NZ248672A

NZ248672A - Ruminant nutrient/medicine: granular active agent coated with chitosan/fat mixture

Info

Publication number: NZ248672A
Application number: NZ248672A
Authority: NZ
Inventors: Homme Christian Prud; Jean-Francois Rostaing
Original assignee: Rhone Poulenc Nutrition Animal
Priority date: 1992-09-18
Filing date: 1993-09-15
Publication date: 1994-04-27
Also published as: AU664642B2; FR2695804A1; EP0588707A1; TW287942B; UY23652A1; AU4734993A; GR3020615T3; CN1087474A; FI934082A; NO933323D0; BR9303818A; CA2101090A1; MX9305143A; FR2695804B1; JPH06189690A; NO933323L; DE69303785D1; HUT67210A; ES2090915T3; EP0588707B1

Abstract

The present invention relates to nutrient or drug compositions for administration to ruminants containing one or more biologically-active substances coated with a composition based on fat and chitosan salt.

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £48672 0 / y /! Priority Datc(a): . J$. Gonipt^io Cpecification Filed; » risen: {U^IPAW,... 0MKWalst) AtAfr ''""'X'' pi.V'""27 APR'twi Publication Dr..0: P.O. Journr!, Mo; ■.. ..i 2 1 5 SEP 1993 F...'- ." '• - NEW ZEALAND PATENTS ACT, 1953 No.: Date: COMPLETE SPECIFICATION NUTRIENT OR MEDICINAL COMPOSITIONS FOR ADMINISTRATION TO RUMINANTS We, RHONE-POULENC NUTRITION ANIMALE, a French body corporate, of 42 Avenue Aristide Briand, 92160 Antony, France hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- - 1 -(followed by page 1A) .fi L' 1A The present invention relates to compositions for the feeding of ruminants, containing one or more biologically active substances, which are stable in an aqueous medium in which the pH is equal to or above 5.5, which is the pH of the rumen, but which enable the active substance or substances to be released in the post-rumen digestive tract. The compositions of the invention for the feeding of ruminants contain one or more nutrient substances or one or more therapeutic substances which, in the absence of the protective composition, would be destroyed in the rumen by the microorganisms residing therein which promote the digestion of amylaceous material. The residence time of active principles in the rumen is often as long as 15 to 20 hours. During this relatively long period of time, labile active principles are often destroyed. In order to protect such substances in the rumen while allowing them to be released thereafter in the digestive tract especially in the abomasum and/or the intestine, where they suffer less attack, many approaches have already been proposed. Among compounds that permit protection in the rumen and release in the abomasum or intestine, two major types of compound may be mentioned. The first type of compound permits release 2 caused by a chemical phenomenon dependent on the difference in the pH between the rumen and the abomasum. In this category, pH-sensitive polymers such as copolymers of styrene and vinyl pyridine may be mentioned. Many patents such as, for example, Patents US 4,877,621 or US 4,832,967 describe compositions containing such compounds. These compositions permit excellent protection of nutrient or medicinal substances, but possess a significant drawback. They contain a synthetic chemical compound which, from a nutritional and ecological standpoint, is not always greatly liked either by the marketing authorization authorities, or by consumers. In this first category, where release is caused by a chemical phenomenon, compositions involving the use of chitosan and carboxylic acids have been proposed. Such compositions are, for example, described in the French Patent published under No. 2,524,269. These compositions contain a quantity of active principle which is always less than 60 % by weight, and more preferably of the order of 30 %, in order to be able to permit protection in the rumen of the order of 80 to 90 % over 24 hours, and they contain, in addition, a significant amount (10 to 20 % by weight) of one or more pH-sensitive inorganic fillers. The second type of compound utilizes the properties of susceptibility to enzymatic hydrolysis shown by certain natural compounds such as zein. Patents describing the use of such compounds include Patent US 4,983,403 or European Patent Application EP 0,406,041. Such compositions permit excellent protection of the active principle in the rumen as well as good post-ruminal release, but zein possesses a major drawback. It is soluble only in organic solvents, so that it must be sprayed onto the active principle as a solution in an organic solvent, thus necessitating a highly expensive recovery of the solvent. The objective which all these compositions is seeking to achieve is the ability to retain approximately 80 % of the active principle or principles in the rumen without degradation for at least 6 hours, and still more advantageously for at least 24 hours, and to permit release of at least 50 %, and preferably at least 80 %, of the same active principle or principles in the space of less than 6 hours in the abomasum and/or the intestine. It is also highly desirable to have available a composition containing at least 60 % by weight of the active principle and containing the largest possible proportion of protective compounds of natural origin and which are recognized as having a nutritional quality for the animals. This goal has been achieved in accordance with the present invention by the provision of nutrient t 4 or medicinal compositions for administration to ruminants containing one or more biologically active substances in granular form coated with a coating composition containing by weight: 5 - 1 to 10 % of chitosan salt, expressed as chitosan equivalent, and - 99 to 90 % of a fat or mixture of fats whose melting point is above 45°C. Melting points may be measured by the drop point using, for example, a 10 Mettler apparatus. Preferably, the coating composition contains 1 to 5 % of chitosan salt. Throughout the description, the content of chitosan salts is expressed in chitosan equivalents, i.e. the weight of the anion with which 15 the chitosan cation is associated is ignored in calculating the percentages by weight of the ingredients of the coating composition. The coating composition of the invention contains, still more preferably, by weight: 20 - 3 to 5 % of chitosan salt - 45 to 97 % of a fat or mixture of fats having a melting point above 50°C, and - 0 to 50 % of a fat or mixture of fats having a melting point below 25°C. 25 In these coating compositions, the chitosan salt may be, for example, the chloride, acetate, adipate, citrate, formate, glutamate, lactate, malonate, oxalate, propionate, pyruvate, succinate or tartrate, or any other salt which enables chitosan to 30 be dissolved in water. Chitosan acetate is preferred. 5 The term "fat" as used herein includes not only fatty acids and fatty acid esters, especially glyceryl esters, but also hydrocarbon waxes. Among fats possessing a melting point above 50°C, or which 5 may be present in mixtures of fats having a melting point above 50°C, there may be mentioned, as examples, fatty acids such as, for example, stearic acid, behenic acid, lauric acid and myristic acid, and mixtures thereof, esters of fatty acids with, for example, 10 glycerol, fatty alcohols in which the fatty chain contains 12 to 22 carbon atoms, paraffin waxes, hydrogenated vegetable or animal oils, and natural waxes such as, in particular, carnauba wax or beeswax. These fats may be used in the pure state, but it is 15 preferred to use them in a mixture such as, for example, stearin (a mixture of glyceryl mono-, di-, and tri-stearates). Esters of fatty acids with glycerol may be glyceryl monoesters, diesters or triesters. Such 20 esters are often marketed as a mixture. Thus, the mixture of glyceryl behenate monoester and triester is marketed, for example, by the company Gatefosse under the tradename Compritol (mp. 70°C), and a mixture of glyceryl monopalmitate and monostearate is marketed 25 under the tradename Geleol (mp. 58°C). Among fats having a melting point below 25"C, there may be mentioned, for example, unsaturated fatty acids having 12 to 22 carbon atoms, which may be pure, e.g. oleic acid, or mixed such as, for example, the 30 food oils (e.g. rapeseed, sunflower, coconut, ground nut, maize, or olive oil). Especially preferred coating compositions comprise: W " ° "" i c. 6 - 3 to 5 % of chitosan salt - 55 to 92 % of one or more fats whose melting point is above 50*C, and ;- 5 to 40 % of one or more fats whose melting 5 point is below 25"C. ;The fat having a melting point above 50 *C is preferably stearic acid, and the fat having a melting point below 25"C is preferably oleic acid. The composition given greatest preference for coating 10 methionine contains by weight: - 3 % of chitosan acetate - 90 % of stearic acid - 7 % of oleic acid Preferred nutrient or medicinal compositions 15 according to the invention contain 60 to 90 %, and preferably 70 to 80 %, by weight of active principle which can be degraded in the rumen of ruminants and contain 4 to 25 %, and preferably 10 to 25 %, by weight of the coating composition. 20 The complement to 100 % of the nutrient or medicinal composition consists of the binding agent which is used to form the granule, especially in accordance with the disclosure of New Zealand Patent Application No. 238754. The nutritional active principle may be, in 25 particular, a so-called "limiting" essential amino acid such as methionine, lysine and/or tryptophan. The medicinal active principle may be, more particularly, a vitamin, antibiotic, antiparasitic compound or hormone. I 7 These active principles are, collectively, biologically active principles. The present invention makes it possible to obtain a content of active principle in the final 5 composition of between 60 and 90 %, and more preferably between 70 and 80 %. The coating layer preferably possesses a thickness of between 20 /im and 200 /um, and more preferably between 60 /m and 120 /im. The granule of active principle preferably has a diameter of 10 between 0.6 and 2.5 mm, and still more preferably between 0.8 and 2 mm. The process for preparing the nutrient or medicinal compositions according to the invention enables all use of organic solvents to be avoided; it 15 consists in producing an aqueous emulsion of the constituents of the coating composition, and then in spraying this emulsion onto granules of the active principle. According to a preferred way of implementing the invention, a solution is prepared containing 20 approximately 2 % by weight of chitosan salt in water. The starting material may be a chitosan salt in the solid state, or alternatively an aqueous solution of chitosan may be prepared at the time of use by dissolving chitosan in water containing an organic or 25 inorganic acid forming a soluble chitosan salt. To this solution, which can optionally be diluted, there are added, according to a preferred way of implementing the invention, the fat or fats having a 8 melting point below 25°C and then, in the molten state, the fat or mixture of fats having a melting point above 50°C, and the mixture is agitated with an apparatus, for example, of the Polytron type. A stable emulsion is 5 obtained, which can be readily sprayed onto a bed of granules to be coated by the fluidized bed technique of, for example, the Wurster type, as described in Patents US 2,799,241 and EP 0,188,953. The granules obtained after coating are used 10 for the feeding or the medicinal treatment of ruminants. The invention is illustrated by the Examples which follow. EXAMPLES 15 1. Preparation of a solution of chitosan acetate A 3-litre glass vessel is charged with: - 15 g of chitosan - 580.4 g of demineralized water, and - 4.62 g of 100 % acetic acid 20 The mixture is agitated at room temperature until the chitosan has dissolved. The solution is then filtered through 60 /im mesh polyester cloth to remove insoluble solid particles (0.41 g). 2. Preparation of a coating composition. 25 In the following, the ingredients and quantities given are those of Example 3 below. The compositions used in the other Examples may be made in exactly the same way by substitution of the appropriate 9 ingredients in the quantities given. The solution of chitosan acetate obtained as described above is diluted with 600 g of demineralized water. A 1.2 % solution of chitosan (in the form of its 5 acetate) is thereby obtained. A two-litre glass vessel is charged with 209.7 g of this solution. 0.425 g of purified oleic acid (PROLABO) is added to this solution, and the mixture is then heated to 90-95"C using a water bath. 10 76.5 g of stearic acid (PRIFAC 2981 of UNICHEMA) mixed with 5.525 g of purified oleic acid (PROLABO), previously melted in a jacketed dropping-funnel heated to 110°C, are then introduced into the mixture in the course of approximately three minutes. 15 During the introduction, the mixture is dispersed using a POLYTRON apparatus rotating at 15,000 rpm. Stirring with the POLYTRON is maintained for a further two minutes after introduction of the molten lipids is complete. 20 A homogeneous and stable dispersion is obtained, which is stored at a temperature in the region of 90°C. 3. Coating of a methionine granulate (Examples 1 to 16) or methionine/lysine hydrochloride granulate 25 (Examples 17 to 19) In the following, the specific quantities given are those of Examples 3 and 18. The other Examples are performed in an exactly analogous manner. 10 A UNIGLATT spray-coating apparatus equipped with a WURSTER system is charged with 500 g of methionine granulate or of methionine/lysine hydrochloride cogranulate, prepared in either case by spheronization extrusion in the molten state according to the process described in French Patent Application FR 91/08,280. The granules have particle diameters of between 2 and 2.5 mm. The methionine granulate contains 88.8 % of methionine, while the cogranulate contains approximately 47 % of lysine HC1 and 13 % of methionine. The above chitosan/lipid emulsion, still kept at 95°C, is then pumped and sprayed in the UNIGLATT apparatus onto the bed of fluidized particles with a stream of hot air. The following film-coating conditions are used: - fluidization air flow rate: 130 m3/h - fluidization air temperature (at outflow): 40°C (48-50°C for the cogranulate), - spraying air pressure: 1.5 bar - coating emulsion flow rate: 10.4 g/min (14.1 g/min for the cogranulate) - spraying air temperature: 90°C (80°C for the cogranulate) - spraying time: 40 min. The total quantity of emulsion sprayed is approximately 414 g for the methionine granulate and approximately 11 620 g for the lysine/methionine cogranulate. 567.5 g of film-coated methionine granules having a methionine titre of 78.4 % and a coating content of 11.7 % or 640 g of methionine/lysine granules having a lysine HC1 titre of 47.1 % and a coating content of 21.2 % are thereby obtained. 4. In vitro evaluation of the protection-release characteristics of the film-coated granules. In a buffer medium at pH 6 and at 40°C, the degree of retention of methionine by the granules of Example 3 after 24 hours is 99.45 %. At pH 2, 75 % of the methionine is released in 7 to 8 hours. Figures for the granules of the other Examples are shown in Tables 1 to 5 below. 5. In sacco evaluation of the protection-release of methionine coated granules according to Example 3 5.1 Experimental procedure Nylon sachets measuring 6x6 cm having a mesh diameter of 48 microns are used, into which 1.5 g of product according to Example 3 are introduced. Into the rumen of a cannulated cow, 1 ruminal sachet (20x20 cm, 100 micron mesh) containing 15 of the above sachets is introduced. The sachets are left for 24 hours in place in the rumen. The sachets are washed with water until the washings are clear. 3 sachets are dried in an oven for 48 hours and their weight is recorded. The other 12 sachets are immersed for 2.5 hours, before reintroduction into the animal, in a 12 solution of pepsin at pH 2 (3 g of pepsin with an activity of 300 to 600 IU/ml/1). The other sachets are introduced into a cow via a duodenal cannula at the evening meal. The sachets are collected in the faeces 5 the following morning at 8 am. They are rinsed with water, dried in an oven and weighed. 5.2 Measurement of the residual methionine At each step, the residual methionine is measured. The percentage methionine available to the 10 animal is determined by the difference between the methionine contained after passage through the rumen and the methionine contained in the faeces, expressed as a percentage of the methionine contained in the initial granules. The results of the tests are shown in 15 Table 6. IQ vivo evaluation of the protection-release characteristics of the film-coated granules Four cows cannulated in the rumen and the duodenum are used. They are fed with a mixture of maize 20 silage and hay, and a portion of them receive a supplementation with protected methionine in the form of 50 g of the product prepared according to Example 3 per animal per day, given in four equal parts four times a day. The plasma methionine concentration of the 25 treated cows was found to be 0.68 mg/100 g, whereas that of a control not receiving methionine was 0.23 mg/100 g. The methionine flux in the duodenum was 33.7 g/d above that of the control group not receiving 13 methionine; this flux corresponds to an ingested quantity of methionine of 38.3 g/d (i.e. 50 g of granulate containing 76.6 % of methionine). TABLE 1 EXAMPLE Coating composition (weight %) Methionine content of coated granules (weight %) Coating content of coated granules (weight %) Methionine released after 1H 2H 3H 6H 15H 24H 1 Chitosan 3.0 Stearic acid 96.5 76.9 12.0 pH2 pH6 15.9 2 Chitosan 3.0 Stearic acid 92.0 Oleic acid 5.0 76.8 13.4 pH2 pH6 19.2 42.5 50.9 90.7 100 5.7 11.8 3 Chitosan 3.0 Stearic acid 90.0 Oleic acid 7.0 78.4 11.7 pH2 pH6 12.8 24.0 36.3 69.5 100 0.3 0.55 4 Chitosan 3.0 Stearic acid 87.0 Oleic acid 10.0 77.4 12.9 pH2 pH6 8.20 19.4 24.7 51.1 100 0.40 0.65 5 Chitosan 3.0 Stearic acid 87.0 Rapeseed oil 10.0 76.1 13.3 pH2 pH6 7.8 17.6 21.9 50.0 56.7 3.75 100 7.75 TABLE 2 EXAMPLE Coating composition (weight %) Methionine content of coated granules (weight %) Coating content of coated granules (weight %) Methionine released after 1H 2H 3H 6H 15H 24H 6 Chitosan 3.0 Stearic acid 86.5 Laurie acid 10.0 Oleic acid 0.5 79.3 10.7 pH2 pH6 7.4 18.5 26.0 52.8 100 1.1 2.1 7 Chitosan 3.0 Stearic acid 86.5 Myristic acid 10.0 Oleic acid 0.5 78.7 12.8 pH2 pH6 11.1 20.7 32.4 60.7 100 5.9 14.4 8 Chitosan 3.0 Stearic acid 86.5 Behenic acid 10.0 Oleic acid 0.5 76.9 12.8 pH2 pH6 12.4 26.6 37.9 69.2 100 4.2 10.0 TABLE 3 EXAMPLE Coating composition (weight %) Methionine content of coated granules (weight %) Coating content of coated granules (weight %) Methionine released after 1H 2H 3H 6H 15H 24H 9 Chitosan 3.o Stearic acid 28.95 Glyceryl trimyristate 67.55 Oleic acid 0.5 77.1 13.2 pH2 pH6 6.9 0.2 18.6 0.2 23.9 0.2 70.1 0.6 1.10 3.00 10 Chitosan 3 Glyceryl trimyristate 29.10 Stearic acid 67.00 77.8 12.4 pH2 pH6 12.1 0.20 0.20 41.40 0.20 80.1 0.30 1.70 11 Chitosan 1.5 Stearic acid 29.4 Glyceryl trimyristate 68.6 Oleic acid 0.5 77.1 13.2 pH2 pH6 2.80 9.70 0.30 17.9 0.50 49.1 2.20 40.0 12 Chitosan 3 Stearic acid 67.55 Glyceryl trimyristate 28.95 Oleic acid 0.5 78.8 11.3 pH2 pH6 8.60 0.20 12.9 0.20 29.9 0.20 65.2 0.20 0.40 0.80 CN Cj 1 f o TABLE 4 EXAMPLE Coating composition (weight %) Methionine content of coated granules (weight %) Coating content of coated granules (weight %) Methionine released after 1H 2H 3H 6H 15H 24H 13 Chitosan 3.0 Stearic acid 28.95 "Compritol" 67.55 Oleic acid 0.5 75.8 12.5 pH2 pH6 13.9 0.6 29.8 0.8 48.0 2.7 80.6 7.2 13.6 23.3 .14 Chitosan 6.0 Stearic acid 28.05 "Compritol" 65.45 Oleic acid 0.5 76.7 11.6 pH2 pH6 25.3 1.2 39 3.5 56.5 5.0 96.6 15.6 33.5 51.2 15 Chitosan 3 Stearic acid 82 "Geleol" 14.5 Oleic acid 0.5 79.4 10.6 pH2 pH6 27.1 0.3 49.3 0.6 69.7 1 100 2 6 10.8 16 Chitosan 3 stearic acid 67.5 "Geleol" 29 Oleic acid 0.5 78.1 12.0 pH2 pH6 21.1 0.2 42.6 0.25 61 0.4 97.7 0.9 7.4 TABLE 5 EXAMPLE Methionine/ lysine.HCl content of the coated granules (weight %) Coating composition (weight %) Coating content of coated granules (weight %) Lysine.HCl released after 1H 2H 3H 6H 15H 24H 17 13.3:47.1 Chitosan 2.0 Stearic acid 68.0 Oleic acid 30.0 21.7 pH2 pH6 1 4.6 26.5 63.4 100 1 6.4 18 13.0:47.1 Chitosan 3.0 Stearic acid 67.0 Oleic acid 30.0 21.2 pH2 pH6 7.3 25.4 43.9 80 100 0.8 8.7 19 13.2:47 Chitosan 5.0 Stearic acid 65.0 Oleic acid 30.0 21.4 pH2 pH6 7.2 31.2 53.6 85.7 100 4.7 10.9 i\D c- { .. i s\ </div>

Claims

<div class="application article clearfix printTableText" id="claims"> TABLE 6 Methionine content of coated granules after exposure to Initial methionine content of coated granules 76.6 % by weight Initial methionine content of coated granules 75.4 % by weight Cow No. 1 Cow No. 2 Cow No. 3 Cow No. 4 Cow No. 5 Cow No. 6 Cow No. 7 Cow No. 8 Rumen 67.7 73.9 73.9 73.8 63 73.4 73.5 72.5 Rumen + Pepsin HCl 51.7 71.1 66.7 66.8 35.4 69.2 61.5 59.7 Rumen + Pepsin HCl + intestine 0.1 0.4 0.1 1.3 0.04 0.6 0.04 2.5 Percentage of total methionine available to the animal 88.3 96 96.4 94.6 83.5 96.6 97.4 93 -Si 20 WHAT #WE CLAIM IS

1. A nutrient or medicinal composition for administration to ruminants, containing one or more biologically active substances in granular form coated with a coating composition containing by weight: - 1 to 10 % of chitosan salt, expressed as chitosan equivalent, and - 99 to 90 % of a fat or mixture of fats whose melting point is above 45#C.

2. A nutrient or medicinal composition according to claim 1, wherein the coating composition contains l to 5 % by weight of chitosan salt.

3. A nutrient or medicinal composition according to claim 1, wherein the coating composition contains: - 3 to 5 % of chitosan salt, - 45 to 97 % of a fat or mixture of fats having a melting point above 50°C, and - 0 to 50 % of a fat or mixture of fats having a melting point below 25"C.

4. A nutrient or medicinal composition according to claim 1, wherein the coating composition contains: - 3 to 5 % of chitosan salt, - 55 to 92 % of a fat having a melting point above 50*C, and - 5 to 40 % of a fat or a mixture of fatty > I, ***■ * ^' v if 21 acids having a melting point below 25°C.

5. A composition according to claim 3 or 4, wherein the fat or mixture of fats having a melting point above 50°c is chosen from fatty acids, fatty acid esters, fatty alcohols, paraffins, hydrogenated vegetable or animal oils, and waxes.

6. A composition according to claim 5, wherein the fat or mixture of fats having a melting point above 50 °C is chosen from the monoesters, diesters and triesters of glycerol with a fatty acid.

7. A composition according to claim 5, wherein the fat or mixture of fats having a melting point above 50°C is chosen from stearic acid, behenic acid, lauric acid, myristic acid and stearin.

8. A composition according to claim 3 or 4, wherein the fat or mixture of fats having a melting point below 25 #C is chosen from unsaturated fatty acids having 12 to 22 carbon atoms, and the mono-, di- and tri-esters of glycerol with such fatty acids.

9. A composition according to claim 8, wherein the fat or mixture of fats having a melting point below 25°C is chosen from oleic acid and rapeseed, sunflower, coconut, ground nut, maize and olive oil.

10. A composition according to any one of claims 1 to 9, wherein the chitosan salt is a chloride, acetate, adipate, citrate, formate, glutamate, lactate, malonate, oxalate, propionate, pyruvate, succinate or O / 22 tartrate.

11. A composition according to claim 10, wherein the chitosan salt is chitosan acetate.

12 A composition according to any one of claims 1 to 11, wherein the active substance is methionine and/or lysine.

13. A nutrient composition according to claim l, comprising methionine and a coating composition containing: - 3 % of chitosan acetate (expressed as chitosan), - 90 % of stearic acid, and - 7 % of oleic acid.

14. A composition according to any one of claims 1 to 13 wherein the granules of active principle have a diameter of between 0.6 and 2.5 mm.

15. A composition according to any one of claims 1 to 14, wherein the thickness of the coating layer is between 20 im and 200 /xm.

16. A composition according to claim 15 wherein the said thickness is between 60 im and 120 jim.

17. A composition according to any one of claims 1 to 16, which contains 60 to 90 % by weight of active principle in granular form and 4 to 25 % by weight of the coating composition.

18. A composition according to claim 1 substantially as described in any one of the foregoing Examples.

19. Process for preparing a composition as 23 claimed in any one of claims 1 to 18, which comprises spraying an aqueous emulsion of the constituents of the coating composition onto granules of the active principle.

20. Process according to claim 19, wherein an aqueous solution of chitosan salt is first prepared, fat or fats having a melting point below 25°C, and fat or fats having a melting point above 50"C are then added with agitation, and then the emulsion obtained is sprayed onto granules of the active principle.

21. Process according to claim 19 substantially as hereinbefore described.

22. A nutrient or medicinal composition when prepared by a process as claimed in claim 19, 20 or 21. rfmrypli By tha authorised egents A J PARK & SON ' PATENT f" 1 - s:p 1093 } -CEIVED </div>