WO2001054673A1

WO2001054673A1 - Method for preparing and administering medicinal plant material

Info

Publication number: WO2001054673A1
Application number: PCT/CA2001/000106
Authority: WO
Inventors: Robert A. Miller
Original assignee: The University Of British Columbia
Priority date: 2000-01-31
Filing date: 2001-01-31
Publication date: 2001-08-02
Also published as: AU2992901A

Abstract

A method for preparing and administering compositions comprising plant material for delivery to the alkaline regions of the gastrointestinal tract where they are available for absorption into the systemic circulation. The method yields a solid dispersion comprising a co-precipitate of the plant material in a continuous phase of an enteric polymer.

Description

METHOD FOR PREPARING AND ADMINISTERING MEDICINAL PLANT MATERIAL

Field of the Invention

This application relates to a method of preparing and administering a solid dispersion comprising medicinal plant material. The solid dispersion comprises a co-precipitate of plant material in a continuous phase of an enteric polymer. The invention may be employed for delivering compositions comprising plant extracts to the alkaline regions of the gastrointestinal tract where they are available for absorption into the systemic circulation.

Background of the Invention

A large number of common herbs are known to have medicinal activity. For example, the expressed juice of E. purpurea, as well as hydroalcoholic extracts of the root of E. angustifolia and E. purpurea, have been shown to have immune stimulant properties. The identity of the specific chemical constituent(s) of echinacea responsible for its medicinal activity is the subject of on-going study, but likely candidates include hydrophilic polysaccharides, caffeic acid derivatives and lipophilic isobutylamides. Currently echinacea is a hriinistered principally in tablet, capsule, lozenge, syrup or tincture form. Some of the active ingredients of the herb may be absorbed to some degree in the oral cavity. However, it is believed that the clinical efficacy of echinacea extracts and other plant-based materials may be diminished by inactivation of active plant constituents in the acidic environment of the stomach before reaching more alkaline regions of the gastrointestinal tract where absorption into the systemic circulation commonly occurs It is quite likely that other commercially important botanicals, such as garlic, ginseng, eleuthero ('Siberian ginseng'), devil's claw and maitake mushrooms include active ingredients that are degraded by stomach acid. For example, crushing, cutting or chewing garlic cloves activates the enzyme allinase which converts the odorless alliin of garlic to allicin that is believed to be the most active ingredient and has the typical odour and taste of fresh garlic. Allicin undergoes further chemical transformations when ingested to produce other sulfur-containing derivatives with differing pharmacological activities. However, if garlic is dehydrated and consumed orally in capsule or tablet form, without enteric coating, dissolution in the presence of stomach acid leads to inactivation of the enzyme allinase and prevents conversion of alliin to allicin, the primary active principle.

It is similarly believed that the immunostimulant activity of ginseng is primarily due to water-soluble polysaccharides, with a lesser contribution from the characteristic constituent ginsenosides, which are claimed to be responsible for a variety of other pharmacological effects. Ginseng oligosaccharides, prominent in traditional hot-water extracts of the root, are likely inactivated to some degree by gastric fluid.

Devil's claw extract, claimed effective in treating certain forms of arthritis, has also been found to be inactive when administered orally, but active when administered intraperitoneally or inrraduodenally. Again, it is believed that the difference in activity depending upon the route of administration may be due to gastric acid degradation of the active principle(s).

The action of gastric and intestinal enzymes may also have a negative impact on bioactivity of some plant preparations. Studies suggest that the free-radical scavenging activity of ginkgo leaf extract is reduced by approximately one-half due to degradation by digestive enzymes.

Drug delivery systems for delayed release of acid-sensitive drugs or other biologically active materials are well known in the prior art. For example, international application No. WO 98/19668 published 14 May, 1998 relates to a delayed delivery system comprising an enteric barrier layer. The enteric layer is relatively insoluble in gastric fluid but rapidly or immediately soluble in intestinal fluid, whereby the drug is released in a pulsatile manner in the proximal segment of the gastrointestinal tract.

Use of enteric polymers (i.e. polymers which are relatively insoluble in acidic gastric fluid) is normally in the form of a coating, either for a tablet, pellet or sphere. The drug to be delivered is formulated into a discrete structure and the polymer is then applied as a coating around this structure. Such structures comprising enteric barriers cannot be administered in dosage forms where small particle sizes are necessary, such as oral suspensions.

Another drawback of such enterically coated tablets and the like is that the active ingredients are not available for absorption in the oral cavity to confer, for example, a local analgesic effect in addition to a systemic effect.

Preparation of co-precipitates of drugs with pharmaceutically acceptable carriers have been proposed previously as a means of enhancing bioavailability of poorly soluble drugs or reducing the release rate of highly soluble drugs. For example, United States Patent No. 5,776,495 relates to a process for the production of a solid dispersion of at least one therapeutic agent in a hydrophilic polymer. The '495 invention may be used, for example, to improve the bioavailability of hormones, such as progesterone, after oral adininistration.

The prior art does not, however, teach the advantages of preparing co-precipitates using enteric polymers rather than highly hydrophilic or hydrophobic polymers. Accordingly, the need has arisen for a method of formulating solid dispersions of enteric polymers and medicinal plant material and the use of such solid dispersions for therapeutic purposes.

Summary of the Invention

In accordance with the invention, a method of preparing a solid dispersion of a pharmacologically active plant material is disclosed. The method includes the steps of (a) providing an extract comprising the plant material and a non-toxic liquid solvent; (b) dissolving an enteric polymer in the extract; and (c) removing the solvent from the extract to yield the solid dispersion, the dispersion comprising a co-precipitate of the extract and the polymer.

The plant material may comprise herbs selected from the group consisting of echinacea, garlic, eleuthero, maitake mushrooms, astragalus, bilberry, black cohosh, cayenne, chamomile, devil's claw, dong quai, evening primrose oil, feverfew, ginger, ginkgo, ginseng, goldenseal, gotu kola, grape seed extract, hawthorn, kava kava, licorice, milk thistle, St. John's wort, saw palmetto, tea tree and valerian.

In one embodiment of the invention the solvent may comprise ethanol and water. The percentage of ethanol in the solvent is preferably within the range of 75 - 95%. In one particularly preferred embodiment, the plant material is echinacea, the enteric polymer is hydroxypropylmethylcellulose phthalate and the alcohol content of the solvent is approximately 80%.

This application also relates to a homogenous solid dispersion prepared in accordance with the above-described method and a method for administering a therapeutically effective amount of the solid dispersion. The solid dispersion may be formulated together with a pharmaceutically effective carrier suitable for oral administration.

Brief Description of the Drawing

In a drawing which describes an embodiment of the invention but which should not be construed as restricting the spirit of scope of the invention in any way,

Figure 1 is a plot showing dissolution of a solid dispersion of echinacea prepared in accordance with the invention in 0.1 N HC1 and pH 7.2 phosphate buffer as measured by ultraviolet absorbance at 260 nm.

Detailed Description of the Preferred Embodiment

This application relates to a method for preparing a solid dispersion of plant material in a continuous phase of an enteric polymer and the use of such a solid dispersion for therapeutic purposes. As used in this patent application, the following terms shall have the corresponding meanings:

"Solid dispersion" means a dispersion of one material in a continuous solid phase of another material. The term solid dispersion includes a solid solution where the dispersed material is present at a molecular or microparticular level and is not visible; and solid suspensions where the dispersed material is present in a visible particulate form.

"Plant material" means material extracted or otherwise derived from plants and having some demonstrated or potential medicinal activity. Plant material includes herbal remedies such as echinacea, garlic, eleuthero, maitake mushrooms, astragalus, bilberry, black cohosh, cayenne, chamomile, devil's claw, dong quai, evening primrose oil, feverfew, ginger, ginkgo, ginseng, goldenseal, gotu kola, grape seed extract, hawthorn, kava kava, licorice, milk thistle, St. John's wort, saw palmetto, tea tree and valerian.

"Enteric polymer" means a polymer which is capable of forming a powder precipitate and is relatively insoluble in gastric fluid, such as hydroxypropylmethylcellulose phthalate. Other possible enteric polymers include methacrylic acid copolymers, polyvinylacetate phthalate, shellac, alginic acid and appropriate salts of enteric polymers such as cellulose acetate phthalate, cellulose acetate trimellitate, cellulose acetate butyrate and cellulose acetate propionate.

"Non-toxic liquid solvent" means a solvent that does not leave a residue when dried that is potentially toxic when ingested by human beings. Examples of non-toxic solvents include water, ethanol and combinations thereof. The term does not include potentially hazardous volatile solvents such as acetone, ethyl acetate or chlorinated solvents.

Although non-prescription herbal remedies have existed for centuries, they have recently achieved increased market acceptance in North America. Many common herbs are known to have multiple active ingredients conferring medicinal benefits. For example, echinacea has been shown to have analgesic and immune stimulant properties. The specific chemical constituents of echinacea which confer its medicinal activity is the subject of on-going study, but likely includes polysaccharides and isobutylamides. It is commonplace for consumers to take echinacea in tincture or capsule form when the first sign of cold or flu symptoms occurs. Recent surveys suggest that approximately 15 - 20% of North Americans consume echinacea from time to time.

Oral ingestion of plant materials exposes such materials to the body's digestive processes. Such processes have evolved to extract nutrition from ingested materials. However, it is believed that the medicinal effectiveness of echinacea and other herbs may be limited by the fact that medicinal ingredients are inactivated in the acidic environment of the stomach before reaching more alkaline regions of the gastrointestinal tract where absorption into the systemic circulation commonly occurs.

The applicant's invention involves a method for preparing a solid dispersion of plant material and an enteric polymer. The solid dispersion may be formulated as a composition suitable for oral ingestion and which is not inactivated in the acidic regions of the gastrointestinal tract.

The method involves providing a plant extract comprising plant material suspended in a non-toxic liquid solvent. Tinctures comprising macerated plant material in a hydroalcoholic solvent may be used, for example, as the starting material. A suitable enteric polymer is then dissolved in the solvent. Enteric polymers have little or no solubility in acidic media, such as gastric fluid, but are soluble in alkaline media, such as intestinal fluids. The solvent is then removed by processes such as spray-drying to yield a solid dispersion comprising a co-precipitate of the plant material and the enteric polymer. In particular, the plant material is uniformly dispersed in a continuous phase of the enteric polymer.

The co-precipitate of plant material and polymer may be produced in a range of particle sizes. This enables the invention to be administered by means of a wide variety of drug delivery systems, including oral systems such as tablets, capsules, lozenges or suspensions. Other delivery systems could include topical semi-solids, topical suspensions, rectal suspensions or suppositories, pulmonary aerosols or other delivery systems where fine particles are required.

As indicated above, the solid dispersion consists of plant material uniformly dispersed throughout the continuous phase of the enteric polymer. Accordingly some of the plant material is exposed at the surface of the particles and is therefore capable of having a therapeutic effect at the site of ingestion. The amount of plant material so exposed may be reduced or increased by varying the plant material to polymer ratio.

The solid dispersion is ordinarily prepared so that the amount of plant material at the surface of the particles potentially exposed to gastrointestinal fluids is minimal. As will be apparent to a person skilled in the art, dissolution of the solid dispersion depends upon the dissolution properties of the continuous phase. Since the continuous phase is an enteric polymer in the present invention, very little dissolution would occur until the dispersion reaches the small intestine, which is normally the site of the most efficient absorption. The polymeric medium in which the plant material is dispersed enhances the stability of the plant materials by reducing the opportunity for oxidative and hydrolytic degradation due to reduced permeability to oxygen and water imparted by the enteric polymer when the dispersion is orally ingested. In addition to preventing acid-catalyzed degradation and enzymatic degradation of plant bioactives in the acidic gastric fluid, the enteric polymer may also confer a degree of protection against destructive pancreatic enzymes in the intestinal tract.

In one preferred embodiment of the invention, a solid dispersion comprising a co-precipitate of echinacea and hydroxypropylmethylcellulose phthalate NF(HPMCP) polymer is administered orally in the form of a syrup or lozenge. Since the echinacea, including its active ingredients, is uniformly dispersed throughout the polymer, some of the active ingredients are available for local absorption in the oral cavity or upper respiratory tract of the patient as discussed above, unlike conventional enterically coated drugs. For example, the active ingredients may have a local analgesic effect in the mouth and throat (i.e. upper respiratory tract) of the patient in addition to a systemic effect when the active ingredients are absorbed in the alkaline regions of the gastrointestinal tract downstream from the stomach. In other words, the fact that the majority of the active ingredients are protected from inactivation by gastric fluids does not preclude the advantages of local absorption of some active ingredients in the upper gastrointestinal tract upstream from the stomach. Further, formulating the echinacea plant material as a solid dispersion helps to mask the taste and odour of echinacea which some consumers consider unpleasant.

An important feature of the invention is the versatility of its application in different formulation media and formats. Since the solid dispersion comprising plant material can be prepared in an extremely fine powder form, this enables the plant material to be formulated for effective delivery in a wide variety of commercially important delivery formats having a pleasant taste and smell, such as ice cream, teas, jellied drinks, soft drinks and fruit juices, cough syrups and a wide variety of food products including candies, lollipops and cough drops. The invention thus enables the ingestion of a high dosage of potentially therapeutic plant materials while masking potentially unpleasant taste and odour.

Example 1

The specific nature of the method and composition of the present invention will be more fully apparent from consideration of the following specific examples of preferred embodiments thereof. In the example, as in the preceding description, all parts and percentages are given by weight unless otherwise indicated.

A plant extract of Echinacea angustifolia root and combined

Echinacea purpurea root and tops was obtained in the form of a commercially available hydroalcoholic tincture comprising 55% ethanol and 45% water. The amount of ethanol in the extract was then increased to approximately 80%. A quantity of a cellulosic enteric polymer , namely hydroxypropylmethylcellulose phthalate NF (HPMPCP), equivalent to the weight of plant solids contained in the extract, was dissolved in the extract. The hydroalcoholic solvent was then removed from the extract by spray-drying to yield a solid dispersion comprising co-precipitate of echinacea and HPMPCP. The solid dispersion consists of a fine off-white to beige powder with particles ranging in size from five microns to less than one micron.

The co-precipitate was not noticeably odoriferous suggesting that the applicant's process can effectively mask the scent of plant material. A similar effect may be achieved by forming solid dispersions of enteric polymers and other markedly odoriferous prominent plant preparations such as those from garlic cloves and valerian root.

Acid resistance of the solid dispersion was tested using USP Dissolution Apparatus II using 0.1 N HCl as the test fluid as illustrated in Figure 1. Release in alkaline fluids was also determined using pH 7.2 phosphate buffer as the test fluid. The first samples were withdrawn from the dissolution flasks approximately two minutes after the materials were introduced into each flask. The resulting absorbance of approximately 0.3 indicates that there is a rapid release of some component(s) of each sample, presumably from the surface of the particles of powder. The horizontal plot of samples in 0.1 N HCl indicates that no further material is released during the test period. The positive slope for samples in pH 7.2 phosphate buffer indicates a further release of material into solution as a function of time.

Other tests relating to the stability of dispersions prepared in accordance with the invention confirm that isobutylamides derived from echinacea are more stable in a solid dispersion of enteric polymer than in a hydroalcoholic extract after an extended storage period (four months).

Example 2

A plant extract of St. John's Wort was obtained in the form of a commercially available hydroalcoholic tincture comprising 55% ethanol and 45% water. The amount of ethanol in the extract was then increased to approximately 80%. A quantity of a cellulosic enteric polymer, namely hydroxypropylmethylcellulose phthalate NF (HPMCP), equivalent to the weight of plant solids contained in the extract, was dissolved in the extract. The hydroalcoholic solvent was then gradually removed from the extract by spray-drying to yield a solid dispersion comprising a co-precipitate of St. John's Wort and HPMCP. The solid dispersion consists of a fine light brown powder with particles ranging in size from five microns to less than one micron. This co-precipitate was not noticeably odoriferous suggesting that the applicant's process can effectively mask the scent of plant material.

To test the acid resistance of this co-precipitate, a known amount was added to USP simulated gastric fluid (without pepsin) at a pH of 1.5. The solution was mixed and then incubated for 30 minutes at 37°C. A 1.0 mL aliquot was taken and extracted with 95% acetone and then injected into a High Performance Liquid Chromatograph. The total hypericins content was found to be low (40 micrograms per gram of co-precipitate). Upon raising the pH to 6.8 (approximating the pH found in the small intestine) the total hypericins content increased to 1770 micrograms per gram of co-precipitate. This result indicates that the HPMCP protected the hypericins in the St. John's Wort co-precipitate from acid exposure until the liquid reached a pH that allowed dissolution of the HPMCP and release of the hypericins. To compare the invention to standard herbal preparations, a sample of a commercially available of St. John's Wort Tincture was treated in a similar manner. The total hypericins content was found to be 15 micrograms per gram after 30 minutes exposure to gastric juice.

However, when the pH of the liquid was increased to 6.8, the hypericins remained low (12 micrograms per gram), indicating that the hypericins from the

St. John's Wort tincture had been destroyed by the gastric juice during the 30 minute exposure period. Since the acidic pH had already destroyed the hypericins in the unprotected St. John's Wort, increasing the pH of the solution to 6.8 did not change the total hypericins content. This indicates that the invention protects the hypericins in St. John's Wort from destruction in the stomach environment yet can release the hypericins in the small intestine for local therapeutic effect or for absorption into the blood stream for a systemic therapeutic effect.

Example 3

A plant extract of Valerian was obtained in the form of a commercially available hydroalcoholic tincture comprising 45% ethanol and 55% water. The amount of ethanol in the extract was then increased to approximately 80%. A quantity of a cellulosic enteric polymer, namely hydroxypropylmethylcellulose phthalate NF (HPMCP), equivalent to twice the weight of plant solids contained in the extract, was dissolved in the extract. The hydroalcoholic solvent was then removed from the extract by spray-drying to yield a solid dispersion comprising a co-precipitate of valerian and HPMCP. The solid dispersion consists of an off-white powder with particles ranging in size from five microns to less than one micron. This co-precipitate was not noticeably odoriferous suggesting that the applicant's process can effectively mask the scent of plant material.

As will be apparent to someone skilled in the art, other enteric polymers could be substituted for HPMPCP. Preferably, such polymers should be soluble in water or hydroalcoholic solvents. This avoids the need to use potentially hazardous volatile solvents such as acetone, ethyl acetate or chlorinated solvents. Accordingly, enteric polymers which are not soluble in a mixture of ethanol and water, such as cellulose acetate phthalate and cellulose acetate rrimellitate, are not preferred unless used in a form, such as a salt, which does not require the use of said hazardous solvents.

The process claimed in this application reduces both the complexity and the material requirements for delivering medicinal plant components in a way that they are protected against gastric inactivation. If conventional formulations were used, a larger mass of plant material would be required to formulate an effective dose. In a typical situation a quantity of the plant material, for example 300 mg, would be required for a normal dose. If this material were to be aclministered in the form of an enteric coated tablet, the core tablet could require up to an additional 300 mg of excipients and require a labour-intensive process such as wet granulation to overcome the variable properties of the plant materials and produce a granulation which could be easily compressed into a robust core tablet. This core tablet, weighing as much as 600 mg, then would require 60 mg or more of the enteric polymer to achieve protection against gastric acid.

As indicated in the above examples, in the process of the present invention, a hydroalcoholic extract of the plant material may be used in which the amount of material extracted may only be 5% or less of the starting material. If this is applied to the above-mentioned material, the amount of material extracted from 300 mg of the crude plant material would be as little as 15 mg. In a 1: 1 co-precipitate, this would mean that the amount of the enteric polymer required would be reduced by 75%. Furthermore, the greater uniformity and reduced level of material (30 mg vs. 300 mg), could be easily incorporated into a direct compression tablet formulation thereby eliminating more complex granulation procedures and eliminating the need for a final coating operation.

As will be apparent to those skilled in the art in the light of the foregoing disclosure, many modifications are possible in the practice of this invention without departing from the spirit or scope thereof. Accordingly, the scope of the invention is to be construed in accordance with the substance defined by the following claims.

Claims

WHAT IS CLAIMED IS:

1. A method of preparing a solid dispersion of a pharmacologically active plant material, comprising:

(a) providing an extract comprising said plant material and a non- toxic liquid solvent;

(b) dissolving an enteric polymer in said extract; and

(c) removing said solvent from said extract to yield said solid dispersion, said dispersion comprising a co-precipitate of said extract and said polymer.

2. The method as defined in claim 1, wherein said plant material comprises herbs selected from the group consisting of echinacea, garlic, eleuthero, maitake mushrooms, astragalus, bilberry, black cohosh, cayenne, chamomile, devil's claw, dong quai, evening primrose oil, feverfew, ginger, ginkgo, ginseng, goldenseal, gotu kola, grape seed extract, hawthorn, kava kava, licorice, milk thistle, St. John's wort, saw palmetto, tea tree and valerian.

3. The method as defined in claim 1, wherein said solvent comprises ethanol and water.

4. The method as defined in claim 3, wherein the percentage of ethanol in said solvent is within the range of 75 - 95%.

5. The method as defined in claim 4, wherein plant material is echinacea.

6. The method as defined in claim 5, wherein said polymer is selected from the group consisting of hydroxypropylmethylcellulose phthalate, methacrylic acid copolymers, polyvinylacetate phthalate, shellac, alginic acid and salts thereof.

7. The method as defined in claim 6, wherein said polymer is hydroxypropylmethylcellulose phthalate or salts thereof.

8. The method as defined in claim 1, wherein said solvent is removed by spray drying.

9. A composition comprising:

(a) a continuous phase of a non-toxic enteric polymer; and

(b) molecules or solid particles of a pharmacologically active plant material substantially uniformly dispersed in said continuous phase.

10. The composition as defined in claim 9, wherein said plant material comprises herbs selected from the group consisting of echinacea, garlic, eleuthero, maitake mushrooms, astragalus, bilberry, black cohosh, cayenne, chamomile, devil's claw, dong quai, evening primrose oil, feverfew, ginger, ginkgo, ginseng, goldenseal, gotu kola, grape seed extract, hawthorn, kava kava, licorice, milk thistle, St. John's wort, saw palmetto, tea tree and valerian.

11. The composition as defined in claim 10, wherein said polymer is selected from the group consisting of methacrylic acid copolymers, polyvinylacetate phthalate, shellac, alginic acid and salts thereof.

12. The composition as defined in claim 11, wherein said plant material is echinacea and said polymer is hydroxypropylmethylcellulose phthalate or salts thereof.

13. The composition as defined in claim 12, further comprising a pharmaceutical carrier suitable for oral administration.

14. A solid dispersion prepared in accordance with the method of claim 1.

15. A method of aάtøiinistering a pharmacologically active plant material to an individual comprising:

(a) providing a solid dispersion of said plant material in a continuous phase of an enteric polymer;

(b) formulating a composition comprising a pharmaceutical carrier and a therapeutically effective amount of said solid dispersion; and (c) administering said composition to said individual.

16. The method as defined in claim 15, wherein said carrier is suitable for oral administration and wherein at least some of the active ingredient of said plant material is available for activity in the oral cavity or upper gastrointestinal tract of said individual.

17. The method as defined in claim 1, wherein said plant material comprises herbs selected from the group consisting of echinacea, garlic, ginkgo, ginseng , eleuthero, maitake mushrooms and devil's claw.

18. The composition as defined in claim 9, wherein said plant material comprises herbs selected from the group consisting of echinacea, garlic, ginkgo, ginseng , eleuthero, maitake mushrooms and devil's claw.