed in Bowman's capsule. The main function of the glomerulus is to filter plasma to remove waste products and form urine. Glomerular injury was reversed or attenuated by regular feeding of CGW3 formulations (Figure 20, panels C-E).

Example 4: A case study on the administration of a pharmaceutical composition after drinking red wine

Look for two adult volunteers to drink 250mL red wine as a control group, and take the S5 pharmaceutical composition containing the three components of Codonopsis pilosula, Poria cocos and tangerine peel (the weight ratio of Codonopsis pilosula, Poria cocos and tangerine peel is 25-35%: 30-50%: 25-35%) and 250mL red wine as experimental group 1, and taking a pharmaceutical composition containing three components of Codonopsis pilosula, Poria cocos and Qingpi (the weight ratio of Codonopsis, Poria and Qingpi is 25-35%: 30-50%: 25-35 %) and 250mL red wine were tested as experimental group 2, and it was confirmed that adding The difference between adding tangerine peel or green peel for the reduction of alcohol concentration, the alcohol concentration was measured using a professional electrochemical alcohol tester (model HOHOGA-AT576-AlcoREAL) of Hansun Technology; the average alcohol concentration of two volunteers The values are shown in Table 12 below.

It can be seen from Table 12 that the alcohol concentration of experimental group 1 after 30 minutes is lower than that of the control group and experimental group 2; and the alcohol concentration of experimental group 1 is 0 after 90 minutes, that is, the alcohol tester cannot detect it. From the above results, it can be seen that the hangover effect of the medicinal composition containing orange peel is better than that of the composition containing green peel, and the alcohol concentration can be reduced to 0 in a shorter time.

Claims (9)

A pharmaceutical composition comprising: (1) herbal medicine mixture, which includes Codonopsis pilosula, Poria cocos and tangerine peel; and (2) a pharmaceutically acceptable carrier, wherein based on the total weight of the herbal medicine mixture, Codonopsis pilosula is 25-35% by weight, 25-35% by weight of tangerine peel and 30-50% by weight of poria cocos. A pharmaceutical composition comprising: (1) herbal medicine mixture, which includes Codonopsis pilosula, Poria cocos, tangerine peel, dried ginger and Atractylodes macrocephala; and (2) a pharmaceutically acceptable carrier, wherein the total amount of the herbal medicine mixture is In terms of weight, Codonopsis Codonopsis is 15-25% by weight, Poria cocos is 25-35% by weight, orange peel is 15-25% by weight, dried ginger is 5-15% by weight and Atractylodes macrocephala is 10-20% by weight. A use of the pharmaceutical composition as described in claim 1 in the preparation of medicines for treating or reducing the influence of alcohol drinking in individuals. A use of the pharmaceutical composition as described in claim 2 in the preparation of medicines for treating or reducing the influence of alcohol drinking in individuals. The use as described in Claim 3 or Claim 4, wherein the pharmaceutical composition is administered before drinking alcohol. The use as described in claim 3 or claim 4, wherein the alcohol drinking effect is selected from the group consisting of symptoms of elevated blood alcohol concentration and alcohol hangover. A use of the pharmaceutical composition as described in Claim 1 in the preparation of medicines for treating or reducing liver cell inflammation and fat accumulation. A use of the pharmaceutical composition as described in Claim 2 in the preparation of a drug for treating or reducing small intestinal mucosal or intestinal function damage. A use of the pharmaceutical composition as described in Claim 1 in the preparation of medicines for treating or reducing glomerular damage or renal function damage.

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