WO1999033341A1 - Matrice a liberation lente, largement insoluble dans l'eau, contenant des substances bioactives - Google Patents

Matrice a liberation lente, largement insoluble dans l'eau, contenant des substances bioactives Download PDF

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Publication number
WO1999033341A1
WO1999033341A1 PCT/NZ1998/000193 NZ9800193W WO9933341A1 WO 1999033341 A1 WO1999033341 A1 WO 1999033341A1 NZ 9800193 W NZ9800193 W NZ 9800193W WO 9933341 A1 WO9933341 A1 WO 9933341A1
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WO
WIPO (PCT)
Prior art keywords
matrix
protein
bioactive substance
cross
urea
Prior art date
Application number
PCT/NZ1998/000193
Other languages
English (en)
Inventor
Patrick Joseph Silcock
Karen Rachel Chenery
Jean-Pierre Ghislain Dufour
Original Assignee
Kiwitech Limited
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
Application filed by Kiwitech Limited filed Critical Kiwitech Limited
Priority to NZ505351A priority Critical patent/NZ505351A/xx
Priority to AU18940/99A priority patent/AU756668B2/en
Publication of WO1999033341A1 publication Critical patent/WO1999033341A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1658—Proteins, e.g. albumin, gelatin
    • C—CHEMISTRY; METALLURGY
    • C05—FERTILISERS; MANUFACTURE THEREOF
    • C05D—INORGANIC FERTILISERS NOT COVERED BY SUBCLASSES C05B, C05C; FERTILISERS PRODUCING CARBON DIOXIDE
    • C05D9/00—Other inorganic fertilisers
    • C05D9/02—Other inorganic fertilisers containing trace elements
    • C—CHEMISTRY; METALLURGY
    • C05—FERTILISERS; MANUFACTURE THEREOF
    • C05G—MIXTURES OF FERTILISERS COVERED INDIVIDUALLY BY DIFFERENT SUBCLASSES OF CLASS C05; MIXTURES OF ONE OR MORE FERTILISERS WITH MATERIALS NOT HAVING A SPECIFIC FERTILISING ACTIVITY, e.g. PESTICIDES, SOIL-CONDITIONERS, WETTING AGENTS; FERTILISERS CHARACTERISED BY THEIR FORM
    • C05G5/00—Fertilisers characterised by their form
    • C05G5/40—Fertilisers incorporated into a matrix

Definitions

  • This invention relates to the release of bioactive substances and in particular to matrices for effecting such release over an extended period.
  • Selenium is an essential trace element for both livestock and humans. Unfortunately, the distribution of selenium on earth is uneven, leaving some regions with very high or alternatively very low levels in the soil, with New Zealand and regions of Australia particularly deficient. The selenate ion is the most biologically active form of selenium and is commonly used for livestock supplementation (usually as sodium selenate).
  • Livestock can be supplemented either directly (through drenching or injection), or indirectly through application to the soil to be taken up by plants to ultimately be ingested by the animal.
  • drenching due to the high toxicity of selenium, only small doses may be used and this increases the frequency with which it must be applied. Frequent re-application is both expensive and inconvenient.
  • the invention provides a matrix which is substantially water-insoluble and which is capable of effecting a slow release of an encapsulated bioactive substance, said matrix comprising a protein or protein-containing material cross-linked by a cross-linking agent to urea to form a 3-dimensional structure throughout which said bioactive substance is substantially uniformly dispersed.
  • the protein or protein-containing material is or contains casein.
  • the protein or protein-containing material is or contains acid casein.
  • the protein or protein-containing material is or contains rennet casein.
  • the cross-linking agent is an aldehyde such as formaldehyde, glutaraldehyde or glyceraldehyde. More conveniently, the cross-linking agent is formaldehyde.
  • the cross-linking agent may be a compound which has an aldehydic function, such as a reducing sugar, or a dialdehyde such as malonaldehyde .
  • the bioactive substance is a trace element or medicament.
  • the bioactive substance is a trace element or a mixture of trace elements, most preferably a source of one or more of selenium, zinc, cobalt or copper-
  • the matrix can further include a particulate inert filler or bulking agent.
  • the inert filler be selected from lime, silica or talc, with milled lime being particularly preferred-
  • the invention provides a process for preparing a matrix as defined above comprising the steps of:
  • the water-insoluble matrix is then dried.
  • the protein is casein, more preferably acid casein.
  • reaction mixture can further include an anti-foam agent and/ or a dispersing agent.
  • the anti-foam agent is polydimethylsiloxane, octamethyl cyclotetrasiloxane or a combination of these.
  • the dispersing agent is maltodextrin.
  • the cross-linking agent is formaldehyde, glutaraldehyde or glyceraldehyde with formaldehyde being particularly preferred-
  • the bioactive substance is a trace element or medicament.
  • the bioactive substance is a trace element which is selected from a selenium source, a zinc source, a cobalt source and a copper source, with a selenium source being presently preferred.
  • said protein and urea are added to the reaction mixture as a water- soluble matrix comprising the protein and urea in aqueous solution.
  • said water-soluble matrix further includes the bioactive substance.
  • said cross-linking agent is added to the reaction mixture alone or in aqueous solution.
  • said cross-linking agent is added in aqueous solution and said bioactive substance is dispersed in said solution.
  • the slow release matrix is to include an inert particulate filler
  • said filler be added to the reaction mixture together with the cross-linking agent.
  • the inert filler is added to the reaction mixture as part of an aqueous solution containing the cross-linking agent and the bioactive substance.
  • the filler be lime, more preferably milled lime.
  • the pH of the reaction mixture is approximately neutral (pH 7.0). More preferably, the pH is 7.1.
  • the slow release matrix containing the bioactive substance is shaped, eg granulated or pelletised.
  • drying step is performed after the shaping step.
  • the reaction mixture will be heated to accelerate the cross-linking between the protein and the urea.
  • the soluble matrix comprises acid casein, urea, maltodextrin, anti-foam agent and alkali in an aqueous solution at a pH of approximately 7. 1.
  • acid casein urea
  • maltodextrin maltodextrin
  • anti-foam agent alkali in an aqueous solution at a pH of approximately 7. 1.
  • the amount of water added to the soluble matrix is preferably in the range of from 0-233g per lOOg of the soluble matrix ingred ents listed above.
  • the soluble matrix comprises, on a wet weight basis:
  • this preferred soluble matrix therefore comprises:
  • the invention provides a slow release substantially water- insoluble matrix obtainable by a process as defined above.
  • the invention provides a water-soluble matrix suitable for use in the preparation of a slow release matrix by a process as defined above comprising, in aqueous solution, casein and urea.
  • the soluble matrix will further include a dispersing agent, an anti-foam agent and an alkali.
  • the soluble matrix will comprise:
  • the water-soluble matrix may optionally further include a bioactive substance, preferably a trace element, most preferably a selenium source, a zinc source, a cobalt source or a copper source.
  • a bioactive substance preferably a trace element, most preferably a selenium source, a zinc source, a cobalt source or a copper source.
  • Figure 1 is a graph showing the cumulative results for elution of selenium from a slow release matrix of the invention.
  • the invention has a number of aspects.
  • it provides a slow release matrix. This matrix is capable of effecting release of a bioactive substance it contains over an extended period.
  • the matrix can be used to effect a sustained release of any bioactive substance or combination of these. It is however preferred that the bioactive substance be a trace element or medicament- In particular, a matrix which is able to effect a slow release of trace elements such as selenium sources, zinc sources, cobalt sources and copper sources is a particular focus of this invention.
  • the slow release matrix of the invention is effectively a 3-dimensional structure containing cross-linked protein and urea.
  • the bioactive substance intended for controlled release is substantially uniformly dispersed throughout the 3- dimensional matrix structure.
  • the preferred protein or protein- containing material included in the matrix is casein. Further, while rennet casein is not excluded, it is particularly preferred that the protein be acid casein.
  • Casein is the preferred protein due to its open structure, relatively large proportion of lysine residues and relatively pure natural state. These properties mean that casein will readily polymerise with little fat or carbohydrate to interfere in the reaction. The result is a highly cross-linked structure.
  • urea allows a high solids level to be attained in the final product while retaining a workable viscosity.
  • Urea is also able to participate in the cross-linking (polymerisation) reaction, particularly where the preferred aldehyde cross-linking agents are used.
  • urea reacts with the aldehyde cross-linking agent to form aldehyde-urea-chains between the protein (casein) monomers.
  • urea is preferred as it is a relatively low cost reagent.
  • the urea and protein (casein) components are cross-linked by a cross-linking agent, which is preferably an aldehyde-based agent.
  • a cross-linking agent which is preferably an aldehyde-based agent.
  • suitable cross-linking agents include glyceraldehyde and glutaraldehyde.
  • Other examples of cross-linking agents which may be used are compounds which contain an aldehydic function, such as reducing sugars or dialdehydes such as malonaldehyde. It is however preferred that the cross-linking agent be formaldehyde. This preference is due to the ability of formaldehyde to react rapidly with both the preferred protein (casein) and urea to form an insoluble matrix.
  • the matrix in addition to the protein, urea, cross-linking agent and bioactive substance, it will be usual for the matrix to include an inert filler or bulking agent.
  • This filler will be particulate, with convenient examples including lime (preferably milled lime) or talc.
  • the inert filler can be added to further reduce the cost of the matrix, or to supplement the bioactivity of the matrix (eg as a fertiliser) .
  • the slow release matrix of the invention can be prepared by taking a number of approaches. Essentially, what is involved is the formation of a reaction mixture in aqueous solution of the protein (preferably casein), the urea, the bioactive substance and the cross-linking agent, and then allowing sufficient time for the cross-linking reaction to proceed to completion.
  • the protein preferably casein
  • the protein and urea components are added to the reaction mixture in aqueous solution together.
  • the protein and urea constitute a soluble matrix.
  • the soluble matrix can optionally include a number of additional components. These include dispersing agents (such as maltodextrin) and anti-foam agents. Desirably, an alkali such as ammonia is also included to maintain the pH of the soluble matrix at approximately 7. 1.
  • the soluble matrix contains acid casein, urea, dispersing agent (maltodextrin D.E. 10), an anti-foam agent, an alkali (ammonia) and added water.
  • these components are included in the soluble matrix in the following proportions, on a dry weight basis:
  • Water may also be included in the soluble matrix. It is preferred that water is present in the soluble matrix in a proportion ranging from 0 to about 233g of water per lOOg of total weight of the remaining ingredients of the soluble matrix. Most preferably, the water soluble matrix is made up of the following components in the following percentages: wet weight basis dry weight basis acid casein 38% 42.2% urea 45% 49.6% maltodextrin (D.E. 10) 5% 5.5% ammonia solution (25% NH 3 ) 2.2% 2.4% antifoam 0.2% 0.2% water 10.0%
  • the water soluble matrix will conveniently be prepared by first blending the dry ingredients (the casein, urea, maltodextrin and powdered antifoam) and then mixing the blended dry ingredients with the water and ammonia solution. The resulting mixture is then blended until free of lumps, and matrix allowed to form.
  • dry ingredients the casein, urea, maltodextrin and powdered antifoam
  • the water-soluble matrix is combined with the cross-linking agent.
  • This will usually be formaldehyde.
  • the formaldehyde will conveniently be added to the reaction mix in aqueous solution.
  • a 37% -40% formaldehyde aqueous solution has been found suitable.
  • the amount of the formaldehyde aqueous solution to be added can vary depending on the desired properties of the finished matrix. However, in a preferred embodiment, an amount of formaldehyde corresponding to approximately 26% by weight of the finished matrix of 40% formaldehyde solution will be added.
  • the bioactive substance to be dispersed throughout the final matrix can be included as part of the water-soluble matrix.
  • the bioactive substance it is more convenient for the bioactive substance to be included with the aqueous solution of the cross-linking agent (usually formaldehyde) and added to the reaction mixture at the same time as the cross-linking agent. This has been found to reduce problems with ensuring adequate mixing of the bioactive substance.
  • the cross-linking agent usually formaldehyde
  • the proportion of bioactive substance included will vary depending on the nature of the bioactive substance and the end use to which the matrix is to be put and in particular the desired release rate of the bioactive substance in the finished matrix.
  • bioactive substance is selenium (in the form of sodium selenate) or cobalt
  • the sodium selenate may conveniently be present in an amount of up to 2.4% of dry weight of the finished matrix, and the cobalt hydroxide may conveniently be present in an amount of up to 1 1% by weight of the finished matrix.
  • the inert filler is also to be included in the final insoluble matrix
  • this is also conveniently added to the reaction mixture at the same time as the cross-linking agent and bioactive substance.
  • the cross-linking agent, the bioactive substance and the inert filler will be mixed in aqueous solution for addition to the reaction mixture.
  • the amount of the inert filler can vary.
  • the inert filler is milled lime
  • it can be added to the reaction mixture in an amount such that the filler constitutes up to 74% of the finished matrix (on a dry weight basis). More preferably, the lime will be added in an amount to be from 29% to 59% by dry weight of the final matrix, more preferably approximately 39% by dry weight of the final matrix.
  • reaction is permitted to proceed to form the substantially insoluble matrix.
  • a suitable reaction period is approximately 7 hours at room temperature.
  • the reaction period can be substantively reduced if desired through heating of the reaction mixture.
  • the insoluble matrix will be formed in as little as 10 minutes by heating the reaction mixture to a temperature of between 60°C and 70°C.
  • the matrix is preferably dried.
  • the matrix can be formed into a relatively thin layer or sheet and then subjected to heat for a defined period. A period of 24 to 72 hours at a temperature of approximately 65°C has been found to be suitable.
  • the drying step serves a number of functions: it reduces the moisture content of the matrix; it allows the polymerisation reaction to go to completion; and it removes any residual formaldehyde. It is further preferred that the matrix be shaped, eg granulated or pelletised, in its final form.
  • the process of production can therefore include a shaping eg granulation or pelleting step. It is preferred that the shaping step be performed prior to drying.
  • the texture of the insoluble matrix is such that it can be readily formed into small pellets or balls. These are preferably formed and then placed or dropped onto a bed of granulated material such as starch. Proceeding in this way allows the granules or balls of matrix to avoid being stuck together. It also ensures that the granules or balls of matrix have smooth surface characteristics.
  • the granulation step involves forming small cylindrical pellets by extrusion of the insoluble matrix, conveniently using a die in a hydraulic press.
  • the granules or balls of matrix have an average weight of approximately 0.01 to 0. 1 g and an average diameter of 1.5 to 3 mm.
  • the particularly preferred matrix formulations which include sodium selenate or cobalt hydroxide as the bioactive substance to be released therefore consist of the following, on a dry weight basis:
  • the soluble casein matrix consisted of a dry blend of acid casein (46g), urea (54g), maltodextrin (6g) and antifoam (0.2g), which were mixed with water ( 1.2g) and lastly ammonia solution (2.6g, 25% ammonia). The mixture was stirred until free of lumps and left to stand overnight-
  • Powdered lime (97g) was dry blended with powdered sodium selenate (4.8g, 99% purity) and mixed under low shear with formaldehyde (32.75g, 40% w/v formaldehyde) at room temperature.
  • a soluble casein matrix formed as in Example 1 (71.8g, 55.7% soluble soUds) was added to the above blend and mixed under low shear until homogenous.
  • the wet mixture was left to stand at room temperature for eight hours with intermittent mixing. Upon standing, the mixture became thick and elastic, prior to being roUed out onto a greased tray. Spherical chips are cut from the mass and dried at 60°C for 48 hours.
  • the selenium release characteristics of 4 separate samples of fertiliser granules made by the general preparative method described in Example 1 were assessed.
  • the granules contained the following, on a dry weight basis: Sample 1 2 3 4 soluble casein matrix ("glue") 30.0% 40.0% 50.0% 40.0% formaldehyde 9.0% 12.3% 18.2% 12.3% sodium selenate 2.4% 2.4% 2.4% 2.4% lime 58.6% 45.3% 29.4% 45.3%
  • Samples 1 and 2 were ball-like in shape whereas samples 3 and 4 were irregular shaped-chips.
  • a spherical product that is very dense with a smooth surface would appear to provide the best release properties.
  • Soluble casein matrix Fertiliser (wet basis) % weight/weight %weight / weight Ingredient Urea 44.67 14.45
  • the urea, casein, maltodextrin and antifoam were blended together; and the water and ammonia also blended together.
  • the water and ammonia were added to a
  • Soluble casein matrix FertiUser (wet basis) % weight/ weight %weight / weight
  • a cobalt fertiUser was prepared using the same method as that described above for Example 4, with the variation that the mixing time for the resulting mass was reduced to between 6-14 minutes.
  • Soluble casein matrix Fertiliser (wet basis) %weight/weight %weight / weight
  • Powdered lime 26.60 Cobalt hydroxide 7.40 Formaldehyde solution (40%) 22.00
  • the urea, casein, maltodextrin and antifoam were blended together; the ammonia and water were also separately blended together.
  • the water and ammonia were then added to the urea, casein, maltodextrin and antifoam and the mixture mixed until it was free of lumps.
  • the powdered Ume, cobalt hydroxide and formaldehyde were blended together then added to the mixture.
  • the resulting mass was left to cure for 1 to 2 hours at room temperature (or until the mass could be roUed into baUs).
  • the mass was then roUed into Uttle balls and the baUs dropped onto a bed of starch. After 3 hours the baUs were removed from the starch by sieving and cured until hard (48 hours at 70 * C).
  • the water-insoluble matrix of the invention has a number of appUcations. These will be dependent primarily upon the bioactive substance dispersed within, and to be released from, the matrix.
  • casein-urea matrices which contain a selenium or cobalt source-
  • Such matrices can be used to supply selenium or cobalt to Uvestock, usuaUy indirectly through appUcation to the soil for uptake by pasture plants.
  • This is especiaUy the case where the matrix includes milled lime as an inert filler, which renders the product suitable for use as a selenium- or cobalt- containing fertiUser.
  • the selenium-or cobalt-containing matrix can be used to coat seeds to ultimately increase the selenium or cobalt content of products such as cereals.
  • the matrix can be used to effect the slow release of other trace elements such as zinc and copper in the same manner as for selenium and cobalt.
  • appUcations wiU involve the use of the matrix to release medicaments, particularly veterinary medicaments.
  • the matrix containing the medicament would normally form part of a bolus for administration to the animal.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Inorganic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pest Control & Pesticides (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne une matrice, largement insoluble dans l'eau, qui permet une libération lente d'une substance bioactive encapsulée. Ladite matrice est constituée d'une protéine, ou d'un matériau contenant une protéine, réticulée à de l'urée, à l'aide d'un agent de réticulation, pour former une structure tridimensionnelle dans laquelle la substance bioactive est dispersée de façon pratiquement uniforme. Dans des réalisations préférées de l'invention, la protéine, ou le matériau contenant la protéine, est de la caséine acide, et la substance bioactive est un oligo-élément comme le cobalt ou le sélénium. La présente invention concerne aussi un procédé de préparation de ladite matrice.
PCT/NZ1998/000193 1997-12-24 1998-12-24 Matrice a liberation lente, largement insoluble dans l'eau, contenant des substances bioactives WO1999033341A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
NZ505351A NZ505351A (en) 1997-12-24 1998-12-24 Sustained release water-insoluble matrix comprising protein crosslinked with urea using a crosslinking agent and a bioactive substances such as a trace element
AU18940/99A AU756668B2 (en) 1997-12-24 1998-12-24 Substantially water-insoluble matrix containing bioactive substances for slow release

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
NZ329499 1997-12-24
NZ32949997 1997-12-24

Publications (1)

Publication Number Publication Date
WO1999033341A1 true WO1999033341A1 (fr) 1999-07-08

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PCT/NZ1998/000193 WO1999033341A1 (fr) 1997-12-24 1998-12-24 Matrice a liberation lente, largement insoluble dans l'eau, contenant des substances bioactives

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AU (1) AU756668B2 (fr)
WO (1) WO1999033341A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105037057A (zh) * 2015-06-25 2015-11-11 合肥工业大学 一种生物可降解的双层包膜缓释肥料及其制备方法
CN107721768A (zh) * 2017-11-28 2018-02-23 芜湖四高农业科技有限公司 一种减少裂果现象的脆桃专用肥制备方法
IT201800003842A1 (it) * 2018-03-21 2019-09-21 Consorzio Patata Italiana Di Qualita Metodo per la preparazione di una composizione per il trattamento di colture agrarie

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1990011129A1 (fr) * 1989-03-24 1990-10-04 Nehézvegyipari Kutató Intézet Procede de production de capsules ecologiques d'origine naturelle pour produits a liberation regulee de l'ingredient actif
WO1991004661A2 (fr) * 1989-09-28 1991-04-18 Sandoz Ltd. Produits chimiques agricoles microencapsules
WO1991010362A1 (fr) * 1990-01-12 1991-07-25 E.I. Du Pont De Nemours And Company Procede de preparation de granules a liberation regulee
WO1992013448A1 (fr) * 1991-02-06 1992-08-20 Zeneca Inc. Microcapsules et procede de microencapsulation
WO1996026719A1 (fr) * 1995-03-02 1996-09-06 Takeda Chemical Industries, Ltd. Composition a liberation prolongee, son utilisation et sa preparation
WO1998035553A1 (fr) * 1997-02-14 1998-08-20 Imperial Chemical Industries Plc Compositions tensioactives agrochimiques

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1990011129A1 (fr) * 1989-03-24 1990-10-04 Nehézvegyipari Kutató Intézet Procede de production de capsules ecologiques d'origine naturelle pour produits a liberation regulee de l'ingredient actif
WO1991004661A2 (fr) * 1989-09-28 1991-04-18 Sandoz Ltd. Produits chimiques agricoles microencapsules
WO1991010362A1 (fr) * 1990-01-12 1991-07-25 E.I. Du Pont De Nemours And Company Procede de preparation de granules a liberation regulee
WO1992013448A1 (fr) * 1991-02-06 1992-08-20 Zeneca Inc. Microcapsules et procede de microencapsulation
WO1996026719A1 (fr) * 1995-03-02 1996-09-06 Takeda Chemical Industries, Ltd. Composition a liberation prolongee, son utilisation et sa preparation
WO1998035553A1 (fr) * 1997-02-14 1998-08-20 Imperial Chemical Industries Plc Compositions tensioactives agrochimiques

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105037057A (zh) * 2015-06-25 2015-11-11 合肥工业大学 一种生物可降解的双层包膜缓释肥料及其制备方法
CN105037057B (zh) * 2015-06-25 2018-05-11 合肥工业大学 一种生物可降解的双层包膜缓释肥料及其制备方法
CN107721768A (zh) * 2017-11-28 2018-02-23 芜湖四高农业科技有限公司 一种减少裂果现象的脆桃专用肥制备方法
IT201800003842A1 (it) * 2018-03-21 2019-09-21 Consorzio Patata Italiana Di Qualita Metodo per la preparazione di una composizione per il trattamento di colture agrarie
EP3543224A1 (fr) * 2018-03-21 2019-09-25 Consorzio Patata Italiana di Qualita' Procédé de préparation d'une composition pour le traitement de cultures agricoles

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Publication number Publication date
AU1894099A (en) 1999-07-19
AU756668B2 (en) 2003-01-23

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