HK1089942A - Film coated tablet comprising an extract of red vine leaves - Google Patents

Description

Coated tablet containing extract of red vine leaves

Field of the invention

The present invention relates to a coated tablet comprising a dried extract of red vine leaves, excipients and a tablet coating, and its use for improving blood circulation and/or oxygen supply in the lower extremities.

Prior Art

Chronic Venous Insufficiency (CVI) is a progressive disease and it causes oedema, coronary vasodilation (witmer stage I), hyperpigmentation, induration, fatty skin sclerosis, atrophia alba (witmer stage II) or varicose leg ulcers (witmer stage III) in many patients-especially untreated. Chronic disturbances of the haemodynamics of deep or superficial veins, which are caused by blocked venous parts or valve insufficiency, often lead to skin diseases in the inner ankle region of the lower limb. It has been thought that: disorders of the cutaneous microcirculation are the major factors responsible for the cutaneous changes associated with chronic venous hypervolemia and venous hypertension (e.g., Fagrell B, "Vital histology and pathophysiology of deep venous insufficiency," Int Angiol 1995; 14: 18-22; Junger M, Klyscz T, Hahn M, RassnerG, "Disturbed blood flow regulation in venous leg ulcers" (Int J Microcirc 1996; 16: 259-.

Clearly, clinically relevant cutaneous microvascular lesions, such as dilated, twisted capillaries surrounded by micro-edema, can contribute to changes in the skin of the lower limb and can determine the course of CVI (Fagrell B, supra and Junger M et al, supra).

The use of laser Doppler (Doppler) technology in venous disorders is well documented (e.g., Tulevski II, Ubbink DT, Jacobs MJHM, "comparison of Red and Green laser Doppler (Doppler) technology with capillary microscopy in identifying microcirculation of The foot skin of healthy subjects, Microvasc Res 1999; 58 (2): 83-88; and Bolliger A, Jager K, Junger M, Seifert H," vascular laboratory: progress in noninvasive technology (The vascular laboratory: advanced in-invasive technologies. ", World J Surg 1998; 12: 724-.

Different techniques have been developed for studying microcirculation in two different functional skin layers: deeper main regulating body temperature layers and shallower nutrition layers, microcirculation disturbance in the superficial nutrition layers has the most correlation to nutritional skin changes. (Junger M et al, supra and Gschwandner ME, Ambrozy E, Fasching S, Willfort A, Schmeider B, Bohler K et al, "microcirculation in venous ulcers and surrounding skin: findings using capillary microscopy and laser Doppler imager," Eur J Clin Invest 1999; 29: 708-.

British patent GB 934,554 discloses that the capillary resistance of vitamin deficient guinea pigs can be enhanced by intraperitoneal application of alcoholic extracts of the leaves of the vine.

International patent application WO 01/28363 discloses a method for preventing or reducing the discomfort associated with mild-to-moderate chronic venous insufficiency of the lower limbs by means of an aqueous extract of the leaves of the red vine plant. In addition, it is recommended to take a dose of 80 to 1000 mg per day, divided into 1 to 3 capsules.

The fundamental problems of the invention are: a dosage form is provided that allows such high doses of an aqueous extract of red vine leaves to be administered with the suggested regimen. In view of patient compliance, it is desirable that these dosage forms not be too large for ease of swallowing. On the other hand, the dosage form must have high stability to ensure long shelf life. Furthermore, high bioavailability is only a prerequisite for the success of the treatment and/or prevention of this dosage form.

Disclosure of Invention

Surprisingly, a coated tablet has been found comprising:

(a) at least 50% by weight of a dried extract of red vine leaves, obtainable by extracting red vine leaves with water and drying;

(b) up to 50% by weight of excipients consisting essentially of:

at least one kind of adhesive agent is used,

at least one disintegrating agent, wherein the disintegrating agent,

at least one filler, and

a lubricant; and

(c) a tablet coating film mainly composed of a film-forming agent, a plasticizer, a coating agent and optionally a colorant;

the tablet meets these requirements and can be used to significantly enhance microcirculation and oxygen supply in the mainly affected near ankle area of the leg of a CVI patient.

Accordingly, the present invention relates to a coated tablet comprising the following ingredients:

(a) at least 50% by weight of a dried extract of red vine leaves, obtainable by extracting red vine leaves with water and drying;

(b) up to 50% by weight of excipients consisting essentially of:

at least one kind of adhesive agent is used,

at least one disintegrating agent, wherein the disintegrating agent,

at least one filler, and

a lubricant; and

(c) coating film mainly comprising film-forming agent, plasticizer, coating agent and optional colorant.

Another aspect of the invention is a process for preparing such a coated tablet comprising the steps of:

(A) mixing a dry aqueous extract of red vine leaves (a) with excipient (b), optionally in the presence of a volatile diluent;

(B) optionally sieving the resulting mixture;

(C) compressing the mixture with a suitable tablet press; and is

(D) The resulting tablets are coated with a coating film (C).

Furthermore, the present invention relates to the use of such a coated tablet for the preparation of a pharmaceutical or dietary composition for the treatment or prevention of discomfort, disorders and/or diseases associated with chronic venous hypervolemia and venous hypertension.

Furthermore, the present invention relates to an aqueous extract of red vine leaves obtainable by a process comprising the steps of:

(a) collecting red vine leaves at a point when the flavonoid content has reached an optimum level;

(b) drying and pulverizing the leaves;

(c) cutting the leaves into pieces;

(d) extracting the leaves with water at elevated temperature for 6 to 10 hours;

(e) concentrating and drying the obtained extract, and

(f) up to 10% by weight of silica relative to the final total amount of the extract obtained is added.

Brief Description of Drawings

Figure 1 shows a protocol design of a clinical study to demonstrate the efficacy of a coated tablet according to the present invention.

FIG. 2 shows 360 mg coated tablet containing extract of vine leavesAS 195-, placebo-o-comparison of the effect on microcirculation as measured using laser Doppler (Doppler) blood flow measurements (LDF 10-37 kHz).

FIG. 3 shows 360 mg of coated tablet containing extract of vine leavesAS 195-₂) The influence of (c) is compared.

Detailed Description

The coated tablet of the present invention is composed of a herbal component (a) obtained by drying an aqueous extract of red vine leaves (folia vitas vinifera; extract vitas vinifera e folium spissum et siccum), an excipient (b) and a tablet coating film (c). The extract contains flavone (alcohol) -glycoside, -glucuronide and flavonoid, and quercetin-3-O-beta-D-glucuronide and isoquercitrin (quercetin-3-O-beta-glucoside) as main active ingredients. Although the scope of its pharmacological effects has not been fully elucidated, in vitro studies indicate: it has antioxidant and anti-inflammatory properties, and it inhibits platelet aggregation and hyaluronidase, and reduces edema by reducing capillary permeability. The anti-inflammatory and capillary wall thickening effects of the composition are proved by in vivo experiments before clinical use.

The coated tablets according to the invention comprise 50% to 70% of an aqueous extract of dried red vine leaves having a high flavonoid content of 2-15%.

In general, the weight relationship of the dry extract to the excipients used to produce the tablet core is between 1: 1 and 2: 1, preferably between 1.1: 1 and 1.8: 1, especially between 1.25: 1 and 1.75: 1.

A coated tablet preferably comprising, based on the total weight of the coated tablet:

(a)50 to 70% by weight of a dried extract of red vine leaves;

(b)25 to 49% by weight of excipients, and

(c)1 to 5% by weight of a coating film.

More preferred are coated tablets comprising the following ingredients (based on the total weight of the coated tablet):

(a)51 to 59% by weight, in particular about 55% by weight, of a dried extract of red vine leaves;

(b)38 to 48% by weight, in particular about 43% by weight, of excipients, and

(c)1 to 3% by weight, in particular about 2.7% by weight, of a coating film.

Another preferred embodiment is a coated tablet, wherein excipient (b) consists essentially of (based on the total mass of the combined excipients):

70 to 85 wt% of at least one binder,

0.5 to 12.5% by weight of at least one disintegrant,

5 to 15% by weight of at least one filler, and

1 to 5 wt% of at least one lubricant.

The term "binder" as used above and below denotes an excipient suitable for binding other components to each other. Preferred binders according to the invention are selected from the following: powdered cellulose, microcrystalline cellulose, sorbitol, starch, polyvinylpyrrolidone (povidone), copolymers of vinylpyrrolidone with other vinyl derivatives (copovidone), cellulose derivatives, especially methylhydroxypropylcellulose (for example methylcellulose (Methocel) a15LV), and mixtures of these compounds. Preferred binders are powdered cellulose, especially microcrystalline cellulose and/or polyvinylpyrrolidone. If the above-mentioned binders are used, the weight, based on the total mass of the tablet according to the invention, is preferably in the range from 15 to 45% by weight, more preferably from 25 to 40% by weight, most preferably in the range from about 33% by weight. Since a particularly preferred binder is microcrystalline cellulose, tablets with high stability and good suitability can be provided to patients who have to apply an aqueous extract of red vine leaves.

The tablet according to the present invention contains, in addition to the above-mentioned ingredients, a disintegrant. Within the scope of the present invention, these disintegrants are also optionally referred to as disintegrants. According to the invention, these disintegrants are preferably selected from the following: sodium starch glycolate, cross-linked polyvinylpyrrolidone (crospovidone), cross-linked sodium carboxymethyl cellulose (cross-linked sodium carboxymethyl ether cellulose), sodium carboxymethyl cellulose, dried corn starch, colloidal anhydrous silica, and mixtures thereof. Within the scope of the present invention, particular preference is given to using sodium starch glycolate, crosslinked polyvinylpyrrolidone and, preferably, crosslinked polyvinylpyrrolidone or sodium salts of crosslinked carboxymethylcellulose and colloidal anhydrous silica. Most preferred is a mixture of croscarmellose sodium, colloidal anhydrous silicon dioxide and, if desired, crospovidone. If the above-mentioned disintegrant is used, the weight based on the total mass of the tablet of the present invention is preferably in the range of 0.5 to 10% by weight, more preferably about 1.5 to 7.5% by weight. Due to the particularly preferred composition of the disintegrant, tablets with high stability can be obtained and high bioavailability of aqueous extracts of red vine leaves can be provided.

The tablets according to the invention also comprise a filler. Typically, the filler is an inert compound such as an inorganic metal oxide or an inorganic phosphate or hydrogen phosphate. The filler is preferably anhydrous dibasic calcium phosphate. If the above fillers are used, the weight, based on the total mass of the tablet of the invention, is preferably in the range of about 1 to 10% by weight, more preferably about 2 to 8% by weight.

The tablets according to the invention also comprise flow agents or flow regulators and lubricants as additional ingredients. Within the scope of the present invention, these ingredients include, for example, silica, talc, stearic acid, sodium stearyl fumarate, magnesium stearate and glyceryl tribehenate. According to the invention, magnesium stearate is preferably used. If the preferred lubricants described above are used, the weight based on the total mass of the tablet of the present invention is preferably in the range of about 0.1 to 10% by weight, preferably about 0.5 to 5% by weight, more preferably between 0.6 and 1.5% by weight.

Furthermore, preferred are coated tablets, wherein the coating film (c) consists essentially of (based on the total mass of the coating film (c)):

50 to 85 wt% of at least one film forming agent,

5 to 10 wt.% of at least one plasticizer,

10 to 20% by weight of at least one coating agent, such as talc, and

0 to 15% by weight of at least one colorant.

The tablets according to the invention also comprise one or more synthetic or natural, pharmaceutically acceptable colorants, preferably one or more inorganic metal oxides, such as titanium dioxide (E171) and/or iron oxide (E172). If the above-mentioned preferred colorants are used, their weight is from 0.01 to 0.5% by weight, based on the total mass of the tablets according to the invention.

It is another object of the present invention to provide a coated tablet comprising herbal ingredients for preventing and/or alleviating discomfort associated with mild-to-moderate chronic venous insufficiency of the lower extremities, wherein the tablet can be manufactured according to a controlled process that maintains the herbal healing quality of the ingredients.

It is a further object of the present invention to provide a coated tablet which is effective for preventing and/or alleviating the discomfort associated with mild-to-moderate chronic venous insufficiency of the lower extremities.

It is a further object of the present invention to provide a coated tablet useful for preventing and/or alleviating discomfort associated with mild-to-moderate chronic venous insufficiency of the lower limbs, which tablet comprises herbal ingredients and has minimal or no side effects and is therefore safe for internal consumption, and which has high stability and good patient compliance.

The aqueous extract prepared from drying red vine leaves is characterized by: a high content of bioactive flavonoid of 2 to 20%, preferably 2 to 10%.

The term "person in need thereof" or "patient" as used above or below refers to a female or male person suffering from clinically irrelevant early stage Chronic Venous Insufficiency (CVI), having been demonstrated to be in stages I and II according to the CVI of vedman. Typically, such patients are elderly between 30 and 80 years of age, preferably between 32 and 76 years of age, with a mean age (± standard deviation) of 55.2 ± 7.7 years of age. Generally, CVI may be more readily expressed in female patients than male patients.

The following examples are set forth in order to provide a more complete understanding of the invention. These examples are for illustrating the present invention and are not to be construed as limiting the scope of the present invention.

The following examples are illustrative and, as recognized by those skilled in the art, particular symptoms may be modified as desired for individual compositions. The materials used in the following tests are either commercially available or readily prepared from commercially available materials by one of ordinary skill in the art.

The main ingredient of the tablet is an aqueous extract of red vine leaves (foliae vitamins vinferae l.). The starting material for the preparation of the extract was red vine leaves collected when the flavonoid content had reached an optimum value. Typically, this occurs before and after the harvest stage of the grapes. The leaves were carefully dried and broken. For extraction, the leaves are cut into pieces, preferably 5 to 10 mm. To obtain high levels of flavonoids, extraction can be carried out at elevated temperatures, preferably in the temperature range of 60 ℃ to 80 ℃ for a period of at least 6 up to 10 hours. The preferred method is complete diafiltration (ex haustive percolation).

The so-called fluid extract obtained in the extraction process is concentrated by using a suitable evaporator. The thick extract obtained in this step is dried, for example, by using a vacuum drying oven or vacuum drying conveyor.

During the drying process, all or some of the excipients may be added to aid in further processing of the extract. One or more excipient ingredients may be added, typically up to 10% during drying.

Preferably, a portion of a flux modifier (such as colloidal anhydrous silica) may be added to the extract either when dry or prior to mixing with other components. The resulting extraction composition preferably comprises 0.5 to 10 wt%, especially 2.5 to 7.5 wt%, optimally about 4 wt% colloidal anhydrous silica.

Surprisingly, tablets obtained from extracts to which a portion of the excipients has been added during drying show enhanced stability.

The coated tablets according to the invention preferably consist of:

■ 300 to 500 mg, preferably 320 to 400 mg, especially about 355 to 380 mg, of a dried aqueous extract of red vine leaves (4-6: 1) (extracum vitas vinferae meliaea quosum siccum) which may contain up to 10% by weight of a flow regulator, especially colloidal anhydrous silica;

■ the following excipients are for the tablet core:

microcrystalline cellulose, croscarmellose sodium, dibasic calcium phosphate (anhydrous), colloidal silicon dioxide (anhydrous), magnesium stearate and optionally crospovidone, and

■ A coating film consisting of:

hypromellose, glycerol tristearate, titanium dioxide (E171), talc, iron oxide, red (E172).

Coated tablets were prepared with the ingredients listed in tables a and B below:

TABLE A

Name of ingredient	The content in each coated tablet [ mg/658.000mg]	Function(s)
			Tablet coreDried aqueous extract of Vitis viniferae folium (4-6: 1) microcrystalline cellulose croscarmellose sodium anhydrous dibasic calcium phosphate colloidal anhydrous magnesium stearate	360.000219.00018.00030.0004.0009.000	Active ingredient binder, disintegrant filler flow regulator, disintegration accelerator lubricant
Coating filmHydroxypropyl methylcellulose glyceryl tristearate titanium dioxide (E171), talc, iron oxide, Red (E172)	11.3831.1380.7833.1311.565	Film former plasticizer colorant coating agent colorant

The extract is mixed with the excipients of the tablet core and compressed in a suitable tablet press.

TABLE B

Name of ingredient	The content in each coated tablet [ mg/658.000mg]	Function(s)
			Tablet coreDried aqueous extract of Vitis viniferae folium (4-6: 1) colloidal anhydrous silicon dioxide microcrystalline cellulose croscarmellose sodium anhydrous dibasic calcium phosphate colloidal anhydrous silicon dioxide magnesium stearate crosslinked polyvinylpyrrolidone	360.00015.000214.00018.00030.0006.0009.00018.000	Active ingredient binder, disintegrant filler flow regulator, disintegration accelerator, lubricant disintegrant
Coating filmHydroxypropyl methylcellulose glyceryl tristearate titanium dioxide (E171), talc, iron oxide, Red (E172)	11.3831.1380.7833.1311.565	Film former plasticizer colorant coating agent colorant

During the drying process, the extract was mixed with 15.000 mg of silica to yield an extract consisting of 96% by weight of the extract component and 4% silica. This resulting mixture is mixed with the remaining excipients of the tablet core and compressed in a suitable tablet press.

The compression force required to produce tablets with a suitable crushing resistance and thus with the desired number of breakages (breakdowns times) depends on the shape and size of the punching tool used. The compaction force is preferably in the range of 2-20-kilonewtons (kN). Higher compression forces can result in extended release of the active substance from the tablet. Lower compression forces can result in mechanically unstable tablets. Tablet cores may have different shapes; circular biplanar or biconvex shapes and elliptical or oblong shapes are preferred.

The coating solution is prepared by mixing the film-forming agent with the colorant and plasticizer in water. The coating solution is applied to the tablet cores using a suitable coating pan.

The tablet preferably has an oblong shape to facilitate swallowing. In the case of a coated tablet containing 360 mg of extract and having the above-described ratio of extract to excipient, an oblong tablet may be about 17-18 mm long and have a width of about 8 to 9 mm. Hereinafter, the coated tablets of Table A are coded as "AS 195”。

To enhance blood circulation and/or oxygen supply in the lower limb, tablets corresponding to doses of 150 and 1000 mg of extract, preferably 300-. The total amount of extract can be divided into 1 to 3 coated tablets per day. The daily dose should be taken once, preferably in the morning.

It is expected that: the disease can be obviously improved within 6 weeks after continuous administration. The best effect can be maintained or enhanced by long-term administration.

Method

Participants

Male and female patients aged 18 years or over 18 years, diagnosed with vicdman-confirmed CVII or CVI and currently suffering from at least one year are enrolled in the experiment. There must be no medically related concomitant diseases. Patients who had taken drugs that alleviated their symptoms of CVI within 4 weeks prior to the first exam or who had been treated with theophylline (theophyllin), diuretics, cardiac glycosides, ACE inhibitors or calcium antagonists within 8 days prior to the first exam were not allowed to participate in the experiment. Compression bandages were prohibited or concomitant treatment of venous problems was performed during participation in the trial.

Design and method

Double-blind, randomized, placebo-controlled crossover trials were performed according to the declaration of Helsinki and the principles of the International Conference of good clinical trials of Goodclinical Practice.

Each patient participated in the 17-week trial: wash-out period of one week (treated with placebo), treatment period of 6 weeks (group _1 with placebo), and wash-out period of 6 weeksAS 195Start, group _2 started with placebo), a 4 week washout period (treated with placebo), and a second 6 week treatment period (group _1 continued with placebo, group _2 continued with placebo)AS 195)。

In the morning, a single dose is taken at random timesAS 195(coated tablets containing 360 mg of dried extract of red vine leaves) or placebo tablets. Both tablets have the same size, shape, weight, appearance (inner appearance) and taste. For laser Doppler blood flow testing, the instrument is supplied by Berlin LMTB, Germany (e.g., Doerschel K, Mueller G. velocity resolved laser flow measurement in skin. laser diameter 1996; 12: 163-. The device is a computer-based mobile unit using a laser frequency of 785 nm. The laser probe is fixed at a distance of 35 cm from the medial ankle of the more affected leg. After sitting for 30 minutes to adjust to room temperature, the measurement was started after standing for another 10 minutes (256 points were measured, duration of measurement: about 0.4 seconds). In the frequency range between 0.2 khz to 37.2 khz, both diodes can detect backscattered light. The data is processed using a fast fourier transform. Finally, for vessels in the reticular venous plexus (larger major thermoregulatory vessels, greater than 30 microns in diameter), output refers to a frequency range between 0.2 kilohertz and 10.0 kilohertz, and for capillaries in the subcapillary venous plexus (shallow small trophoblasts, 6 microns to 30 microns in diameter), output refers to a frequency range between 10.1 kilohertz and 37.2 kilohertz.

Transcutaneous oxygen pressure (tcPO2) was measured using a modified clark-type polarographic electrode (TCM3, radiometer copenhagen Br Φ nsh Φ j, denmark) containing a noble metal cathode and a silver/silver chloride anode. The heating element adjacent the anode maintains the skin temperature at 43 degrees celsius. At this temperature, The arterioles expand maximally, and tcPO2 approximates PO2 of arterial blood (e.g., Bollinger A, Jager K, Junger M, Seifert H. vascular laboratory: evolution of non-invasive technology (The vascular laboratory: advanced-mvase technologies) World J Surg 1988; 12: 724-731.).

The electrodes were attached to the skin surface 3.5 cm from the anterior-lateral side of the laser doppler probe by an adhesive ring device filled with saline. After sitting for 30 minutes to room temperature, the measurement was started after standing for 10 minutes. The measurement lasted about 15 minutes. pcPO2 values are expressed in millimeters of mercury (mmHg). The normal values attainable from the instep of a patient not suffering from CVI are in the range of 40mmHg to 80 mmHg.

Local skin temperature at the peripheral area of the ankle was measured using a thermistor fixed adjacent to the oxygen electrode. To minimize the effect on skin perfusion, measurements of LDF and tcPO2 were made at local skin temperatures between 28 and 32 ℃.

A measuring tape is used to measure the circumference of the lower leg and ankle. Measurements were taken on the lateral and medial sides of the ankle and in the middle of the calf.

Subjective symptoms of CVI (heavy leg fatigue, tension, tingling and pain) were measured using a visual analogue scale of 10-cm with 0 for "none" and 10 cm for "very strong".

At the end of each treatment cycle, the overall treatment efficacy was rated by the patient and investigator according to a 4-grade oral rating scale (good, satisfactory, unsatisfactory and poor).

The overall tolerability was rated by the patient and investigator according to a 4-rated oral rating scale (good, satisfactory, unsatisfactory and poor). At each visit, the patient is typically asked for well being.

Results

A total of 71 women and men aged between 32 and 76 years, who have been identified as stages I and II in the CVI stage according to virdman, were enrolled. Mean age (+ -standard deviation) 55.2 ± 7.7 years; 55 women and 16 men. Venous status revealed that 47 (67.1%) patients had moderate or severe varicose veins, 27 (38.6%) had pigmentation, 26 (37.1%) had ankle edema and 25 (35.7%) had lower limb edema. There were signs of mild atrophy in 13 (18.6%) patients, and none had eczema (table 1).

Table 1: demographic and reference features of CVI

	AS 195/placebo (n ═ 36)	placebo/AS 195(n ═ 35)
			Continuous variable (mean (range)) age [ years of age [ ]]Height [ cm ]]Weight [ kg]Body quality index [ kg/m ]2]Systolic blood pressure [ mmHg]Diastolic blood pressure [ mmHg]	66(32-76)168(150-186)76.5(48-97)27.6(20.6-32.0)130(100-150)80(60-90)	66(37-76)165(150-191)73(55-120)26.7(20.1-42.5)135(120-140)80(65-90)
Categorical variable (n (%)) female then smoker moderate to severe venous status varicose pigmentation atrophy eczema ankle edema lower limb edema during stage I and stage II of CVI stage I	24(66.7)4(11.1)26(72.2)10(27.8)26(72.2)11(30.6)0(0.0)0(0.0)13(36.1)12(33.3)	31(88.6)1(2.9)23(65.7)12(34.3)22(62.9)17(48.6)0(0.0)0(0.0)14(40.0)14(40.0)

The protocol was not violated in the remaining patients. Thus, all patients were left for treatment analysis (fig. 1). In addition to the male-female ratio (12 men in group _1, 4 men in group _2), the patient characteristics were evenly distributed over the two treatment sequences (group _1, group _2) (table 1). Laser doppler parameters, transcutaneous oximetry, baseline values for ankle and lower leg circumferences and subjective symptoms (table 2) were comparable for groups 1 and 2. The suitability of the coated tablets according to the invention is about 100% in both treatment sequences.

Table 2: mean of baseline characteristics (. + -. SD) for each treatment cycle

	Stage 1		Stage 2
					AS 195(n＝36)	Placebo (n ═ 34)	AS 195(n＝34)	Placebo (n ═ 36)
	Laser Doppler blood flow measurement { AU]Transdermal blood oxygen measurement [ mmHg ] 10-37kHz < 10kHz]Peripheral edge [ cm ]]Subjective symptom of ankle and shank [ cm ]]Tingling sensation of fatigue/heavy pain and tension in the legs	303.5(135.2)352.7(87.7)32.1(7.0)20.3(2.2)34.7(3.1)4.3(2.8)4.0(3.2)4.5(2.9)3.3(3.1)	333.5(153.0)370.8(120.0)32.3(6.4)20.4(2.4)34.2(3.0)3.7(2.9)3.2(3.1)4.1(2.8)2.7(2.9)	275.4(126.4)174.7(77.0)30.1(6.2)20.2(2.6)34.0(3.1)4.6(2.9)4.5(2.7)4.5(2.6)3.7(2.6)					293.3(119.9)189.4(67.6)30.8(6.4)20.3(2.2)34.6(3.2)5.2(2.6)4.9(3.1)5.1(2.5)4.2(2.8)

Laser doppler blood flow measurements at the primary target (primary endpoint) are selected in the frequency range of 10-37 khz. These frequencies are determined by the amount of red blood cells in the capillaries in the superficial layers of the leg skin and their movement (flow rate). After 6 weeks, the laser Doppler frequency (10-37kHz) wasAS 195Increased in the group (plus 241.8 + -18.7 AU) but decreased in the placebo group (minus 41.0 + -18.7 AU, p < 0.0001) (Table 3). This effect appeared as early as 3 weeks after the start of treatment (p < 0.0001) (Table 4, FIG. 2).

Table 3: in an amount of 360 mgAS 195Or mean (± SEM) and p-value of the change from baseline adjusted cycle effect at 95% confidence interval for treatment control 3 weeks after placebo treatment

	Treatment of		Treatment controls
						AS 195(n＝70)	Placebo (n ═ 70)	The difference (n is 70)	Confidence interval (n ═ 70)	p value
	3 cycle laser Doppler blood flow measurement [ AU]10-37kHz < 10kHz transdermal oximetry [ mmHg [ ]]Peripheral edge [ cm ]]Subjective symptom of ankle and shank [ cm ]]Tingling sensation of fatigue/heavy pain and tension in the legs	132.2(11.9)-3.7(9.2)0.62(0.97)-0.19(0.09)-0.24(0.04)-0.94(0.25)-1.17(0.23)-1.00(0.24)0.99(0.26)	-28.2(11.9)-99.9(9.2)-3.84(0.97)0.21(0.09)0.04(0.04)0.21(0.25)-0.24(0.23)-0.52(0.24)-0.20(0.26)	160.596.24.46-0.40-0.28-0.73-0.94-0.49-0.79	127.0 to 194.070.2 to 122.21.72 to 7.20-0.65 to-0.15-0.40 to-0.17-1.42 to-0.04-1.59 to-0.28-1.17 to 0.191.52 to-0.06						＜0.0001＜0.00010.00180.0025＜0.00010.03960.00610.15880.0335

Table 4: in an amount of 360 mgAS 195Or mean (± SEM) and p-value of baseline variation from adjusted cycle effect at 95% confidence interval for treatment control 6 weeks after placebo treatment

	Treatment of		Treatment controls
						AS 195(n＝70)	Placebo (n ═ 70)	The difference (n is 70)	Confidence interval (n ═ 70)	p value
	6 cycle laser Doppler blood flow measurement [ AU]10-37kHz (initial target) < 10kHz transcutaneous oximetry [ mmHg-]Peripheral edge [ cm ]]Subjective symptom of ankle and shank [ cm ]]Tingling sensation of fatigue/heavy pain and tension in the legs	241.8(18.7)57.0(12.4)1.35(0.97)-0.39(0.09)-0.54(0.05)-0.78(0.33)-0.76(0.35)-0.96(0.35)-0.55(0.30)	-41.0(18.7)-107.7(12.4)-7.27(0.97)0.29(0.09)0.14(0.05)-0.94(0.33)-0.86(0.35)-1.40(0.35)-0.66(0.30)	282.8164.78.63-0.68-0.680.160.100.440.11	229.9 to 335.7129.7 to 199.75.88 to 11.38-0.94 to-0.43-0.83 to-0.53-0.76 to 1.09-0.88 to 1.09-0.46 to 1.44-0.75 to 0.96						＜0.0001＜0.0001＜0.0001＜0.0001＜0.00010.72850.83230.38190.8044

Laser doppler flow measurements are made in the frequency range below 10khz, determined by the number of red blood cells in the deep capillaries of the leg skin, which primarily regulate body temperature, and their movement (flow rate). After 6 weeks, the laser Doppler frequency (below 10kHz) wasAS 195Increased in group (plus 57.0 + -12.4 AU) but decreased in placebo group (minus 107.7 + -12.4 AU, p < 0.0001) (Table 3). The effect appears to be dependent on the climatic conditions during the treatment cycle. During the medium temperature (April/May) study period, the laser Doppler measurements (< 10kHz) were atAS 195In the treatment group, the values remained unchanged after the initial decline, whereas in the placebo-treated group the values decreased (p < 0.0001). During the higher temperature (July/August) study period, laser Doppler measurements (< 10kHz) were made atAS 195Increase in the treated group, but remain constant in the placebo treated group (p < 0.0001).

In thatAS 195Transdermal oxygen pressure increased in the group (plus 1.35 + -0.97 mmHg) but decreased in the placebo group (minus 7.27 + -0.97 mmHg, p < 0.0001). This observation was consistent over both treatment cycles and thus coincided with the laser doppler flow in the skin nutritive superficial (i.e., 10-37kHz) (tables 3, 4, fig. 3).

Statistically significant and clinically relevant reductions in ankle circumference (after 3 weeks: AS 195 minus 0.19. + -. 0.09cm, placebo plus 0.21. + -. 0.09cm, p ═ 0.0025) and calf circumference (after 3 weeks: AS 195 minus 0.24. + -. 0.04cm, placebo plus 0.04. + -. 0.04cm, p < 0.0001) indicate onset of action AS early AS 3 weeks after initiation of treatment (Table 3). This effect was more pronounced after 6 weeks (AS 195 ankle: minus 0.39 + -0.09 cm, calf: minus 0.54 + -0.05; placebo ankle: plus 0.29 + -0.09 cm, calf: plus 0.14 + -0.05 cm, p < 0.0001) (Table 4).

After 6 weeks of treatment, there was no associated change in subjective symptom intensity (intensity) for CVI. This result is consistent with the results in the previous study in which subjective symptoms measured on the visual analogue scale were reduced only after a longer treatment period (12 weeks).

Adverse events rarely occurred in this study. 13 of 71 patients experienced at least one adverse event, of which 12 patients experienced an initial effect (on of action) on placebo treatment and another experienced an adverse eventAS 195The treatment period (moderate bronchitis, investigator considered drug independent). Patients who died from cardiac arrest had received placebo treatment (never taken in this trial)AS 195). The overall tolerability of all patients was rated as good or satisfactory. Experimental parameters were unchanged during the study.

Discussion of the related Art

It has been shown in a previous study (WO 01/28363): red vine leaf extractAS 195In addition to improved acceptance for 12 weeks⁷In addition to subjective symptoms associated with chronic venous insufficiency in patients treated once daily, lower limb edema, lower leg circumference and ankle circumference may also be reduced. The study was designed to provide additional information about the underlying mechanism of action by studying microcirculation as a clinically relevant surrogate parameter for leg problems related to CVI. This study was the first study in CVI patients to investigate the interaction with Sargentodoxa cuneata in addition to the reduction of leg edemaAdditional clinically relevant effects of this plant leaf extract treatment are relevant. The reduced venous return results in poor skin microcirculation and thus skin malnutrition. This condition may even lead to venous leg ulcers if the CVI remains untreated. Laser Doppler (Doppler) blood flow measurements as used in this study is an effective and sensitive method for measuring the objective therapeutic effect, which can be related to the subjectively experienced volume reduction after 3 months of treatment.

The results of these studies are in line withAS 195And it adds information about the initial effect. Leg volume as an objective parameter will decrease after 6 weeks of treatment, in a clinically relevant and statistically significant degree. Recently, extracts of European horse chestnut seeds (e.g., Diehm C, Transmission HJ, Lange S, Schmidt C, "Comparison of leg compression stockings with oral European horse chestnut seed extract treatment for patients with chronic venous insufficiency (comprehensive of compression storage and oral horse chestnut-treated extract treatment)", Lance 1996; 347: 292-294) and pseudo-tilia (Bureau) trees (e.g., Vanscheit W, Jost V, Wolna P et al, "pseudo-tilia formulation (Ruscus aculeus L. 243)" have been reported to have Efficacy and safety comparisons with placebo for patients with chronic venous insufficiency "(Efficacy of cancer seed of cucumber' ingredient (2002) 52. objective compression and results of treatment for patients with chronic venous insufficiency).

In this study it was shown that: laser doppler blood flow measurement parameters, ankle and calf periphery, and transcutaneous oxygen tension were affected as early as 3 weeks after treatment. In contrast, as shown in previous studies, the subjective symptoms of CVI assessed on the visual analogue scale were not significantly different after 6 weeks of treatment compared to placebo. Treatment for 12 weeks is mandatory in order to reduce the subjective symptoms of CVI accordingly.

The results of this study show that the main role of red vine leaf extract is to prevent the development of CVI and the occurrence of skin dystrophy, and even to prevent or delay the transition from the early stage of CVI to CVII, which is clinically irrelevant.

Claims (16)

1. A coated tablet comprising the following ingredients:

(a) at least 50% by weight of a dry extract of red vine leaves, obtainable by extracting red vine leaves with water, drying and optionally adding up to 10% by weight of silica relative to the total amount of component (a);

(b) up to 50% by weight of excipients consisting essentially of:

-at least one binder,

-at least one disintegrating agent,

at least one filler, and

-a lubricant; and

(c) a tablet coating consisting essentially of a film-forming agent, a plasticizer, a coating agent and, if desired, a coloring agent.

2. The coated tablet according to claim 1, which comprises the following ingredients, based on the total mass of the coated tablet:

(a)50 to 70% by weight of a dried extract of red vine leaves;

(b)25 to 49% by weight of excipients, and

(c)1 to 5% by weight of a tablet coating.

3. The coated tablet according to claim 1 or 2, comprising the following ingredients, based on the total mass of the coated tablet:

(a)51 to 59% by weight of a dried extract of red vine leaves;

(b)38 to 48% by weight of an excipient, and

(c)1 to 3% by weight of a tablet coating.

4. A coated tablet according to any one of the preceding claims wherein the aqueous extract of red vine leaves is obtained by a process comprising the steps of:

(a) collecting red vine leaves when the flavonoid content has reached an optimum value;

(b) drying and pulverizing the leaves;

(c) cutting the leaves into pieces;

(d) extracting the leaves with water at elevated temperature for 6 to 10 hours;

(e) the obtained extract is concentrated and dried, and

(f) if necessary, up to 10% by weight of flow regulators, relative to the final total amount of the extract obtained, is added in the drying process (e).

5. A process as claimed in claim 4, wherein the leaves in step (iv) are extracted with water at a temperature of 60 to 80 ℃.

6. A coated tablet according to any one of the preceding claims, wherein excipient (b) consists essentially of the following ingredients, based on the total mass of excipient (b):

70 to 85 wt% of at least one binder,

0.5 to 12.5% by weight of at least one disintegrant,

5 to 15% by weight of at least one filler, and

1 to 5 wt% of at least one lubricant.

7. A coated tablet according to any one of the preceding claims wherein the binder is selected from powdered cellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, copolymers of vinylpyrrolidone with other vinyl derivatives, cellulose derivatives, and mixtures of these compounds.

8. A coated tablet according to any one of the preceding claims wherein the disintegrant is selected from the group consisting of colloidal silicon dioxide, sodium starch glycolate, cross-linked polyvinylpyrrolidone (cross-linked polyvinylpyrrolidone), cross-linked sodium carboxymethyl cellulose salt (cross-linked carboxymethyl ether sodium salt of cellulose), sodium carboxymethyl cellulose, dried corn starch, and mixtures thereof.

9. The coated tablet according to any one of the preceding claims, wherein the filler is an inorganic phosphate or hydrogen phosphate.

10. The coated tablet according to any one of the preceding claims, wherein the filler is selected from the group consisting of silicon dioxide, talc, stearic acid, sodium stearyl fumarate, magnesium stearate and glyceryl tribehenate.

11. The coated tablet according to any one of the preceding claims, wherein the tablet film (c) consists essentially of the following ingredients, based on the total mass of the tablet film (c):

50 to 85 wt% of at least one film forming agent,

5 to 10 wt.% of at least one plasticizer,

10 to 20% by weight of at least one coating agent, and

0 to 15% by weight of at least one colorant.

12. A process for preparing a coated tablet as claimed in any one of claims 1 to 11, comprising the following steps:

(A) mixing a dry aqueous extract of red vine leaves (a) with excipient (b) if necessary in the presence of a volatile diluent;

(B) the mixture obtained is sieved if necessary;

(C) compressing the mixture using a suitable tablet press; and is

(D) The resulting tablets are coated with a tablet coating film (c).

13. Use of a coated tablet according to one of claims 1 to 11 for the preparation of a pharmaceutical or dietetic composition for the treatment or prevention of discomfort, disorders and/or diseases associated with chronic venous hypervolemia and venous hypertension.

14. An aqueous extract of red vine leaves obtainable by a process comprising the steps of:

(a) collecting red vine leaves when the flavonoid content has reached an optimum value;

(b) drying and crushing the leaves;

(c) cutting the leaves into pieces;

(d) extracting the leaves with water at elevated temperature for 6 to 10 hours;

(e) concentrating and drying the obtained extract, and

(f) up to 10 wt.% of flow regulator relative to the final total amount of the obtained extract is added in the drying process (e).

15. The aqueous extract according to claim 14, which comprises 2.5 to 7.5% by weight of colloidal anhydrous silica.

16. The aqueous extract of claim 15, comprising about 4.0% by weight colloidal anhydrous silica.