GB2033915A - Organopolysiloxane/silica pharmaceutical compositions - Google Patents

Organopolysiloxane/silica pharmaceutical compositions Download PDF

Info

Publication number
GB2033915A
GB2033915A GB7934912A GB7934912A GB2033915A GB 2033915 A GB2033915 A GB 2033915A GB 7934912 A GB7934912 A GB 7934912A GB 7934912 A GB7934912 A GB 7934912A GB 2033915 A GB2033915 A GB 2033915A
Authority
GB
Grant status
Application
Patent type
Prior art keywords
powder
organopolysiloxane
method
silica
substantially
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
GB7934912A
Other versions
GB2033915B (en )
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Wyeth LLC
Original Assignee
Wyeth LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K33/00Medicinal preparations containing inorganic active ingredients
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0053Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08KUSE OF INORGANIC OR NON-MACROMOLECULAR ORGANIC SUBSTANCES AS COMPOUNDING INGREDIENTS
    • C08K3/00Use of inorganic substances as compounding ingredients
    • C08K3/34Silicon-containing compounds
    • C08K3/36Silica

Abstract

An antacid chewable tablet containing an antacid, an organopolysiloxane, and silica in an amount of 1 to 70% of the weight of the siloxane/silica mixture has rapid defoaming action. The tablet is prepared by adding the organopolysiloxane and silica, premixed in powder form, to an antacid. Additionally, the premixed powder can be used as an antiflatulent alone or in combination with other medicinal agents.

Description

SPECIFICATION Orgariopolysiloxane compositions This invention relates ta organopolysiloxane compositions useful for preparing improved antacid compositions. More specifically, this invention includes a method for combining the organopolysiloxane with silica resulting in a powder.

This powder may then be combined with an antacid and compressed into tablets. The powder can also be used as an antiflatulent alone or in combination with other medicinal agents.

The use of organopolysiloxanes in antacid compositions is known in the art. For instance, U.S. Reissue Patent 25,205 describes the use of organopolysiloxanes with antacids. U.S. Patents 3,210,208 and 3,382,150 describe methods for preparing coated organopolysiloxane particles. Both of these patents utilize an emulsion of organopolysiloxane, a nontoxic coating material and water. The emulsion is spray-dried to form particles of organopolysiloxane which is then coated with the coating material. U.S. 3,501,571 describes a method for absorbing organopolysiloxanes on an inert absorbent filler such as sugar or mannitol, granulating the resulting mixture and then drying the mixture which results in the organopolysiloxane in a powder form.

All of the above methods require either some form of liquid to form an emulsion or granulation of the organopolysiloxane material and use of an inert absorbent filler. The above methods then require a spray drier or oven to dry the material. This is both time consuming and costly.

U.S. 3,422,189 describes anti-flatulent compositions which contain an organopolysiloxane and finely divided silica or a silica aerogel. The finely divided silica is used in amounts sufficient to form a viscous mixture with the organopolysiloxane resulting in a honey-like orsalve-like consistency. A weight range, based on the organopolysiloxane employed, of 1-10% is employed with a range of about 3-7% being preferred. British Patent 1,047,470 describes defoaming compositions which are prepared by adding finely divided silica to a polysiloxane component and heating this mixture to disperse the silica. The silica is disclosed as being present in an amount of at least 3% by weight It has now been discovered that a uniform powder comprising spherical particles and essentially consisting of an organopolysiloxane and silica can be prepared withoutthe use of liquid or heat.The novel silica and organopolysiloxane powder of this invention consists essentially of organopolysiloxanes, from about 1% to 70%, preferably from about 5% to about 60%, and more particularly about 15% to about 60% by weight of the powder. The novel powder can then be formulated with suitable excipients to form an antiflatulent tablet composition or can be mixed with an antacid and compressed into tablets. The novel powder of the invention can also be mixed with excipients or other medicinal agents and excipients and used in various pharmaceutical forms.

The use of this amount of organopolysiloxane results in a uniform powder and distinguishes this formulation from prior combinations of silica and organopolysiloxanes. The expression "uniform powder" is intended herein to mean a powder obtainable by blending the ingredients in a suitable blender until a substantially uniform product is obtained.

The organopolysiloxane type compound that is utilized in this novel formulation is usually a liquid, oily or semi-solid organopolysiloxane represented by the following formula. <img class="EMIRef" id="027283404-00010001" />

wherein R is a lower alkyl group having from 1 to 5 carbon atoms or an organic radical such as phenyl and n can be 0 to 2000. A preferred organopolysiloxane is simethicone which is a mixture of fully methylated linear siloxane polymers containing repeating units of the formula [-(CH)2-Si -]n, stabilized with trimethylsiloxy end-blocking units of the formula [(CH3)3-Si 0-1 and silicon dioxide. Simethicone contains at least 93.0 percent and not more than 99.0 percent of[-(CH3)2-Si 0Jn n (dimethylpolysiloxane), and at least 4.0 percent and not more than 7.0 percent of silicon dioxide.

Suitable antacids which can be utilized in this invention include magaldrate, magnesium hydroxide, aluminum hydroxide, magnesium carbonate, calcium carbonate, magnesium oxide, magnesium trisilicate, aluminum phosphate, dihydroxy aluminum aminoacetate, bismuth subcarbonate and combinations thereof. The preferred antacid of this invention is magaldrate. The antacid composition may have a rapid defoaming action.

The finely divided silica used in this invention are available from various commercial sources. A preferred source of silica is sold underthe tradename CAB-O-SIL and is a submicroscopic fire-dried fumed silica. The particle size can vary from 70 to 500 angstroms in diameter.

As has been noted before, the organopolysiloxane powder of this invention can be incorporated with an antacid in the formulation of a chewable antacide tablet. A preferred method of preparation of this tablet is to add sucrose to a simethicone-silica powder before mixing with the antacid. A preferred formula for 1000 tablets is listed below: Ingredient Amount Magaldrate, U.S.P. 470.0 g Simethicone N.F. 23.2 g Silica, Colloidal 17.37 g Sucrose, Powdered 153.0 g Methylcellulose, U.S.P., 15 cps 1.34 g Dextrates, Hydrous 500.0 g Polyethylene Glycol 6000, U.S.P., Milled 120.0 g Spearmint, Aromalok 26380, Fritzsche 4.0 g Magnesium Stearate, U.S.P. 5.4 g Water, U.S.P., Purified 28.0 ml TheoreticalTabletWeight 1,294. mg The term "theoretical tablet weight" is used because all commercial dimethylpolysiloxanes are somewhat volatile.Recently, low volatility dimethylpolysiloxane has been introduced on the market and this product appears to perform better.

As can be seen from the above formulation, pharmaceutically inert ingredients such as extenders, binders, lubricants, coloring agents, flavorings and the like can be added to the antacid formulation.

Examples of pharmaceutically inert ingredients which can be added to the antacid formulation include extenders or diluents such as lactose, mannitol, sorbitol, microcrystalline cellulose and starch.

Examples of binders that can be added to the formulation of this invention are natural gums and gum constituents such as acacia, tragacanth, agar, and pectin; proteinaceous materials such as gelatin, casein, and zein; polyvinylpyrrolidone; cellulose compounds; and starch. Examples of lubricants that can be used are calcium stearate, talc, stearic acid, sodium benzoate or mixtures thereof.

The uniform powderofthis invention is simply prepared by blending the simethicone with the silica in a suitable blender until uniform. The simethicone silica powder is then as, previously noted preferrably granulated with sucrose prior to formulation of an antiflatulent dosage form alone or formulation of a combination antacid antiflatulent dosage form.

More specifically, the above formulation is prepared in the following manner and is illustrative of the manner of preparation for all the compositions encompassed by this invention.

1. Heat about 14 ml of Purified Waterto 80-90"C.

Add Methylcellulose, 15 cps, and stir until uniformly dispersed. Bring up to a volume of 28 ml with Purified Water and cool to room temperature.

2. Blend the simethicone with Colloidal Silica in a suitable blender until uniform.

3. Blend the mixture from Step &num;2 with Powdered Sucrose in a suitable blender until uniform.

4. Granulate the blend from Step &num;3 with the solution prepared in Step &num;1, adding additional Purified Water if necessary to obtain suitable granulation.

5. Dry the granulation from Step &num;4 overnight at 45"C in a forced draft dryer and pass through a Fitz Mill using a &num;20 screen, medium speed, knives forward.

6. Blend Magaldrate Powder, Dextrates Hydrous, Polyethylene Glycol 6000 Milled and Spearmint Aromalok26380. Pass through a Fitz Mill using a &num;16 screen, medium speed, knives forward.

7. Blend the ingredients from Step &num;5 and &num;6 in a suitable blender until uniform.

8. Add the Magnesium Stearate and blend.

9. Compress to make a tablet.

Examples of other medicinal agents which can be used in combination with an organopolysiloxane powder include the following: 1. Digestants such as bile constituents, pancreatin, pepsin, and digestive enzymes such as amylase, lipase and protease.

2. Anticholinergic Agents such as atropine sulfate, hyoscyamine sulfate, scopolamine hydrobromide and mixed alkaloidal extracts.

3. Barbiturates such as phenobarbital and butabarbital sodium.

The following examples further illustrate the above described invention: EXAMPLE I Simethicone 800 g Colloidal Silica 600 g Mix simethicone and the colloidal silica together in a suitable mixer with high shear. The resulting mixture is a powder. It is understood that this powder can be prepared by dissolving simethicone in a suitable solvent as taught by the prior art, dispersing the simethicone on the silica and evaporating the solvent.

EXAMPLE II The powder as prepared in Example I can be mixed with antacids such as magaldrate and pharmaceutically inert ingredients and compressed into tablets. This example illustrates such a preparation.

Simethicone Powder from Example I 35.0 g Magaldrate 470.0 g Powdered Sucrose 70.0 g PEG 6000 120.0 g Dextrates, Hydrous 425.0 g Sorbitol 100.0 9 Saccharin 0.3 9 Spearmint 4.0 g Magnesium Stearate 5.4 g Theoretical Tablet Weight 1229.7 mg All the ingredients except magnesium stearate were mixed in a suitable mixer. The magnesium stearate was blended in and all the ingredients were compressed.

EXAMPLEIII Simethicone powder as described in Example I can first be mixed with a pharmaceutically inert ingredient, granulated with a binder and dried and sized to convert the mixture into granules Simethicone - 400.0 g Colloidal Silica - 300.0 g Powdered Sucrose - 2625 g 5% Methylcellulose (15 cps) Aq.Sol.

450.0 ml The simethicone and colloidal silica were mixed in a suitable mixer with high shear. The powdered sucrose was added and mixed well. Granulate the mixture with 450 ml of 5% methylcellulose aqueous solution and dry it in a forced air oven at 45 C. Size the dried material by passing through a suitable screen.

EXAMPLE Simethicone granules as prepared in Example Ill can be mixed with antacids and pharmaceutically inert ingredients and compressed to make tablets as follows: Simethicone Granules from Example lil 167.38 g Magaldrate 470.0 g Dextrates, Hydrous 500.0 g PEG 6000 120.0g Spearmint 4.0g Magnesium Stearate 5.4 g Theoretical Tablet Weight 1266.78 mg This formulation is prepared as in Example II.

EXAMPLE V Simethicone Powder from Example I 140.0 g Dextrates, Hydrous 600.0 g Polyethylene Glycol 6000 80.0 g Spearmint Flavor 2.7 g Magnesium Stearate 2.0 g Theoretical Tablet Weight 824.7 mg All the ingredients except Magnesium Stearate were mixed in a suitable mixer. The Magnesium Stearate was blended in and all the ingredients were compressed.

EXAMPLE Vl Simethicon Granulation from Example Ill 669.5 g Spearmint Flavor 2.7 g Magnesium Stearate 2.0 g Theoretical Tablet Weight 674.2 mg The Simethicone Granulation and Spearmint were mixed in a suitable mixer. The Magnesium Stearate was blended in and all the ingredients were compressed.

Examples V and VI illustrate anti-flatulent formulations.

Claims (26)

1. A uniform powder comprising substantially spherical particles and consisting essentially of an organopolysiloxane and silica wherein the organopolysiloxane is present in an amount from about 1% to about 70% based on the weight of the powder.
2. A powder as claimed in claim 1, wherein the organopolysiloxane is present in an amount from about 5% to about 60%.
3. A powder as claimed in claim 1, wherein the organopolysiloxane is present in an amount from about 15% to about 60%.
4. A powder as claimed in any one of claims 1 to 3, wherein the organopolysiloxane is simethicone.
5. A powder as claimed in claim 1, substantially as described in Example
6. A method for preparing a uniform powder comprising spherical particles, comprising blending in the absence of heat or a solvent about 1% to about 70%, based on the weight of the powder, of an organopolysiloxane with finely divided silica.
7. A method as claimed in claim 6, in which the organopolysiloxane is simethicone.
8. A method as claimed in claim 6 or 7, wherein the organopolysiloxane is present in an amount from about 15% to 60%.
9. A method as claimed in claim 6, carried out substantially as described in Example I herein.
10. A method of preparing a granulation, comprising a method as claimed in any one of claims 6 to 9 and granulating the powder with sucrose.
11. A method as claimed in claim 10, carried out substantially as described in Example Ill herein.
12. A powder whenever prepared buy a method as claimed in any one of claims 6 to 9.
13. A granulation whenever prepared by a method as claimed in claim 10 or 11.
14. A composition comprising a powder as claimed in any one of claims 1 to 5 and 12 and sucrose.
15. A composition as claimed in claim 14, substantially as described in Example Ill herein.
16. A pharmaceutical composition comprising a powder as claimed in any one of claims 1 to 5 and 12 and pharmaceutically acceptable excipients.
17. A composition as claimed in claim 16, substantially as described in Example V orVI herein.
18. A compressed tabletcomprising a powder as claimed in any one of claims 1 to 5 and 12, an antacid and pharmaceutically acceptable excipients.
19. Atablet as claimed in claim 18, wherein the antacid is magaldrate.
20. Atablet as claimed in claim 18, formulated substantially as described with reference to Example II or IV herein.
21. Atablet as claimed in claim 18, formulated substantially as described with reference to the aforesaid "preferred formula for 1000 tablets".
New claims or amendments to claims filed on 29 Feb 1980.
Additional claims:- 22 to 26.
New or amended claims:
22. As an antiflatulant, a powder as claimed in any one of Claims 1 to 5.
23. A pharmaceutical composition comprising a powder as claimed in any one of Claims 1 to 5 and another medicinal agent.
24. A composition as claimed in Claim 23, which also contains pharmaceutically acceptable excipients.
25. A composition as claimed in Claim 23, wherein the agent is an antacid.
26. A composition as claimed in Claim 25, wherein the agent is magaldrate.
GB7934912A 1978-10-10 1979-10-09 Organopolysiloxane/silica pharmaceutical compositions Expired GB2033915B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US95033278 true 1978-10-10 1978-10-10

Publications (2)

Publication Number Publication Date
GB2033915A true true GB2033915A (en) 1980-05-29
GB2033915B GB2033915B (en) 1983-02-09

Family

ID=25490285

Family Applications (1)

Application Number Title Priority Date Filing Date
GB7934912A Expired GB2033915B (en) 1978-10-10 1979-10-09 Organopolysiloxane/silica pharmaceutical compositions

Country Status (3)

Country Link
CA (1) CA1139221A (en)
DE (1) DE2940905A1 (en)
GB (1) GB2033915B (en)

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0068566A1 (en) * 1981-06-30 1983-01-05 Sociéte d'Importation de Parfumerie et de Produits Pharmaceutiques en abrégé "Sipar-Pharma" Société Anomyme Edible pharmaceutical form of a composition of matter containing a fluid dimethyl polysiloxane
US4396604A (en) * 1982-05-17 1983-08-02 Norcliff Thayer, Inc. Simethicone antacid lozenge
FR2559063A1 (en) * 1984-02-08 1985-08-09 Leribault Loic Compositions for therapeutic use comprising organo-silicon compounds
US4764374A (en) * 1985-03-06 1988-08-16 Grimberg Georges Serge Pharmaceutical composition based on guar gum and other antacids for protection of the oesogastroduodenal mucous membrane
WO1990007930A1 (en) * 1989-01-19 1990-07-26 Steigerwald Arzneimittelwerk Gmbh Use of dimethylpolysiloxane for treating disorders of the gastrointestinal tract
EP0465234A1 (en) * 1990-07-03 1992-01-08 McNEIL-PPC, INC. Pharmaceutical compositions and methods for alleviating gastrointestinal distress symptoms induced by nonsteroidal anti-inflammatory drugs
US5173305A (en) * 1985-03-06 1992-12-22 Grimberg Georges Serge Composition for protection of oesogastroduodenal mucous membrane
WO1993010797A1 (en) * 1991-12-05 1993-06-10 Paul Bolder Arzneimittelfabrik Gmbh & Co. Kg Dimeticon pastilles
GB2279009A (en) * 1993-06-04 1994-12-21 Dow Corning Sa Antifoam compositions
WO1995030407A1 (en) * 1994-05-06 1995-11-16 Bolder Arzneimittel Gmbh Chewable anti-gastric acidity pastilles
US5935604A (en) * 1993-05-20 1999-08-10 Danbiosyst Uk Limited Nasal drug delivery composition containing nicotine
EP1018895A1 (en) * 1996-07-26 2000-07-19 Kristine A. Bateman Dietetic one-to-one sugar substitute composition for table top, baking and cooking applications

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2096575C (en) * 1992-05-21 2003-05-13 Charles A. Stevens Novel simethicone containing pharmaceutical compositions
JP3001440B2 (en) * 1996-11-25 2000-01-24 日本電気通信システム株式会社 Virtual lan system
US7341742B2 (en) 2002-09-30 2008-03-11 L. Perrigo Company Simethicone containing tablet composition and method

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0068566A1 (en) * 1981-06-30 1983-01-05 Sociéte d'Importation de Parfumerie et de Produits Pharmaceutiques en abrégé "Sipar-Pharma" Société Anomyme Edible pharmaceutical form of a composition of matter containing a fluid dimethyl polysiloxane
US4396604A (en) * 1982-05-17 1983-08-02 Norcliff Thayer, Inc. Simethicone antacid lozenge
FR2559063A1 (en) * 1984-02-08 1985-08-09 Leribault Loic Compositions for therapeutic use comprising organo-silicon compounds
EP0152366A2 (en) * 1984-02-08 1985-08-21 Ribault Loic Le Compositions for therapeutic use comprising organo-silicon compounds
EP0152366A3 (en) * 1984-02-08 1988-01-27 Leribault Loic Compositions for therapeutic use comprising organo-silicon compounds
US4764374A (en) * 1985-03-06 1988-08-16 Grimberg Georges Serge Pharmaceutical composition based on guar gum and other antacids for protection of the oesogastroduodenal mucous membrane
US5173305A (en) * 1985-03-06 1992-12-22 Grimberg Georges Serge Composition for protection of oesogastroduodenal mucous membrane
US5424064A (en) * 1989-01-19 1995-06-13 Schmidt; Alfred Treatment of reflux esophagitis using dimethylpolysiloxane
WO1990007930A1 (en) * 1989-01-19 1990-07-26 Steigerwald Arzneimittelwerk Gmbh Use of dimethylpolysiloxane for treating disorders of the gastrointestinal tract
US5120533A (en) * 1989-01-19 1992-06-09 Steigerwald Arzneimittelwerk Gmbh Treatment of ulcers of the gastrointestinal tract using dimethylpolysiloxane
EP0465234A1 (en) * 1990-07-03 1992-01-08 McNEIL-PPC, INC. Pharmaceutical compositions and methods for alleviating gastrointestinal distress symptoms induced by nonsteroidal anti-inflammatory drugs
US5633005A (en) * 1991-12-05 1997-05-27 Bolder Arzneimittel Gmbh Dimeticon pastilles
WO1993010797A1 (en) * 1991-12-05 1993-06-10 Paul Bolder Arzneimittelfabrik Gmbh & Co. Kg Dimeticon pastilles
US5935604A (en) * 1993-05-20 1999-08-10 Danbiosyst Uk Limited Nasal drug delivery composition containing nicotine
US5458886A (en) * 1993-06-04 1995-10-17 Dow Corning France S.A. Antifoam compositions
GB2279009A (en) * 1993-06-04 1994-12-21 Dow Corning Sa Antifoam compositions
GB2279009B (en) * 1993-06-04 1997-08-27 Dow Corning Sa Organopolysiloxane antifoam compositions
WO1995030407A1 (en) * 1994-05-06 1995-11-16 Bolder Arzneimittel Gmbh Chewable anti-gastric acidity pastilles
EP1018895A1 (en) * 1996-07-26 2000-07-19 Kristine A. Bateman Dietetic one-to-one sugar substitute composition for table top, baking and cooking applications
EP1018895A4 (en) * 1996-07-26 2000-11-22 Kristine A Bateman Dietetic one-to-one sugar substitute composition for table top, baking and cooking applications

Also Published As

Publication number Publication date Type
DE2940905A1 (en) 1980-04-30 application
CA1139221A1 (en) grant
CA1139221A (en) 1983-01-11 grant
GB2033915B (en) 1983-02-09 grant

Similar Documents

Publication Publication Date Title
US3499960A (en) Palatable coated particles of an anion exchange resin
US3624209A (en) Composition for treatment of gastro-intestinal disorders
US3282789A (en) Stable liquid colloidal tannate compositions
US3255082A (en) Method of preparing stable aluminum chlorhydrate-alkali metal- and alkaline earth metal salt complex antiperspirant stick
US5494681A (en) Tastemasked pharmaceutical materials
US3590117A (en) Long-lasting troche containing guar gum
US3836647A (en) Wash-resistant skin preparation
US4835142A (en) Powdery pharmaceutical composition suitable for application to mucosa of oral or nasal cavity
US6368638B1 (en) Process of making an aqueous calcium carbonate suspension
US5093387A (en) Denture adhesive
US4446135A (en) Chewable antacid tablets
EP0235986A1 (en) Slow release formulation
US5993834A (en) Method for manufacture of pigment-containing cosmetic compositions
US4486412A (en) Encapsulated antacid dispersions
EP0452145A2 (en) Coated composition and its preparation process
US6180138B1 (en) Process for preparing solid formulations of lipid-regulating agents with enhanced dissolution and absorption
US4252796A (en) Stable water-in-oil emulsions
US4533674A (en) Process for preparing a sugar and starch free spray-dried vitamin C powder containing 90 percent ascorbic acid
US4597969A (en) Stabilization of unstable drugs or food supplements
US5073384A (en) Maltodextrin/defoaming composition combinate
US5348745A (en) Aqueous granulation solution and a method of tablet granulation
US4699779A (en) Waterproof sunscreen compositions
US4421736A (en) Sustained release diethylpropion compositions
US4689080A (en) Base material composition for dental treatment
US4678664A (en) Mineral oil gels

Legal Events

Date Code Title Description
PE20 Patent expired after termination of 20 years

Effective date: 19991008