วิธีการสำหรับการผลิตสารสกัดแห้ง

Abstract

DC60(07 / 05 / 57) การประดิษฐ์เกี่ยวข้องกับวิธีการสำหรับการผลิตสารสกัดแห้งของพืชและการเตรียม เภสัชภัณฑ์ที่มีสารที่เหมือนกัน,โดยเฉพาะอย่างยิ่งเภสัชภัณฑ์สมุนไพร,ซึ่งมีอย่างน้อยหนึ่งส่วนของ สารสกัดเอทานอล / เอเควียสของพืช(ยา),พืชถูกเลือกจากกลุ่มที่ประกอบด้วยRumicisherba; Verbenaofficinalis;Sambucusnigra;PrimulaVeris;และGentianaluteaสารผสมของสาร ดังกล่าวการประดิษฐ์เพิ่มเติมเกี่ยวข้องกับเภสัชภัณฑ์สำหรับการรักษาการอักเสบและ / หรือโรคติดเชื้อ ของจมูกและบริเวณลำคอและ / หรือโพรงรูจมูกรวมทั้งการใช้ของสารดังกล่าว       การประดิษฐ์นี้เกี่ยวข้องกับวิธีการสำหรับการผลิตสิ่งสกัดแห้งของพืช และสิ่งเตรียมเชิง เภสัชกรรมที่มีสิ่งเหมือนกัน โดยเฉพาะอย่างยิ่งพฤกษเภสัชภัณฑ์ ซึ่งมีอย่างน้อยหนึ่งสิ่งสกัด แอลกอฮอล์ / แอคเควียสของพืช(ยา)ซึ่งพืชถูกเลือกจากกลุ่มที่ประกอบด้วย Rumicis herba; Verbena officinalis;Sambucus nigra;Primula veris; Gentiana lutea และของผสมของมัน กระ ประดิษฐ์นี้เกี่ยวข้องเพิ่มเติมกับเภสัชภัณฑ์สำหรับการบำบัดการอักเสบ และ / หรือ โรคติดเชื้อของ บริเวณ จมูกและช่องคอ และ / หรือโพรงอากาศข้างจมูก เช่นกันกับการใช้ของมัน;

Description

[0001] METHOD FOR THE PREPARATION OF DRY EXTRACTS

[0002] Description

[0003] The invention relates to a method for producing

[0004] Plant dry extracts and those containing them

[0005] Pharmaceutical preparations, in particular phytopharmaceuticals, which contain at least one ethanolic / aqueous extract from a plant (drug), wherein the plants are selected from the group consisting of: Rumex acetosa L., Rumex acetosella L., Rumex obtusifolius L., Rumex patientia L., and Rumex crispus L., (hereinafter referred to collectively as "Rumicis herba"); Verbena officinalis; Sambucus nigra;

[0006] Primula veris; and Gentiana lutea, as well as mixtures thereof. The invention further relates to a medicament for the treatment of inflammatory and / or infectious diseases of the nasopharynx and / or the paranasal sinuses, as well as a

[0007] Dietary supplements and their use.

[0008] The medicinal plants listed above are known for their expectorant properties in treating upper respiratory tract infections, particularly sinusitis. Each individual herb contributes to the unique efficacy of the composition.

[0009] The root of Gentiana lutea (yellow gentian, gentian root) is generally used medicinally. Its constituents include, among others, various...

[0010] Secoiridoid glycosides with expectorant properties.

[0011] Of the aforementioned Rumex species, hereinafter referred to as "Rumicis herba" (sour dock herb), the leaves and stems are generally used medicinally. These contain flavonoids and various tannins, which have anti-inflammatory properties and also positively support the body's natural defenses. Unter dem Sammelbegriff "Rumicis herba (Sorrel herb)" wird eine Mischung folgender Spezies verstanden:

[0012] Rumex acetosa L., Synonym: Lapathum acetosa SCOP, Synonym: Lapathum pratense LAM, Synonym: Acetosa pratensis MILLER;

[0013] Rumex acetosella L, Synonym: Rumex infestus SALISB;

[0014] Rumex obtusifolius L., Synonym Lapathum obtusifolium MOENCH, Synonym Lapathum obtusantum MONTAD, Synonym Rumex actus WALLR. Synonym Rumex silvestris WALLR;

[0015] Rumex patientia L., Synonym Rumex olympicus BOISS., Synonym Lapathum hortense MOENCH;

[0016] Rumex crispus L.;

[0017] Rumex thyrsiflorus FINGERH., Synonym Acetosa thyrsiflora

[0018] FINGERH, Synonym Rumex acetosa subsp. auriculatus WALLR

[0019] The leaves and stems of Verbena officinalis (vervain, common verbena) are primarily used medicinally, as they contain iridoid glycosides, phenylethanoid glycosides, and flavonoids as their main constituents, which have expectorant and decongestant properties.

[0020] Antiviral effects can be achieved.

[0021] From Sambucus nigra (Black Elderberry, Elderflower,

[0022] Elderflowers are typically used medicinally, as their constituents contain various flavonol glycosides and, as the main active ingredient, sambunigrin, a cyanogenic glycoside, which has expectorant and antiviral effects (Grabovac, A. and Ullmer, A., Österreichische Apotheker-Verlagsgesellschaft mbH, 2003).

[0023] From Primula veris (cowslip, Primula flower,

[0024] Primrose flowers (both the flowers and calyx) are used medicinally. The constituents include triterpene saponins and phenolic glycosides, such as primulaverine. They have expectorant and antiviral properties. The constituents act as a mild decongestant. Secretolytic and expectorant in the treatment of respiratory diseases.

[0025] The combination of the aforementioned medicinal plants is known as

[0026] The secretolytic agent is known under the registered trademark Sinupret® and has been on the market for approximately 75 years. The medicinal plants used in Sinupret® are specifically selected, tested, and processed. The manufacturer, BIONORICA, achieves the consistent quality of the drug through optimized cultivation and harvesting strategies as well as rigorous quality control.

[0027] The composition underlying Sinupret® is particularly effective in treating inflammation and infections of the ear, nose and throat area and is especially suitable for the treatment of acute and chronic sinusitis and / or rhinosinusitis.

[0028] Both acute and chronic sinusitis are common. In three out of four cases, sinusitis develops as a consequence of a common cold, spreading to the...

[0029] sinuses affected by inflammation of the mucous membrane

[0030] is accompanied by. The respiratory tract extends from the main nasal cavity with its various sinuses to the alveoli of the lungs. The paranasal sinuses include the frontal sinuses, which

[0031] Ethmoid cells, the sphenoid sinus and the maxillary sinuses.

[0032] All of the aforementioned bony cavities are lined internally with mucous membrane and open into the main nasal cavity via narrow openings called ostia.

[0033] The surface of the respiratory tract is covered with a protective mucus to which dirt particles and pathogens such as viruses, bacteria or fungi, which are carried in the air we breathe, adhere.

[0034] penetrate, adhere. The mucus contains antibodies, which attack and neutralize the invading substances. To allow the foreign substances to be flushed out of the body, the mucus is usually cleared with the help of...

[0035] Cilia of the ciliated epithelium pointing towards the throat

[0036] transported away, where it can be swallowed.

[0037] In order to ward off infection-related respiratory diseases, the mucous membrane must be unimpeded by protective and

[0038] The mucous membranes possess cleansing mechanisms. The unimpeded function of the cilia, which transport the mucus through wave-like movements, is essential for the removal of pathogen-laden mucus. During an infection or inflammatory process of the upper respiratory tract, the protective and cleansing mechanisms of the mucous membrane are impaired.

[0039] functional.

[0040] For example, viruses such as rhinoviruses, adenoviruses, or coronaviruses trigger inflammatory reactions in the mucous membranes, causing them to swell and produce more mucus. This initially results in a watery, then thick, viscous mucus flow. As the inflammation of the nasal mucosa progresses, the sinus openings can swell, obstructing or even preventing the drainage of mucus. This leads to a buildup of thick mucus in the sinuses, resulting in impaired function and / or...

[0041] This leads to a loss of function of the cilia. This ultimately results in a loss of the cleaning mechanism of the

[0042] Mucous membrane.

[0043] Such a microenvironment promotes rapid

[0044] Increase in the number of ubiquitous microorganisms.

[0045] If these unfavorable conditions persist for a longer period, such as swollen mucous membranes and cilia stuck together by thick mucus, it can lead to a chronic condition.

[0046] Sinusitis can develop, resulting in permanent damage. of the mucous membrane and the ciliated epithelium. Respiratory tract-relevant pathogens, which also include, in particular, ENT-relevant germs that colonize the mucus, are

[0047] for example Staphylococcus aureus, Staphylococcus

[0048] epidermidis, Streptococcus pyogenes, Streptococcus pneumoniae, Streptococcus mutans or Haemophilus influenzae.

[0049] In the event of an obstruction of the upper airways due to

[0050] The ingredients of the thick mucus induce the formation of

[0051] used composition (Gentiana lutea : Rumicis herba : Verbena officinalis : Sambucus nigra : Primula veris =

[0052] 1:3:3:3:3) the formation of fresh, thin mucus, thereby achieving the above-described process of mucus loosening and removal, reducing inflammatory symptoms, and initiating the healing process of the nasal mucosa. Sinupret® gently achieves the

[0053] Sinupret® restores the self-cleaning function of the airways and simultaneously exerts a strong antimicrobial effect. A hallmark of Sinupret® is its good tolerability, thanks to the composition and dosage determined by BIONORICA, which rarely causes side effects in patients. Furthermore, no interactions with other medications are known.

[0054] Plant dry extracts are generally described and

[0055] Plant dry extracts are made from aqueous / ethanolic solutions.

[0056] Excerpts are known.

[0057] For example, plant dry extracts can be produced in large quantities according to the technical teaching of EP0753306. However, there is a great need to provide a new Sinupret® plant dry extract that offers a beneficial, improved effect from the plant combination.

[0058] The German Pharmacopoeia (DAB) 2010 sets minimum levels of ingredients for drug quality, thus ensuring consistent and improved quality.

[0059] Efforts must be made. Extraction and drying processes, in particular, represent a bottleneck for achieving sufficient quality in phytopharmaceuticals. Based on this prior art, the object of the present invention is therefore to provide an improved process for producing a plant dry extract, as well as an improved plant dry extract itself, which includes at least one ethanolic / aqueous extraction step, wherein the plants are selected from the group consisting of: Rumex acetosa L., Rumex acetosella L., Rumex obtusifolius L., Rumex patientia L., and Rumex crispus L., (hereinafter and in the claims referred to collectively as "Rumicis herba"); Verbena officinalis; Sambucus nigra;

[0060] Primula veris; and / or Gentiana lutea and their mixtures.

[0061] Surprisingly, it was possible to achieve this using a double

[0062] Extraction, whereby in a first step a

[0063] aqueous / ethanolic extraction followed by a second aqueous extraction step results in an improved

[0064] Plant dry extract is obtained.

[0065] Surprisingly, this inventive method can be used to increase the content of advantageous active ingredients in the

[0066] The existing active ingredient mixture is enriched in the respective total extract after drying, resulting in an improved pharmacological efficacy of the obtained

[0067] This is achieved with plant dry extract.

[0068] Therefore, the invention relates to a process for the production of plant dry extracts, comprising the steps of: alcoholic / aqueous extraction of Rumicis herba, Verbena officinalis, Sambucus nigra, Primula veris and Gentiana lutea,

[0069] Separating the excess,

[0070] c. second aqueous extraction of the residue from a.), separation of the supernatant,

[0071] Combining the residues obtained from b.) and d.), drying the residues and preserving the

[0072] Plant dry extract. The procedural improvement consists in the fact that

[0073] compared to a typical simple aqueous-ethanolic

[0074] For faster effectiveness, see extract.

[0075] Examples. This is surprising, since a change of

[0076] solvent for extraction is at most linear

[0077] Extrapolation could have been expected (e.g. if extraction is exclusively aqueous / ethanolic or exclusively aqueous).

[0078] In particular, the method according to the invention allows for improved dosing, so that an increased curative effect can be achieved with the same dose.

[0079] Therefore, the invention also relates to a

[0080] Plant dry extract, produced according to an invention

[0081] The process is obtained or is available (hereinafter referred to as the inventive (plant) dry extract, Sinupret).

[0082] Dry extract (TE) ) . In a further preferred embodiment of the

[0083] According to the inventive method, the ratio of Gentiana lutea : Rumicis herba : Verbena officinalis : Sambucus nigra : Primula veris is 1:3:3:3:3, each + / - 0.3 to 0.5 (such as 1 : 3.2 : 2.9 : 2.5 : 3.2 : 3).

[0084] Furthermore, it is preferred that a complete set of all plants (drugs) in a batch is submitted, wherein the

[0085] The ratio of the plants (drugs) is as stated above. Furthermore, it is preferred that the submitted plants (drugs) are cleaned and cut.

[0086] In a further preferred embodiment of the

[0087] The inventive method, in step a.) the

[0088] Aqueous / alcoholic extraction solvents have a water / alcohol ratio of 40:60 (v / v) to 60:40 (v / v), in particular 41:59 (v / v) or 50:50 (v / v). Ethanol is preferred, but methanol and propanol or mixtures thereof are also included. The use of 96% ethanol is further preferred.

[0089] It is also provided according to the invention that the extraction in steps a.) and c.) is carried out at 20 to 40 DEG C, wherein the extraction in steps a.) and c.) is carried out in 2 to 8h.

[0090] For the purposes of this invention, a “separation of the supernatant” after extraction according to the invention by means of drainage,

[0091] Decanting, filtration, sieving or a separation process known to a person skilled in the art can be carried out continuously or discontinuously. Furthermore, it is preferred that the drying according to step f.) takes place in a vacuum at 30 to 60 DEG C, in particular at 40 to 50 DEG C, preferably in a vacuum stirred dryer.

[0092] The dry extract according to the invention has a residual ethanol content of max. 0.5%.

[0093] Further suitable drying processes according to the invention are explained below:

[0094] Plant dry extracts are typically produced by extracting plant material using a solvent or solvent mixture, for example by maceration or percolation, and after separating the

[0095] Extraction residue, the resulting fluid extract or tincture is concentrated to dryness. Conventional drying processes are included according to the invention and include fluid bed drying or concentration to a thick or succulent extract and subsequent

[0096] Vacuum belt drying or tray drying of this

[0097] Spissum extract. Likewise, classical methods for the production of plant dry extracts according to the invention can be used via a

[0098] Fluid extract (or liquid plant extract) or a

[0099] Tincture should be taken into account; whereby after subsequent

[0100] Distillation of the solvents, a so-called

[0101] A viscous extract (spissum extract) is obtained, to which excipients and / or additives such as lactose, polyvinylpyrrolidone, sucrose, silicon dioxide, etc., are often added. This moist, viscous mass is then processed in rack cabinets or dryers to produce the desired dry extract. A procedure that is very common in the

[0102] When used in dry extract production, the so-called...

[0103] Vacuum belt drying process. In this process, the Spissum extract is pre-dried via falling film evaporators to

[0104] dry extract preparation.

[0105] A drying process using a fluidized bed dryer requires temperatures between approximately 47°C and 117°C. Drying using this method is carried out under normal conditions.

[0106] Pressure conditions were carried out.

[0107] A gentle drying process for obtaining

[0108] The plant dry extracts according to the invention are described in EP 0 753 306. According to the described method, the fluid extract obtained in the extraction is extracted from the

[0109] Plant materials according to the inventive method in a vacuum drying system, preferably

[0110] Vacuum stirred dryer with a multi-legged agitator extending through a cylindrical mixing and drying chamber, with its own drive, and, if required, equipped with a vapor filter and backflushing device.

[0111] Solvent condenser with aftercooler and collection vessel, recondenser and a process, control and regulating unit, and optionally with granulating nozzles, inserted and placed in the mixing chamber with a surface extending over the entire depth of the mixing chamber.

[0112] chopper extending from drying chamber with a

[0113] comb-shaped stator rotating blades

[0114] The material was dried in a dryer equipped with a flow and return temperature between 120°C and 5°C, an internal temperature between 10°C and 80°C, a vapor temperature of 15°C to 55°C, a pressure between 0.5 and 1,000 mbar, agitator speed of 0 to 10 rpm, and a chopper speed of 200 to 800 rpm. This was carried out in accordance with EP 0 753 306. The vacuum drying systems used, for example, by the former companies Inox Glatt AG or Inox-Maurer AG, are

[0115] It was sold under the names "IUT" or "INOX". Current manufacturers and distributors include, for example, De Dietrich.

[0116] Process Systems GmbH, Mainz, Germany (Rosemund ®) .

[0117] In this vacuum drying system, the fluid extract to be dried is fed into the mixing and drying chamber from above in a batch process.

[0118] Drying chamber pumped in and then a vacuum was applied.

[0119] A preferred vacuum drying system has the following features, as implemented, for example, in a known IUT / INOX system (supra): a.) A multi-armed agitator extending through a cylindrical mixing and drying chamber, with its own drive and, depending on requirements, a vapor filter, backflushing device, solvent condenser with aftercooler and collection vessel, recondenser, a process control unit, and, if necessary, granulation nozzles. b.) Furthermore, a chopper extending over the entire depth of the drying and mixing chamber with

[0120] c.) A drive independent of the agitator may be provided, as well as an optional comb-like stator to increase the chopping effect. Furthermore, one or more nozzles may optionally be provided for introducing the liquid plant extract from a reservoir into the drying chamber, as e.g. in...

[0121] WO2002073108 described.

[0122] The plant dry extracts obtained in this way are further processed into pharmaceutical preparations. The antimicrobial agent containing the plant dry extract according to the invention can thus

[0123] It can be used advantageously in the treatment of infections caused by respiratory pathogens. The expectorant and anti-inflammatory effects are complemented by the additional antimicrobial action. This not only weakens upper respiratory tract infections by loosening the viscous mucus laden with pathogens, but also by killing and / or reducing the proliferation of the bacterial pathogens, thereby containing or even completely eliminating them.

[0124] The invention described above enables, for example, the creation of a

[0125] Sinusitis and / or rhinosinusitis and / or inflammation of the paranasal sinuses, especially in their acute form, in a gentle manner without the patient

[0126] The use of synthetic chemical components is discussed.

[0127] The antimicrobial (pharmaceutical) composition of the present invention is particularly effective against

[0128] effective against respiratory pathogens, specifically against gram-positive cocci such as Staphylococcus aureus, Staphylococcus aureus (MRSA), Staphylococcus epidermidis, Streptococcus pyogenes, Streptococcus pneumoniae and Streptococcus mutans, and against gram-negative rod-shaped bacteria such as Haemophilus

[0129] influenzae, as well as against Enterobacteriaceae faecalis

[0130] It demonstrates antimicrobial efficacy. Furthermore, it shows efficacy against viruses.

[0131] The galenic formulation of the antimicrobial agent may be selected from the group consisting of: drops, juice, syrup, tablets, coated tablets, capsules, sustained-release formulations, rectal or vaginal suppositories, infusion, in particular

[0132] Throat sprays and disinfectant solutions; ointments, emulsions, powders, nasal sprays, liquid or solid preparations for Inhalation, compresses, dressings, especially wound and gum dressings, tamponades, also for teeth, rinsing solutions, especially in combination with physiological and

[0133] Hyperosmolar concentrations of salts or salt mixtures, preferably sodium chloride, especially sea salt. Naturally, the formulation may contain standard pharmaceutical excipients.

[0134] Thus, the present invention also relates to the use or application of the antimicrobial agent according to the invention, containing a plant dry extract according to the invention, for the treatment of infections caused by respiratory pathogens, as well as its use in the production of a

[0135] Both the medicinal product and a medicinal product as such.

[0136] In a further embodiment, the invention relates to a medicament for use or application in sinusitis and / or rhinosinusitis and / or inflammation of the

[0137] Paranasal sinuses, especially in their acute form, particularly for the treatment and prophylaxis of sinusitis and / or rhinosinusitis and / or inflammation of the

[0138] Paranasal sinuses, especially in their acute form.

[0139] Due to the ENT relevance of the tested pathogens, the agent according to the invention is also ideally suited wherever bacteria are directly and immediately present locally or

[0140] can be combated topically. The agent according to the invention can therefore preferably be applied – in addition to systemic application – directly at the contaminated site, e.g. in the form of a 100% biodegradable product.

[0141] Disinfectant solution or, of course, for direct topical application to skin and mucous membranes in both humans and animals. Various options are available for this purpose. Consider the various forms of application. The formulations, such as solutions, creams, ointments, and emulsions, are particularly suitable for dermatological use in both human and...

[0142] Veterinary medicine. Here, the agent according to the invention can be applied directly to the diseased area of ​​skin and / or used in the form of soaked compresses, pads or tampons.

[0143] The application of the

[0144] The agent according to the invention is naturally effective in the entire area of ​​diseases of the respiratory tract, particularly the upper airways, preferably in the area of ​​the pharyngeal, nasal, and paranasal sinus mucosa. Nasal irrigation is of particular importance, especially in combination with salts, such as a physiological or hyperosmolar saline solution. The invention also includes a nasal spray containing the agent according to the invention.

[0145] Medium .

[0146] From tonsil brush solutions, gargling solutions for pharyngeal infections to powder inhalation preparations or

[0147] The wide range of new application possibilities extends to nebulizer inhalation preparations.

[0148] Further areas of application and indication include wound and gum dressings, e.g. in the form of cotton dressings or cotton thread dressings, which are impregnated with the agent according to the invention.

[0149] Ear irrigation with solutions that... is also conceivable.

[0150] The inventive agents are used in cases of ear canal infections.

[0151] Therefore, the invention also relates to a medicinal product for the use and application of diseases of the entire

[0152] Respiratory tract, especially the upper airways, especially in the area of ​​the throat, nose and

[0153] Sinus mucous membranes, respiratory diseases,

[0154] especially mucovicidosis (cystic fibrosis), particularly its treatment and prophylaxis. Mucovicidosis can be treated particularly effectively; compare Figures 7A and 7B.

[0155] Another preferred embodiment relates to a

[0156] Dietary supplement containing the inventive

[0157] Means, especially in the form of a dietary

[0158] Composition. Suitable food or

[0159] Foodstuffs, including water, are those such as, for example, baked goods, beverages, and baby food preparations, which are not exhaustively defined in Regulation (EC) No 178 / 2002 of 28 January 2002. The invention

[0160] Dietary supplements can be used with a suitable

[0161] physiologically compatible carriers are placed.

[0162] The pharmaceutical preparations according to the invention can be produced in the form of dosage units.

[0163] This means that the preparations are in the form of individual parts, preferably capsules and ampoules, whose

[0164] The active ingredient content of plant dry extracts can correspond to a fraction or a multiple of a single dose.

[0165] Dosage units can contain, for example, 1, 2, 3, or 4 single doses, or 1 / 2, 1 / 3, or 1 / 4 of a single dose.

[0166] A single dose preferably contains the amount of

[0167] The plant dry extract (active ingredient) according to the invention is administered in a single dose, which usually corresponds to a whole, half, a third, or a quarter of a daily dose. A dosage of three times daily is preferred, preferably in the form of a tablet, particularly in the morning, at midday, and in the evening, optionally with meals. In another preferred embodiment, the

[0168] The galenic formulation of a calcium-coated tablet is chosen as disclosed in EP EP1392337.

[0169] Among non-toxic, inert, pharmaceutically suitable

[0170] Carrier materials are solid, semi-solid, or liquid.

[0171] To understand diluents, fillers and formulation aids of any kind, such as a) fillers and extenders, e.g. starches, lactose, cane sugar, glucose, mannitol, dextrins, maltodextrin and silica, highly dispersed silicon dioxide, b) binders, e.g. carboxymethylcellulose, cellulose powder, microcrystalline cellulose, alginates, gelatin,

[0172] Polyvinylpyrrolidone, c) humectants, e.g. glycerin, d) disintegrants, e.g. agar-agar, calcium carbonate and

[0173] Sodium carbonate, e) solution retarders, e.g., paraffin, and f) absorption accelerators, e.g., quaternary ammonium compounds, g) wetting agents, e.g., cetyl alcohol, glycerol monostearate, h) adsorbents, e.g., kaolin and bentonite, and i)

[0174] Lubricants, e.g. talc, calcium and magnesium stearate and solid polyethylene glycols or mixtures of the substances listed under a) to i).

[0175] The tablets, coated tablets, capsules, pills and granules can be packed with the usual, if necessary opaque agents.

[0176] containing coatings and shells, e.g., such as non-exhaustive hypromellose, microcrystalline methylcellulose

[0177] Cellulose, stearic acid, titanium dioxide, and also so

[0178] The formulation should be such that the active ingredient(s) are released only or preferentially in a specific part of the intestinal tract, possibly with a delayed effect, and polymer substances and waxes, for example, can be used as embedding materials. Examples: These examples serve solely to illustrate the invention, without limiting the invention to these examples.

[0179] limit.

[0180] Below, “dry extract (TE)” means the

[0181] Plant dry extract produced according to the invention.

[0182] Example 1:

[0183] The antiviral activity of the inventive

[0184] The effectiveness of dry extract has been confirmed in numerous in vitro experiments. These experiments initially focused on the general properties of the extract.

[0185] The cell-damaging (cytotoxic) effect of the dry extract according to the invention of the known Sinupret® (alcoholic / aqueous) was investigated. After incubating suitable cell lines (e.g., HeLa, HEp-2) with different viruses for a period of one hour, the infected cell lines were treated with different concentrations, and the effect on viral replication was subsequently measured.

[0186] The quantitative determination of antiviral activity in vitro was carried out either by detecting a cytopathogenic

[0187] Effects (Adeno5 Virus), in plaque reduction assay (FluA, HRV14, RSV) and in virus-specific enzyme immunoassays (ELISA;

[0188] Adeno5, RSV) .

[0189] When a cytopathogenic effect is detected, the

[0190] confluently grown virus-sensitive cells with a

[0191] The sample is infected with a defined viral solution (MOI, multiplicity of infection). After a one-hour incubation period, the...

[0192] Virus inoccult removed and the infected cell lawn

[0193] The samples are washed. Then, the physiological substance concentrations are added. The respective test procedures are then... The virus is cultured until a 70-90% cytopathogenic effect (CPE) is observed microscopically in the untreated virus controls, manifested as destroyed cell areas. The area of ​​destroyed cell areas is defined as 100% infection. The cell areas of the respective test samples are then evaluated comparatively, allowing the inhibitory effects of the substances being analyzed to be shown as percentage inhibition (% inhibition).

[0194] In the plaque reduction assay, the confluently grown virus-sensitive cells are treated with a defined viral solution.

[0195] (MOI, multiplicity of infection) is applied. After a one-hour incubation, the virus inocculum is removed and the infected cell lawn is washed. The physiological concentrations of the substance are then added, along with a solid medium component (agarose or methylcellulose), and further incubation takes place. The solid component in the superimposed medium limits the infection area, resulting in a focus of infected cells ("plaque"). The respective test samples are cultured until the set plaque count (MOI) is observed microscopically in the untreated virus controls. By fixing and staining the cell lawn, the virus plaques can be visualized as light halos in the

[0196] The dark-stained cell lawn is made visible.

[0197] Plaquely stone count is determined using

[0198] Image processing systems. The plaque count of the untreated control is defined as 100% infection. In contrast, the plaque count of the respective test samples is evaluated so that inhibitory effects of the test substance can be shown as percentage inhibition (% inhibition). In the ELISA, virus production is analyzed. Test strips with antibodies against the specific viruses bind to the in

[0199] cell culture supernatant of the infected cell lines located Viruses. To visualize the reaction, a pathogen-specific detection antibody labeled with peroxidase is used. After adding a substrate / chromogen and...

[0200] Hydrogen peroxide and tetramethylbenzidine are used to obtain

[0201] Color reaction. The intensity of the staining is determined photometrically and is proportional to the viral antigen content. Virus production in infected and treated cells is analyzed after infection of confluently grown cells.

[0202] virus-sensitive cells with a defined virus solution

[0203] (MOI, multiplicity of infection). After a one-hour incubation, the viral inocculum is removed and the

[0204] infected cell lawns are washed. This is followed by the

[0205] Addition of physiological substance concentrations. The respective test samples are cultured until a 70-90% cytopathogenic effect (CPE) is observed microscopically in the untreated virus controls.

[0206] Newly synthesized viruses are located in the cell culture supernatant at this stage. The photometrically determined

[0207] Extinction values ​​of the untreated controls are considered

[0208] 100% infection is defined. For comparison, the...

[0209] Extinction values ​​of the respective test approaches were evaluated, so that inhibitory effects of the test substances could be expressed as a percentage.

[0210] Inhibition (% inhibition) can be displayed.

[0211] In all experiments, a significant inhibition of viral replication was observed, i.e., a reduction in viral load, see Figure 1.

[0212] The dry extract according to the invention inhibits the multiplication of human (FluA) and swine (pFluA) influenza viruses.

[0213] (Influenza viruses). Concentrations of 124.8 pg Sinupret / ml (FluA) or 43.4 pg Sinupret / ml (pFluA) are sufficient to inhibit (reduce) 50% of the viral load. The Sinupret dry extract according to the invention shows efficacy against the viral strains HRV 14, Adeno5 and RSV have a lower EC50 and therefore correspondingly higher efficacy than Sinupret® alcoholic / aqueous (see Figures 1 and 2).

[0215] Example 2:

[0216] The anti-inflammatory activity of Sinupret was demonstrated in

[0217] Animal model confirmed. For example, carrageenan-induced paw edema in rats (male Wistar Han rats, 220-230g) was chosen as a test model. In this model,

[0218] Test substances are investigated for their anti-inflammatory effect by measuring their inhibitory effect on carrageenan-induced paw edema or pleuritis. (RS)-2-[4-(2-Methylpropyl)] serves as a reference substance.

[0219] phenyl]propanoic acid (Ibuprofen®) and 2-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]acetic acid (Indomethacin, “indo”). In the present experiments, groups of 10 rats each were treated with either Ibuprofen®, Indomethacin, Sinupret® dry extract (SIN TR), or Sinupret®

[0220] The patient was treated with a drug mixture (SIN, as commercially available) and carrageenan was injected one hour later. The inhibition of edema formation by the test and reference substances led to various Time points after carrageenan injection are determined, whereby the

[0221] Paw volumes from animals treated only with carrageenan served as a control (vehicel = blind control). The results of these experiments are presented in Tables 1 and 2 and Figures 3 to 6 and are explained below.

[0222] Figure 3: The carrageenan model showed that the

[0223] The dry extract according to the invention inhibits carrageenan-induced paw edema as early as 30 minutes after carrageenan injection, and does so more strongly than the Sinupret drug mixture, whereas ibuprofen® has no effect at this early stage.

[0224] The anti-inflammatory effect was observed. Even one and two hours after edema induction, the anti-inflammatory effect of the dry extract according to the invention is still stronger than that of Ibuprofen® and Sinupret® drug mixture (SIN). Table 1 shows the effect of Sinupret® (SIN) in carrageenan-induced pleuritis based on the inflammatory markers (PGE2, LTB4, TNF-alpha, I1l-beta) measured after 4 hours.

[0225] Rats (10 per group) were treated with either 100 mg / kg or 500 mg / kg SIN and, for comparison, with 5 mg / kg indomethacin and a blank sample, and 1 hour later with carrageenan.

[0226] injected.

[0227] “Inflammatory cells” correlate with PMN (polymorphonuclear neutrophils) accumulation / infiltration.

[0228] Statistics: Mean + / - SEM, n = 10, ** p< 0.01; ***p<0.001 vs vehicle (blind sample) (Tukey test), p< 0.05 is statistically significant.

[0229] A comparative graphical representation is given in Figure 4.

[0230] Table 2 shows the effect of Sinupret® dry extract (SIN TR) in carrageenan-induced pleuritis based on the

[0231] Inflammatory markers (PGE2, LTB4, TNF-alpha, Ill-beta) measured after 4 hours.

[0232] Rats (10 per group) were treated with either 100 mg / kg or 500 mg / kg SIN TR and, for comparison, with 5 mg / kg.

[0233] Indomethacin and a blind sample were treated, and carrageenan was injected 1 hour later.

[0234] “Inflammatory cells” correlate with PMN (polymorphonuclear neutrophils) accumulation / infiltration. Statistics: Mean + / - SEM, n = 10, ** p< 0.01; ***p<0.001 vs vehicle (blind sample) (Tukey test), p< 0.05 is statistically significant.

[0235] A comparative graphical representation is given in Figure 4.

[0236] Figure 5 shows the effect of Sinupret® drug mixture (SIN) and Sinupret dry extract (SIN TR) on the expression of COX-2 protein in rat lungs. Rats (10 per group) were treated with either 100 mg / kg or 500 mg / kg of SIN or SIN TR, respectively, and, for comparison, with 5 mg / kg indomethacin and a blank control. One hour later, carrageenan was injected. A Western blot was performed using 30 μg of homogenized rat lung protein on 10% SDS-polyacrylamide gel, and COX-2 was analyzed. Figure 6 shows the effect of Sinupret® drug mixture (SIN) and Sinupret dry extract (SIN TR) on cytokines.

[0237] Rats (10 per group) were treated with either 100 mg / kg or 500 mg / kg SIN or SIN TR, respectively, and comparatively with 5 mg / kg indomethacin and a blank sample, and 1 hour later

[0238] Carrageenan was injected. The inflammatory markers Ill-beta and TNF-alpha were measured 4 hours after the carrageenan injection.

[0239] Statistics: Mean + / - SEM, n = 10, ** p< 0.01; ***p<0.001 vs vehicle (blind sample) (Tukey test), p< 0.05 is statistically significant.

[0240] Conclusion :

[0241] The Sinupret dry extract (SIN TR) according to the invention shows a particularly advantageous significant inhibition of PGE2 formation (30%; p<0.01; Figure 4C, Table 2) compared to Sinupret® drug mixture (SIN). Furthermore, the Sinupret dry extract (SIN TR) according to the invention is

[0242] lower dosage more effective than the well-known Sinupret®

[0243] Drug Mixture (SIN) .

[0244] Example 3: The following example demonstrates that the dry extract according to the invention, when used topically, activates chloride secretion, probably via activation of CFTR. Furthermore, the dry extract according to the invention stimulates the ciliary beat frequency. Material: Cell culture: Human bronchial epithelial cells (HBE) were obtained from Lonza (Walkersville, MD) and expanded with Lonza (Walkersville, MD) bronchial epithelial cell growth medium (BEGM). 250 mg of the dry extract according to the invention.

[0245] Dry extract was dissolved in 1 ml of 50% ethanol and in Ultrasound treatment at 35 kHz for 30 minutes followed by centrifugation at 3000 g for 10 minutes at room temperature. The supernatant was aspirated. Amiloride (Sigma, St. Louis, MO) was dissolved in distilled, deionized water and diluted 1000-fold. Forskolin (Kaliokemm, EMD, San Diego, CA) was dissolved in DMSO and diluted 1000-fold.

[0246] diluted.

[0247] A Ussing chamber (Physiology Instruments San Diego, CA, USA) was used, containing Transwell inserts (Corning Life Sciences) with feedthrough at 37 degrees and a monolayer with a voltage clamp of 0 volts (VCC 600) (Physiology Cal Instruments San Diego, CA, USA) after setting the

[0248] Flow resistance. Transwell filters were placed in the solution at 37°C, and the solution was continuously infused with 95% oxygen to 5% CO2. The transepithelial resistance (RT) was measured using a computer program.

[0249] (Physiology Instruments San Diego, CA, USA) aligned at 640 ms, bipolar 10 mV potential measured across the monolayer according to Ohm's law. By definition, a positive deflection represents anion secretion or cation absorption. The experiments were repeated at least three times in HBE cell cultures.

[0250] Electrolyte solution used (in mM): 120 NaCl, 25 NaHCO3, 3.3 KH2PO4, 0.8 K2HPO4, 1.2 MgCl2, 1.2 CaCl2, and 10 Glucose. Ciliary beat frequency (CBF) measurements were performed according to a method by Woodworth et al. (Woodworth, BA, Zhang S,

[0251] Tamashiro E, Zinc increases ciliary beat frequency in a calcium-dependent manner, Am J Rhinol Allergy 24: 6-10, 2010). The images were acquired with a Leica Microsystems, Inc., Bannockburn, IL, using a 63x lens (Model A 602f-2, High Speed ​​Monogram Digital Video Camera, Basler). AG, Ahrensburg, Germany). The dry extract according to the invention was investigated with regard to transepithelial electrolyte transport. The dry extract was applied to the basolateral surface of HBE cells in increasing concentrations in the

[0252] Ussingkammer raised the issue before he subsequently...

[0253] It was mixed with amiloride and forskolin.

[0254] Figures 7a and 7b show the invention

[0255] Dry extract after addition of amiloride and forskolin causes a change in the transepithelial short-circuit current (I sc ) (7A), so that a dose-dependent increase in ciliary

[0256] Central beat frequency (CBF) measurements can be observed (7B), which is accompanied by chloride ion secretion.

[0257] These results demonstrate the beneficial use of the

[0258] dry extract according to the invention, e.g. by means of a

[0259] Nasal sprays, as improved mucociliary clearance (MCC) can be achieved.

[0260] Conclusion: The dry extract according to the invention is suitable for the treatment of respiratory diseases, in particular for the treatment of mucovicidosis (cystic fibrosis). Example 4:

[0261] The anti-inflammatory effect of the Sinupret dry extract and Sinupret drops (alcoholic / aqueous ("Sinupret OD") according to the invention was investigated as follows.

[0262] Carrageenan-induced paw edema (supra): First, the test animals (n=8 / group) were weighed in a fasted state and the basal volume of the hind paw was measured. The test substances were then administered orally to the animals (10 mL / kg body mass).

[0263] administered (Sinupret dry extract (TE): 5 mg / kg, equivalent to the amount of drug mixture in 1 mL drops / kg; 50 mg TE / kg) corresponding to 1 x human equivalent dose (1 x HED);

[0264] Sinupret drops (Sinupret OD): 1 mL OD / kg, corresponding to 1 x the human equivalent dose (1 x HED); 2.5 mL OD / kg,

[0265] equivalent to the amount of drug mixture in 50 mg TE / kg;

[0266] Indomethacin (20 mg / kg as positive control; 10% v / v ethanol as vehicle control). After 60 min, the animals were provoked by a subcutaneous injection of carrageenan (0.1 mL of a 1% w / v solution in physiological saline) into the left hind paw (plantar). Paw volumes were measured using

[0267] Plethysmography was determined before (-1 h) and after carrageenan infusion (Study 1: +1 h (Figure 8), Study 2: +15 min, +30 min, +1 h (Figure 9)) in all animals. The percentage

[0268] Inhibition of paw swelling versus vehicle control was calculated individually for each animal. The results are shown comparatively in Figure 8.

[0269] (Anti-inflammatory effect after 1 hour) .

[0270] Figure 8: A: Sinupret TE and Sinupret OD were each administered at 1 time the human equivalent dose. Sinupret TE has a faster and stronger anti-inflammatory effect than Sinupret OD. The anti-inflammatory effect of Sinupret TE, but not of Sinupret OD, is comparable to the inhibitory effect of the

[0271] well-known anti-inflammatory drug indomethacin.

[0272] B, C: The dose of Sinupret TE and Sinupret OD administered here is comparable based on the amount of drug mixture (DM) used in their preparation (B: 23.6 mg / kg, C: 223 mg / kg). Sinupret TE acts faster and more strongly.

[0273] Sinupret TE is anti-inflammatory, unlike Sinupret OD. According to LH, the anti-inflammatory effect of Sinupret TE, but not Sinupret OD, is comparable to the inhibitory effect of the well-known [product name missing].

[0274] Anti-inflammatory drug indomethacin. The results are shown comparatively in Figure 9 (inflammation reduction after +15 min, +30 min, +1 h)

[0275] Figure 9: The administered dose of Sinupret TE and Sinupret OD is based on the amount of drug mixture used in their manufacture (23.6 mg drug mixture / kg).

[0276] Sinupret TE is comparable to Sinupret OD. It is characterized by an earlier and stronger onset of action compared to Sinupret OD. Sinupret OD only begins to inhibit inflammation after 30 minutes. Sinupret TE inhibits inflammation comparably and quickly throughout the entire study period as the well-known Sinupret OD.

[0277] Anti-inflammatory drug indomethacin.

[0278] Example 5:

[0279] The following example describes specific marker compounds from the multi-component mixture. Procedure:

[0280] All samples were taken immediately after the individual

[0281] extracted during the extraction steps, filtered and placed in a

[0282] Concentration of 600 mg / L (in 30% vol. MeOH)

[0283] The samples were analyzed by mass spectrometry. Methylparaben was used as an internal standard. The samples were analyzed twice.

[0284] The data was processed and analyzed twice. The following parameters and devices were used:

[0285] MS: 5600 Triple ToF (ABSciex) ; HPLC: Agilent 1290

[0286] Software: Analyst TF 1.5.1, MultiQuant 2.1.1, MarkerView 1.2.1 Stationary phase: Zorbax RRHD Eclipse Plus C18, 2.1 x 50 mm, 1.8 μιη

[0287] LC method: 30

[0290] If quantified using reference standards, the amounts of ingredients are given as absolute content in [g]. Otherwise, the ingredient content is given as a percentage of the respective total extract (after step f.). Data originates from a laboratory AI approach and a production PI approach. The signals were detected during negative ionization.

[0292] If quantified using reference standards, the amounts of ingredients are given as absolute content in [g]. Otherwise, the ingredient content is given as a percentage of the respective total extract (after step f.). The data originate from laboratory assay AI and the

[0293] Production approach PI. The signals were detected during negative ionization.

Claims

Revised 15 / 2 / 2016 9. The method according to one of the preceding claims, characterized by a drying process according to step f.) is carried out under vacuum stirring drying.

10. Pharmaceutical preparations containing dried plant extracts that comply with one of the claims 1 through 9, herein the applied substances include suitable carriers, especially in the form of lozenges, coated tablets, tablets, film-coated tablets, dried powders, capsules or diluted liquids, especially solids, juices or syrups, ointments, emulsions, granules, dried powders, nasal sprays, liquid or solid preparations for inhalation, compresses, wound and gum dressings, compresses, tonsil ointments, and gargle solutions or rinse dressings.

11. Pharmaceutical products containing dried plant extracts that comply with one of the claims 1 through 9 or pharmaceutical preparations according to claim 11. 12.Pharmaceuticals containing dried plant extracts under any one of the claims in Articles 11 to 12 for use or application in cases of sinusitis and / or sinus mucositis and / or inflammation of the nasal cavity, especially in the acute form in individual cases, particularly for the treatment and prevention of sinusitis and / or sinus mucositis and / or inflammation of the nasal cavity, especially in the acute form in individual cases.

14. Pharmaceuticals containing dried plant extracts under any one of the claims in Articles 11 to 12 for use and application in all respiratory diseases, especially the upper respiratory tract, especially in the area of ​​the throat, nose and nasal mucosa, and respiratory diseases, especially mucovicidosis (cystic fibrosis), particularly for the treatment and prevention of all respiratory diseases, especially the upper respiratory tract, especially in the area of ​​the throat, nose and nasal mucosa, and respiratory diseases, especially mucovicidosis (cystic fibrosis). 15.Dietary supplements containing dried plant extracts comply with one of the claims 1 through 9.---------------------------------------------------------------1. A method for the production of dried plant extracts which includes the following steps: a.) Alcoholic / aqueous extraction of Rumicisherba, Verbena officinalis, Sambucus nigra, Primulaveris Gentianalute; a.) Separation of supernatant; c.) Aqueous extract of residual; d.) Separation of supernatant; e.) Combination of supernatants obtained from b.) and d.); f.) Drying of supernatant and determination of dried plant extracts.