WO1994015595A1

WO1994015595A1 - Medium comprising a pharmacological/biological active substance

Info

Publication number: WO1994015595A1
Application number: PCT/DK1994/000007
Authority: WO
Inventors: Lasse Hessel
Original assignee: Jemo-Pharm A/S
Priority date: 1993-01-06
Filing date: 1994-01-05
Publication date: 1994-07-21
Also published as: AU5832794A

Abstract

A medium is described, primarily in the form of a chewing gum, a lozenge for sucking/chewing, or a plaster (4). This medium contains ubiquinone, primarily in a prophylactic and/or therapeutic dosage.

Description

Medium comprising a pharmacological/biological active substance

This invention concerns a medium containing a pharmacolcgically/biologically active substance which can be released from the medium in controlled fashion.

More specifically, this invention concerns a type of chewing gum and a lozenge for sucking/chewing for use in controlled release or the medium to the mucous membr ana in the mouth and elsewhere, and a plaster for use in controlled release of the medium through t he skin.

Ubiquinone is the name given to the co-enzyme Q10 \CoQ10), which is also Known as vitamin Q, and whose chemical name is 2,3-dimethoxy-5-methyl-6-decaprenyl-1.4-benzoquinone. Ubi quinone forms an important part of the so-called electron transport chain in the membrane of the mitochondrions, which binde the energy in nutrients to adenosine triphosphate (ATP), the energy store of the body cells. To be more specific, ubiquinone is part of the enzyme known as succinate dehydrogenase-co-Q10 (see Flytlie, K.T. and Dhalvad, T.: Q10 - Din krops br ndstof, Ny Videnskab Publishing House, 1991, 96 pp. and Hessel, L. : Hemmeligheden bag Q10, Lademanns health series, Det ny Lademann A/S, 1992, 64 pp., which are included in their entirety here by way of reference).

The addition of ubiquinone to chewing gum leads to the slow release or the substance during the period in which the chewing gum is chewed.

The addition of ubiquinone to lozenges for sucking or chewing leads to the slow release of the substance during tha period in which the lozenges are sucked or chewed.

The use of plaster containing ubiquinone leads to the controlled release of the substance through the skin.

The release ot pharmacologically/biologically active substances from chewing gum is not a new technique. European patent application no. EP-472428-A describes a type of chewing gum containing stimulants such as nicotins and caffeine, antibiotics, water-soluble vitamins and minerals. European patent application no. EP-205133-A also describes a type of chewing gum that contains a tincture of herbal derivatives which have, among other things, an anti-paradentosis effect or refreshing effect, or which provide compensation for nicotins.

However, these well-known chewing gum compounds do not contain ubiquinone, and the aim of this invention is to provide a chewing gum with an improved effect on complaints in the oral cavity, including paradentosis. At the same time, a number of other beneficial effects are obtained which are not limited to the oral cavity, since once released the ubiquinone will pass with the saliva through the oesophagus and stomach, and will then be absorbed in the alimentary canal. The beneficial effects of ubiquinone comprise both a prophylactic effect and treatment of a range of complaints such as angina pectoris, hypertension, muscular dystrophy and periodontal complaints (see Greenberg: J. Clin. Pharmacol. 1990, 30:596-608). The importance of ubiquinone with regard to weight regulation has also been investigated (see Van Gaal, L., DeLeeuw, J., vadhsn- svikit, S. and Folkers, K.: Biomed. and clin. aspects of Q10 ;

4:369-373. (1984).

The release of pharmacologically/biologically activa substances from lozenges or sweets is not a new technique. Lozenges are often used to treat complaints in the oral cavity and pharynx, e.g. Hexokain^® lozenges from DAK-Laboratoriet A/S in Copenhagen, which contain the act ive subatances benzocaine and chlorhexadine hydrochloride. The production of sweets contai- ning anti-cough medicine is also well-known.

However, these well-known lozenges or sweets do not contain ubiquinone, and the aim of this invention is to provide a lozenge with an improved effect on complaints in the oral cavity, including paradentosis . At the same time, a number of other beneficial effects are obtained which are not limited to the oral cavity, since once released the ubiquinone will pass with the saliva through the ossophagus and stomach, and will then be absorbed in the alimentary canal

The release of pharmacologically/biologically active substances from plasters is not a new technique. Plasters containing nicotine have been produced to counteract the unpleasant effects experienced by people trying to stop smoking. Car sickness can also be counteracted by the application of a plaster containing ginger or scopolamine.

However, none of the plasters produced until new contain ubiquinone, and the purpose of this invention is to provide a plaster which has an effect on complaints associated with ubiquinone deficiency, or complaints for which ubiquinone has a soothing, prophylactic or healing effect. Especially in connection with the treatment of cardiac complaints and other serious illnesses which weaken the patient, it must be assumed that the oral application ot ubiquinone does not ensure the optimum absorption and/or effect of ubiquinone. in such cases, the maintenance of a constant. high level of ubiquinone in the blood is desirable, and this can be achieved by using plasters for the controlled release of ubiquinone through the skin into the bloodstream.

The new thing about this invention is that the active substance used is ubiquinone, and that the medium used is chosen from among media used for the release or the active substance through the mouth or skin (primarily a chewing gum, a plaster, or a lozenge for sucking/chewing). The medium used is infused with ubiquinone in a prophylactic and/or therapeutic dosage.

Chewing this new type of chewing gum leads to the extended or controlled release of ubiquinone to the mucous membrane in the mouth and, secondarily, to the gastrointestinal canal. This ensures the direct effect of ubiquinone for the prevention or treatment of complaints in the oral cavity (primarily paraden tosis).

In the preferred design of this invention, an amount of ubiquinone ranging from 1 mg to 200 mg iprimarily trom 10 to 30 mg , from 50 to 75 mg, or from 100 to 150 mg , and primarily in the form of micro-capsules) is added to each piece of chewing gum weighing 1 g. Micro-encapsulation protects the ubiqinone from the surrounding chewing gum matrix, and ensures protection from oxidation and slow release during chewing. Primarily, the micro-capsules have a diameter of less than 100 μm.

Ubiguinone is lipid soluble, so an oil solution is preferred, e.g. a soya oil solution, to which a natural emulsifier such as lecithin (primarily soya lecithin or a suspension or emulsion in soya lecithin) is added to ensure absorption in the aqueous environment in the oral cavity and gastrointestinal canal. Hiro et al. (Biomedical and clinical aspects of coenzyme Q. Volume 4, Elsevier, (1984)) have shown that ubiquinone is absorbed best in the form of a lipid solution. In addition, other additives may be used to promote the absorption of ubiguinone either on their own or in connection with lecithin.

The ubiquinone solution, suspension or emulsion can be micro- encapsulated in a colloid matrix such as gelatins, gum acacia (gum arabic), starch, etc., or in sugar.

Ubiquinone can also be added to the chewing gum direct in solid form (e.g. as a granulate), or in powder form in a blend with soya lecithin primarily in the ratio 1;1, but in such cases dosages should be increased by the amount of the active substance fixed in the gum base.

The minimum daily dosage should be approx. 30 mg to approx. 100 mg of ubiquinone, which has been declared to be almost free from side effects, see Langsjoen, P.H. and Folkers , K.: Am. J. Cardiol.: 65:7:521-3 (1990). Consequently, the recommended dosage is to Chew at least one piece of chewing gum containing 30 mg of micro-encapsulated ubiquinone for at least 10 minutes per day.

The chewing gum also contains a gum base and primarily flavourings such as oil of peppermint and fruit flavours, and sweeteners such as sugar, including saccharose, fructose and glucose, or sugar alcohols, primarily sorbitol or xylitol.

Among other things, the gum base contains gums, natural and synthetic resins, synthetic polymers, paraffins and waxes.

Ubiquinone has no distinctive taste, so it can be mixed into most standard chewing gum recipes without adding any other flavourings or sweeteners.

This invention concerns primarily a chewing gum containing 60- 80% sugar, 17-37% gum base, 0.1-0.3% flavourings, and 1.9-3.7% of a mixture of ubiquinone and lecithin in a ratio of from 1:0.5 to 0.5: 1, or a sugar free chewing gum containing 10-30% sorbitol, 67-67% gum base, 0.1 0.3% flavourings, and 1.9-3.7% of a mixture of ubiquinone and lecithin in a ratio of from 1 : 0 . 5 to 0 . 5 : 1 .

Sucking or chewing the above-mentioned new tablet leads to extended or controlled release of ubiquinone to the mucous membrane in the mouth and, secondarily, to the gastrointestinal canal. This ensures the direct effect of ubiquinone for the prevention or treatment of complaints in the oral cavity

(primarily paradentosis).

For the production of lozenges for sucking containing ubiquinone, a hard tablet is preferred which dissolves or disintegrates slowly in the oral cavity while ubiquinone is released. Lozenges are made by moulding and cutting, or by compression. During moulding the components are mixed in the form of a powder or in liquid form with the tablet base (usually sucrose, gum acacia or tragacanth) to produce a paste which is than cut into uniform pieces which are dried in a heat chamber. Flavourings and colourings may be added. Lozenges produced by compression are made like standard tablets, using standard tablet additives such as lactose, dextrose, starch, sodium chloride and gum acacia, by dry or moist granulation, but by compression when a higher pressure is applied.

For the production of lozenges for chewing containing ubiquinone, a softer tablet is preferred, primarily a gelatine, starch or pectin tablet in which ubiquinone is distributed, primarily in the form of a dispersed powder.

In the preferred design of this invention, an amount of ubiquinone ranging from 1 mg to 200 mg (primarily from 10 to 30 mg, from 50 to 75 mg, or from 100 to 150 mg, and primarily in the form of micro-capsules) is added to each lozenge weighing 1 g, Micro-encapsulation ensures protection from oxidation and slow release during sucking/chewing. Primarily, the micro- capsuies have a diameter of less than 100 μm .

Ubiquinone is lipid soluble, so an oil solution is preferred, e.g. a soya oil solution, to which a natural emulsifier such as lecithin (primarily soya lecithin or a suspension or emulsion in soya lecithin) is added to ensure absorption in the aqueous environment in the oral cavity and gastrointestinal canal. Hiro et al. (Biomedical and clinical aspects of coenzyme Q. Volume 4, Elsevier, (1984)) have shown that ubiquinone is absorbed best in the form of a lipid solution. In addition, other additives may be used to promote the absorption of ubiquinone either on their own or in connection with lecithin.

The ubiquinone solution, suspension or emulsion can be micro- encapsulated in a colloid matrix such as gelatine, gum acacia, starch, etc., or in sugar.

Ubiquinone can also be added to the lozenge direct in solid form (e.g. as a granulate or in powder form), in a blend with soya lecithin primarily in the ratio 1:1.

The minimum daily dosage should be approx. 30 mg to approx. 100 mg of Ubiquinone, which has been declared to be almost free from side effects, see Langsjoen, P.H, and Folkers, K.: Am. J. Cardiol.: 65:7:521-3 (1990). Consequently, the recommended dosage is to suck or chew at least one tablet containing 30 mg of micro-encapsulated ubiquinone for at least 10 minutes per day,

The tablet also contains primarily flavourings such as oil of peppermint and fruit flavours, and sweeteners such as sugar, including saccharose, fructose and glucose, or sugar alcohols, primarily sorbitol or xylitol.

Ubiquinone has no distinctive taste, so it can be mixed into most standard lozenge recipes without adding any other flavourings or sweeteners,

This invention concerns primarily a lozenge containing 10-100 mg, primarily 30-70 mg, of a mixture of ubiquinone and lecithin in a ratio of from 1:0.5 to 0.5:1.

Using the new plaster leads to the extended and/or controlled absorption of ubiquinons through the skin. This ensures the direct effect of ubiquinone for the prevention or treatment of iliness or obesity. Shortly after application of the plaster the skin starts to sweat. The skin dissolves slightly; thereby allowing the ubiquinone to be absorbed.

In the preferred design of this invention, an amount of ubiquinone ranging from 1 mg to 200 mg (primarily from 10 to 30 mg, from 50 to 75 mg. or from 100 to 150 mg) is suspended in a gel or gel-like substance, which seeps through a permeable membrane under almost complete control and through the skin for absorption by the body, using a plaster.

Ubiquinone in the form of a powder, solution, suspension or emulsion can be distributed in a gel such as ethanol gel or propanol gel consisting of alcohol, in which hydroxy propyl cellulose or similar cellulose derivatives have been dissolved or absorbed. The gel may also consist of paraffinum liquidum, polyisobutylenum, or other lipophilic gelling agents to promote absorption through the skin. The gel may contain the granulation agent known as Eudragit E100.

The minimum daily dosage should be approx. 30 mg to approx. 100 mg of ubiquinone, which has been declared to be almost free from side effects, see Liangajoen, P.K, and Folkers, K. : Am. J. Cardiol.: 65:7:521-3 (1950). Consequently, the recommended dosage is to apply at leaat one plaster containing 30 mg of ubiquinone daily. Direct absorption through the skin makes it possible to avoid passing with the blood through the liver first, which would result in the partial break-down of ubiquinone. Consequently , It may be assumed that the effective daily dosage is less when ubiquinone plaster ie used.

The invention is described in detail below, with reference to the examples given and the attached drawing, where

Figure 1 shows the preferred design of the plaster containing ubiquinone. Example 1.

Chewing gum is produced in standard fashion weighing 1.2 g per piece, with the following contents (percentages in terms of weight);

sweetener saccharose 70% sorbitol 20%

gum base 27% 77%

flavourings 0.2% 0.2%

ubiguinone/lecithin

mixture 1:1 2.8% 2.8%

The chewing gum should be packed in light-proof packaging, since ubiquinone breaks down when exposed to sunlight.

Example 2.

Lozenges are produced in standard fashion weighing 1 g each, with the following contents (expressed in mg);

sucrose 300 mg

lactose 639 mg

flavourings 1 mg

ubiquinoae/lecithin

mixture 1 : 1 60 mg

The tablets should be packed in light-proof packaging, since ubiquinone breaks down when exposed to sunlight.

Example 3,

Lozenges are produced in standard fashion weighing 1 g each, with the following concents (expressed in mg):

liquorise extract 70 mg

aniseed oil 5 mg

menthol 5 mg

saccharine sodium 300 mg

magnesium stearate 600 mg

ubiquinone/lecithin

mixture 1:1 20 mg

Example 4,

Lozenges are produced in standard fashion weighing 1 g each, with the following contents (expressed in mg):

gum acacia 35 mg

tragacanth 10 mg

eucalyptus oil 5 mg

sorbitol 150 mg

magnesium stearate 700 mg

ubiquinone/lecithin

mixture 1:1 100 mg (1) is a leak-proof plastic membrane on tha outside of the plaster. The material used is primarily polypropylene or polyethylene.

(2) is the carrier, primarily a hydroxy propyl cellulose/ethanol gel, in which ubiquinone is incorporated.

(3) is a semi-permeable or perforated plastic membrane, the pore size of which regulates the race of release of the active substance (in this case ubiquinone) . The larger the pores, the faster the release. The preferred diameter of the pores ensure the regular release of ubiquinone over a period ot 6-12 hours.

14) shows a typical plaster design. The middle field contains ubiquinone, and the edges are coated with a skin-friendly adhesive.

The plaster is packed primarily in a light-proof foil pack (e.g. aluminium foil), which exposes the adhesive field when removed.

The plaster should not be applied to the same area of skin two or more times in a row. A new area of skin should be chosen each time a new plaster is applied, and ubiquinone is absorbed most easily by areas of skin in which there is no hair.

The speed of absorption is determined by the area of the plaster, the permeability, and the concentration of ubiquinone in the carrier.

Claims

PATENT CLAIM.

1. A medium containing a pharmacologically/biologically active substance which can be released from the medium in controlled fashion, characterised by the fact that the active substance is ubiquinone, and by the fact that the medium used can be chosen from among media used for the release of the active substance through the mouth or skin (primarily a chewing gum, a plaster, or a lozenge for sucking/chewing).

2. A medium according to claim 1, characterised by the fact that it contains ubiquinone in a prophylactic and/or therapeutic dosage.

3. A medium according to claim 1 or 2, characterised by the fact that it contains 10-30 mg of ubiquinone per piece.

4. A medium according to claim 1 or 2, characterised by the fact that it contains 50-75 mg of ubiquinone per piece.

5. A medium according to claim 1 or 2, characterised by the fact that if contains 100-150 mg of ubiquinone per piece.

6. A medium according to any of the above-mentioned claims, characterised by the fact that the ubiquinone is micro-encapsulated.

7. A medium in the form of a chewing gum according to any of the above-mentioned claims, characterised by the fact that it contains 60-80% sugar, 17-37% gum base, 0. 1.0.3% flavourings, and 1.9-3.7% of a mixture of ubiquinone and lecithin in a ratio of from 1:0.5 to 0.5:1.

8. A medium in the form of a chewing gum according to any of the above-mentioned claims, characterised by the fact that it contains 10-30% aorbitol. 67-87% gum base, 0.1-0.3%

flavourings, and 1.9-3.7% of a mixture of ubiquinone and lecithin in a ratio of trom it 0.5 to 0.5:1.

9. A medium in the form of a tablet according to any of the claims 1-6, characterised by the fact that it contains 1-10% of a mixture of ubiquinone and lecithin in a ratio of from 1:0.5 to 0.5:1.

10. A medium according to any of the claims 7-9 for the prevention/treatment of paradentosis.

11. A medium in the form of a plaster according to any of claims 1-6, consisting of a leak-proof plastic membrane (1) which forms the outside of the piaster when applied, a layer (2) consisting of a carrier containing ubiquinone and covered by a semi-permeable or perforated plastic membrane d ) , located within the area of the leak-proof membrane, with an adhesive applied to the edges of the plaster.

12. A medium according to claim 11, characterised by the fact that the carrier consists of a gel of hydroxy propyl cellulose in ethanol.

13. A medium according to any of the above-mentioned claims for the prevention and/or treatment of cardiac complaints.

14. A medium according to any of the above-mentioned claims for the prevention and/or treatment of obedity.