HK1209375B - Compositions for treatment of cancer-related fatigue - Google Patents

Description

Compositions for treating cancer-related fatigue

Technical Field

The present invention relates to a preparation containing extracts of Panax ginseng (C.A.Mayer), ginger (Zingiber officinale), Echinacea angustifolia, and milk thistle (Silybum marianum). The composition of the present invention can be used to treat fatigue in cancer patients.

Background Art

The availability of effective cancer treatments has led to a significant increase in the number of "long-term survivors," which has made the fundamental issue of ensuring an improved quality of life for these patients even more prominent. Cancer-related fatigue is a broad symptom that is difficult to define and significantly impairs the quality of life of patients from a psychosocial perspective. Although its origins are multifactorial and physiologically based, its perception remains individual and is related to complex psychological concepts. Its basic characteristics are weakness, that is, a reduced ability to exert maximum muscle strength, and easy fatigue, in other words, the inability to maintain an activity for a long time. Some researchers have tried to determine the cause of fatigue to be a state of muscle weakness, while others have argued from a behavioral perspective that the cause of fatigue is mainly due to a general state of physical discomfort. Cancer-related fatigue is a serious symptom that affects 28-90% of cancer patients and 80-90% of cancer patients who have undergone chemotherapy and radiotherapy, and it can impair the patient's quality of life for a long time even after treatment has stopped [CA: Cancer J. Cli., 2012, 62(1), 10-29]. Cancer-related fatigue is very different from ordinary fatigue caused by work or stress, which patients can recover from by rest. Over 75% of cancer patients reportedly experience excessive fatigue, accompanied by severe, generalized weakness requiring unusual rest, and this weakness is often irreversible. A significant proportion of patients also reportedly experience a lack of motivation, anxiety, respiratory problems, cognitive impairment, and fatigue caused by sleep deprivation. This syndrome is often accompanied by diffuse pain, which reduces patient compliance with maintenance treatment and, more importantly, the recovery process is still labor-intensive. Chemotherapy and radiotherapy are essential treatments for cancer, but they can induce a range of adverse effects, such as systemic inflammation, hepatotoxicity, nephrotoxicity, and neurological damage, all leading to severe physical debility. Furthermore, the immune system impairment commonly associated with cancer treatment can lead to immunosuppression, which can make patients more susceptible to other infectious agents. Furthermore, radiotherapy can also cause anemia, weight loss, anorexia, nausea, and peripheral neuropathy.

These complex clinical manifestations seriously affect the quality of life of patients. Although people have made various attempts to improve these symptoms, the results are still limited.

Currently, drugs used in symptomatic treatment include COX-2 inhibitors, such as methylphenidate for improving attention and alertness, steroid hormones, and glucocorticoids. However, these drugs have serious side effects and are sometimes seriously disproportionate in risk-benefit ratio. Most importantly, the combination of commonly used drugs in these symptomatic treatments is very difficult.

Under such circumstances, treatment methods using natural substances such as medicinal plant extracts as medicines have been proposed.

One example is ginseng extract, known for its anti-fatigue and vitality-boosting properties, which also have immunostimulatory and anti-cancer properties. One study [Proc. Am. Soc. Clin. Oncol. 2003 Abst. 2947] has shown encouraging results, demonstrating a significant improvement in fatigue compared to placebo in the ginseng extract group. However, perhaps due to nonstandardized preparations, results in other studies have been inconsistent, questionable, and sometimes even unfavorable.

Silymarin, a substance found in milk thistle extract, has been shown in experimental animal models and human clinical trials to effectively protect cells against cytotoxic substances and support normal liver function in various pathological conditions. Silymarin complexes with phospholipids promote its absorption even in conditions of decreased gastrointestinal function. In the specific area of allopathological treatment for cancer patients, a recent study in young patients demonstrated that silymarin exhibited a high safety profile and beneficially reduced hepatotoxicity in typical treatment of acute lymphoblastic leukemia [Cancer, 2010, 116, 506-13].

Due to the anti-inflammatory effects of gingerol and its congeners, ginger may work by reducing the inflammatory state associated with the release of pro-inflammatory cytokines, thereby improving the patient's quality of life. In addition, due to its well-known anti-nausea effect, numerous studies have shown that ginger can effectively treat the high frequency and early onset of nausea in cancer patients, even in the absence of emetogenic substances (chemotherapeutic drugs) [Support Care Cancer, 2012, 20(7), 1479-89].

Echinacea extracts, which have immunostimulatory properties, can improve immunosuppression and prevent the onset of infectious processes and the invasion of saprophytic bacteria that can seriously affect patients' well-being and quality of life [Int Immunol. Pharmacol. 9, 850-85, 2009]. In addition, Echinacea angustifolia alkylamides have anti-inflammatory and analgesic effects comparable to known steroidal and nonsteroidal anti-inflammatory drugs, but have the following advantages: they are absorbed more quickly, do not affect the arachidonic acid cascade and the resulting gastric damage, and can reach the brain in sufficient quantities to interact with cannabinoid receptors, which can modulate analgesic and symptomatic responses.

Summary of the Invention

Applicants have discovered that the combination of ginseng, ginger, echinacea angustifolia, and milk thistle extracts acts synergistically and thus affects disease states more beneficially than extracts of either plant alone.

Therefore, the present invention provides a composition comprising extracts of ginseng, ginger, echinacea angustifolia, and milk thistle as active ingredients and suitable excipients.

The active ingredients of the present invention are known, commercially available or can be prepared by known methods.

Preferably, the ginseng extract is obtained from roots of ginseng that are at least four years old and is extracted using a mixture of water and ethanol. The resulting extract contains 8% ginsenosides, with a ginsenoside Rg1/ginsenoside Rb1 ratio of 0.5/1.

The ginger extract is preferably a lipophilic extract extracted from the roots and rhizomes of the plant using carbon dioxide under supercritical conditions. A powder is extracted from the roots in an extractor at a pressure of 230-260 bar, preferably 235 bar, at a temperature of 40-60°C, preferably 50°C, for 1-10 hours, preferably 7 hours. The extract is collected in a condenser, dehydrated with an inert gas dissolved in n-hexane or heptane, and concentrated in a vacuum at a temperature below 40°C. The extract contains approximately 30% gingerol and can be used directly in the formulation of the present invention.

The extract of Echinacea angustifolia can be obtained under supercritical carbon dioxide conditions as described in EP 464298. The weight ratio of isobutyramide in the lipophilic extract exceeds 20%.

Although commercial extracts of milk thistle or its main component silymarin (a mixture of silymarin, isosilymarin and hyposilymarin) can be used, it is preferred to use a complex of silymarin and a lipid, particularly soya lecithins or phosphatidylcholine, obtained as described in EP 209 038.

The dosage of the active ingredient in each dosage form is approximately within the range specified below:

- Ginseng: extract 10-500mg, preferably 50-250mg;

- Ginger: extract 5-100 mg, preferably 10-50 mg;

- Echinacea purpurea extract: 1-50 mg, preferably 5-20 mg;

- Complex of silymarin and phospholipids: 10-500 mg, preferably 50-250 mg.

Preferably, these doses are administered orally one to four times daily, preferably three times daily.

The compositions of the present invention can be formulated into a formulation according to conventional methods as described in Remington's Pharmaceutical Handbook (Mack Publishing Co., N.Y., USA). Specifically, the compositions of the present invention can be formulated into a formulation according to conventional botanical ingredient formulation techniques, with particular care being taken to avoid interactions between the excipients and the capsule base. Examples of oral formulations include tablets, dragees, soft gelatin capsules, hard gelatin capsules, and cellulose capsules.

According to another aspect, the composition of the present invention can be used in combination with other useful or complementary drugs to make susceptible patients more resistant to future treatments and less likely to relapse.

Specific implementation methods

The following examples further illustrate the present invention.

Example 1

Unit composition (film-coated tablets)

Example 2 - Clinical Trial

To investigate the efficacy of the combined therapy, adult patients with a history of cancer-related fatigue were enrolled. The Edmonton Symptom Assessment Scale (ESAS), a validated symptom assessment tool used in allopathic medicine, was used to assess the primary endpoint. The ESAS scale assesses nine different symptoms on a scale of 0 to 10, with 0 representing no symptoms and 10 representing the most severe form of symptoms. A 10-point scale (quality of life) was also introduced, derived from the average score of the nine indicators.

When selecting patients, the first inclusion criterion was the presence of fatigue for at least one month and a life expectancy of at least 8 months.

Combination product containing the following ingredients:

- 100 mg of ginseng extract containing 8% ginsenosides, with a ginsenoside Rg1 to ginsenoside Rb1 ratio of 0.5/1, prepared by water-ethanol extraction from main rhizomes that are at least 4 years old.

- 20mg of lipophilic ginger extract containing 25% gingerol and shogaol,

- 5mg of lipophilic extract of Echinacea angustifolia, containing 25% isobutyramide,

- 100mg of a 1:2 ratio of silymarin and phospholipid complex (lecithin 30%),

The combination product was administered to male patients who had undergone radiation and chemotherapy for primary lung, prostate, pancreatic, and colon tumors for 60 days, two tablets three times a day, 30 minutes before meals (breakfast, lunch, and dinner). The extract was formulated into 470 mg tablets.

The patients were divided into 5 groups and treated according to the following regimen:

Group 1: placebo treatment (excipients used in the composition described in Example 1);

Group 2: treated with the composition described in Example 1;

Group 3: treated with ginger/echinacea combination (same dosage as described in Example 1);

Group 4: treated with silymarin phospholipid complex only (same dose as described in Example 1);

Group 5: treated with ginseng extract (same dosage as described in Example 1);

The results of the clinical trials are listed in the table below.

As these data demonstrate, the composition described in Example 1 has significant effects on vital energy and peripheral pain, significantly improving patients' mood and appetite, possibly due to accelerated gastric emptying and reduced nausea, or improved liver function. A direct comparison of the results of the composition described in Example 1 with other treatments showed that the mean quality-of-life score for this group returned to normal (scores of 0-3), while the placebo group remained pathological (scores of 6-7) and the other groups remained subclinical (scores of 5-6), despite the expected improvement in some parameters. This significant and unexpected improvement in quality of life activates a beneficial process that increases the desire for protein, perhaps due to liver reactivation and improved intestinal transit function, or perhaps due to the choleretic effects of silymarin and phospholipid complexes. The ingestion of protein, combined with muscle mass recovery and physical activity, can reverse the tendency toward catabolism and reduce fatigue, significantly contributing to the patient's psychosocial recovery, as some studies have shown.

Claims (4)

1. The use of the composition in the preparation of a medicament for treating cancer-related fatigue selected from pain, weakness, depression, anxiety, loss of appetite, and quality of life, wherein the composition contains the following components as active ingredients and suitable excipients: (a) Ginseng extract (b) Ginger extract, (c) Echinacea angustifolia extract, and (d) Phospholipid complex of silymarin and phospholipids. 2. The use according to claim 1, wherein the ginger and Echinacea angustifolia extracts are lipophilic extracts. 3. According to the use of claim 1, wherein the ginseng extract contains 8% ginsenosides, the ratio of ginsenosides Rg1 and Rb1 is 0.5/1, the ginger extract contains 30% gingerol, and the weight ratio of isobutyramide in the echinacea angustifolia extract is higher than 20%. 4. The use according to any one of claims 1-3, wherein the medicament is in the form of tablets, sugar-coated pills, soft gelatin capsules, hard gelatin capsules or cellulose capsules.