WO1992002538A1

WO1992002538A1 - Product and method for transfer of colostrum-derived disease preventing constituents across the gastrointestinal tract

Info

Publication number: WO1992002538A1
Application number: PCT/US1991/005326
Authority: WO
Inventors: Steven B. Binion; Ernest P. Brody; Richard M. Walsh; Eileen F. Bostwick
Original assignee: Procor Technologies, Inc.
Priority date: 1990-07-30
Filing date: 1991-07-29
Publication date: 1992-02-20

Abstract

A method is used for producing a mixture using natural colostrum and having disease-preventing constituents. The mixture has an improved transportability across a gastrointestinal tract of an animal compared to other man-made antibody formulations. The method uses colostrum pooled from up to the first ten milkings of a postpartum animal. The pooled colostrum which has been treated to remove a fat portion is ultrafiltered to remove components having a molecular weight less than 20.000 units. The disease preventing mixture is administered orally to an animal.

Description

Product *and Method For Transfer of CoJostruπi-derived - Disease Preventing Constituents across the Gastro¬ intestinal tract.

BACKGROUND OF THE INVENTION The present invention is a method for producing a disease-preventing mixture derived from a natural colostrum. The natural colostrum has been obtained from an immunized animal postpartum. The method includes pooling the colostrum. The method also includes ultrafiltering the natural colostrum to remove components having a molecular weight of less than 20,000 daltons. The present invention additionally includes a product prepared by this method as well as a method for treating an animal with the product. Colostrum, which is milk produced by an animal postpartum, is a natural source of immunizing antibodies for a newborn animal. For some species, immunity acquired from colostrum within the first 24 hours of the newborn's life is the newborn's primary protection against infectious disease. In the case of bovines, about three weeks are required for the newborn to develop its own immune system. Unfortunately, if the newborn's mother has not been challenged with an array of pathogens, her colostrum is deficient in the disease- preventing constituents the newborn needs to survive. Alternatively, a newborn*s mother will not make enough colostrum or a newborn will not suckle. When such deficiencies occur, the newborn is susceptible to serious illness and even death. Prior efforts to remedy this unfortunate situation have been largely unsuccessful. One of the early endeavors described in the Bauer, U.S. Pat. No. 1,766,590 is a process for making liquid food for young animals using cow's milk, lactic acid, and corn sugar. The Link, U.S. Pat. No. 2,607,716, describes a composition for the prevention of scours which includes blood serum from inoculated dairy cows, enzyme-digested milk solids and vitamin K. A liquid form of the composition is orally administered to animals at risk for scours.

The Michaelson, U.S. Pat. No. 3,553,317 and 3,646,193 describe antibody compositions made by separating colostrum in a carboxymethyl cellulose column to extract lactimmunim, and an immunoglobulin antibody. The composition confers immunity upon parenteral administration. The Plymate U.S. Pat. No. 4,051,235 describes a method for preparing bovine colostrum for use in treating livestock. The preparation includes removing fat casein and a whey fraction from the colostrum to isolate the immunoglobulin portion. The Newson et al. U.S. Pat. No. 4,096,244 describes an immunoglobulin fraction derived from dried blood serum and administered orally to newborn piglets.

The Roberts U.S. Pat. No. 4,112,123 describes a protein composition obtained by ultrafiltration of whey. The composition also includes medium-chain triglycerides and carbohydrates for oral ingestion by individuals having abnormal catabolic states.

The use of ultrafiltration to extract casein from milk products is known in the art. Likewise, extraction of im unoglobulins from blood serum using a variety of methods is well-known in the art. A common means of administering these extracted immunoglobulins is a parenteral route. Attempts to orally administer concentrated immunoglobulin solutions to newborn animals, particularly bovines, have historically been frustrated by a disturbance of the newborn recipient's intestinal function. This intestinal disturbance is believed to be caused by the immunoglobulin solution itself. J.F. Grongnet et al., hypothesized that high molecular weight immunoglobulins were responsible for the intestinal disturbance and that a low molecular weight constituent extracted from colostrum, tempered the disturbance.

SUMMARY OF THE INVENTION The present invention is a method for producing a mixture of disease-preventing constituents using a natural colostrum obtained from an immunized animal postpartum. The method includes pooling the natural colostrum of the female animal. The method further includes ultrafiltering the natural colostrum to retain components having a molecular weight of at least 20,000 daltons. In one embodiment, the method includes concentrating the ultrafiltered natural colostrum to a protein concentration of 50 to 90 percent on a dry weight basis. In another embodiment, the method includes heat treating and spray drying the disease- preventing mixture to make a powder. In one preferred embodiment, the method includes orally administering the disease-preventing mixture to a newborn animal.

A product of the present invention is a mixture of disease-preventing constituents having a molecular weight of at least 20,000 daltons. The mixture is characterized by an improved transportability across a gastrointestinal tract of an animal upon oral administration compared to other man-made immunoglobulin formulations. Also, the product contains protective im unological properties which are transferable to an animal once the product is orally administered. BRIEF DESCRIPTION OF THE DRAWINGS The Figure is a graph illustrating the relative antibody potency in the sera of two groups of bovine calves.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention is a method for producing a mixture of disease-preventing constituents using a natural colostrum. The natural colostrum is obtained from an immunized female animal following parturition. The present invention includes pooling the natural colostrum obtained from the female animal. The present invention further includes ultrafiltering the pooled natural colostrum to retain components having a molecular weight greater than 20,000 daltons. The present invention additionally includes treating an animal with the ultrafiltered mixture.

The product of the present invention is a mixture of disease-preventing constituents having a molecular weight which is substantially within a range of 20,000 to 1,000,000 daltons. The mixture is characterized by an improved transportability of disease-preventing constituents across the gastrointestinal tract of an animal upon oral administration relative to otherman-made immunoglobulin formulations. Also, the product of the present invention has protective immunological properties which are transferrable to an animal when the product is orally administered.

In one embodiment of the present invention, the female animal selected to supply colostrum is immunized while pregnant. The immunization of the animal is accomplished by vaccination. Preferably, the pregnant animal is vaccinated as early as 120 days prior to giving birth. The vaccination is performed using a conventional method intramuscularly, subcutaneously, by intramam ary injection, or orally. In one embodiment, the vaccine is a mixture. The mixture is composed of an antigen component and an adjuvant component. The antigen component is selected to protect the newborn animal from an infection by a pathogenic agent. The adjuvant component is selected to boost the effectiveness of the antigen without overly sensitizing the animal. In one preferred embodiment, the pregnant animal is immunized against pathogenic agents residing in an animal's gastrointestinal tract. These pathogenic agents include but are not limited to bacteria such as EffCheriftia coli and Salmonella ss. as well as viruses such as rotaviruses. The antigen-adjuvant mixture is administered to the pregnant animal as frequently as two week intervals until the pregnant animal gives birth. Variations and frequency of administration do not significantly affect the method and product of the present invention.

In an alternative embodiment, immunization of the animal selected to supply colostrum is accomplished by natural exposure to a pathogenic agent. Natural exposure is characterized by the animal becoming infected with the pathogen during its daily activities. It is not necessary for the method and product of the present invention that the infected animal become physically ill. It is also not necessary for the present invention that the exposure to the pathogenic agent occur while the animal is pregnant. Natural exposure to the pathogen is quantified by measuring the concentration of immunoglobulins specific to the pathogen in the female animal's blood serum. It is believed that the relative potency of pathogen specific immunoglobulin concentration in the female animal's colostrum increases with the increased relative potency of immunoglobulins in the animal's blood serum.

Pooling of the natural colostrum used in the present invention begins once the pregnant animal gives birth and a sample of her colostrum is obtained. In one preferred embodiment, samples of colostrum including up to the first ten milkings of the postpartum animal are pooled. Pooling occurs when samples collected at a milking are combined to form one pooled liquid sample. The method of the present invention does not require that all pooled samples be obtained from the same female animal.

Preferably, colostrumsamples arerefrigerated once they have been collected. If a time delay between sample collection and ultrafiltration is anticipated, the samples are preferably frozen. Pooling of frozen samples occurs by thawing the samples to a liquid state and combining the samples. In one embodiment, a diluent such as water is added to the colostrum samples.

Once the pooling step of the method is completed, the pooled colostrum samples are separated into an aqueous phase and a fat phase using procedures known in the art. The desired disease preventing constituents of the mixture of the present invention are extracted into the aqueous phase. The fat phase is not needed in the method and product of the present invention.

In one embodiment, the pooled colostrum is acidified to form a casein curd fraction. The acidified colostru is then centrifuged to separate the remaining fat fraction and a casein fraction from the aqueous phase. A base is added to the aqueous phase to bring the aqueous phase pH to a neutral level. In one preferred embodiment, the aqueous phase is subjected to heat treatment. Heat treatment is performed at a time and temperature sufficient to inactivate bacterial species such as Escherichia coli and Salmonella sp. In one embodiment, heat treatment is conducted by heating the colostrum mixture within a temperature range of 150-160°F for a time period of 15 to 200 seconds. In one preferred embodiment, heat treatment is conducted at 150-154°F for 115 to 125 seconds. It is not necessary to the method and product of the present invention that heat treatment be performed. This is because it is not a necessary condition that the product of the present invention be sterilized. In one embodiment, where heat treatment is performed, the heat treatment of the pooled colostrum sample is performed prior to an ultrafiltration step. Alternatively, heat treatment of the pooled colostrum sample is performed both prior to and following the ultrafiltration step.

The ultrafiltration step of the method of the present invention retains molecules having a molecular weight that is greater than or equal to 20,000 daltons. In an instance where bovine colostrum is processed, this retentate is believed to contain 25 to 60 percent bovine immunoglobulin G (IgG) on a dry weight basis. Ultrafiltration is accomplished with equipment from a variety of equipment and membrane manufacturers. Suitable ultrafiltration manufacturers include Romicon, Inc., Woburn, Mass., Koch Membrane System, Evansville, Ind., and Dorr-Oliver, Inc., Stamford, Conn. Ultrafiltration is performed so that constituents of the pooled natural colostrum having a molecular weight within a range generally of 20,000 daltons and 1,000,000 daltons are separated and retained.

In one embodiment, the temperature at which ultrafiltration occurs falls within a range of 100 to 120°F. The pressure required to ultrafilter the colostrum mixture varies with the size of the ultrafilter. In a case where the ultrafilter batch capacity is within a range of 225-250 gallons, the pressure of ultrafiltration is 25 pounds per square inch.

In one alternative embodiment, the ultrafiltered colostrum is dialyzed. Dialysis is performed to adjust pH and ionic strength concentrations to desired levels. Alternatively, dialysis is performed to remove undesirable constituents from the ultrafiltered mixture. Dialysis is not required for the method and product of the present invention.

The colostrum mixture is preferably concentrated to a protein concentration having a range of 50 to 90 percent on a dry weight basis. It is not necessary for the method of the present invention that the ultrafiltered colostrum be dried. Ultrafiltered colostrum which has not been dried requires refrigeration and has a shorter shelf life than ultrafiltered colostrum which has been dried. Suitable methods of drying include but are not limited to freeze drying and spray drying. In one preferred embodiment, the product of the present invention is spray dried. The spray dried product does not require refrigeration. Also the spray dried product has a minimum shelf life of 18 months and is convenient to package. Spray drying yields a solid product having immunoglobulin levels proportional to levels in the liquid product. The spray dried product is easily reconstituted in water or other suitable liquid.

One example of conditions for an ultrafiltration run of the present invention, using bovine colostrum is described in Example 1.

EXAMPLE 1

Approximately 10,000 pounds of frozen blocks of bovine colostrum collected from up to the first six milkings of a group of postpartum cows were thawed by placing the frozen blocks in a vat with 2,000 pounds of water. The colostrum mixture was circulated to a heating plate and returned to the vat. Once all the colostrum mixture was thawed, the mixture was warmed to 125°F and a cream fraction was separated with a dairy cream separator. The cream fraction was washed with 125°F water. Fractions of colostral skim and the cream washing skim were combined and diluted with water. The quantity and temperature of the dilution water were chosen so that the final temperature of the solution was 110^βF and the ratio of total water to starting colostrum was 2.0-to-l to 5.0-to-1.0.

The approximately 25,000 pounds of diluted colostral skim was acidified to a pH of 4.2 to 5.0 with 5 percent phosphoric acid. The acid was added at a rate so that the pH of the mixture decreased 0.2 pH units per 5 minutes. Once a pH of 4.2 to 5.0 was reached, the mixture was held for 30 minutes and was then clarified by a centrifuge. A supernatant fraction was cooled to 40°F. The curd was washed with two volumes of water and reclarified.

The approximately 25,000 pounds of the supernatant fraction was neutralized to a pH of 6.0 to 6.4 with 10 percent sodium hydroxide and then heat treated at 150-158°F for 15-140 seconds and cooled to 90-110°F. The heat treated supernatant was concentrated approximately 10-foldusing an ultrafiltrationmembrane. The 2,500 pounds of immunoglobulin concentrate was then heat treated at 145-158^βF for 15 seconds to 30 minutes and cooled to a temperature which is less than 50°F.

Prior to spray drying, the immunoglobulin concentrate was warmed to 80-120°F. The dryer outlet temperature was 178-185°F. The immunoglobulin concentrate solution was fed to the dryer at 1,000-1,400 pounds per square inch and the nozzle was used in the 0.O40 to 0.045 inch range. Approximately 175 pounds of immunoglobulin concentrate powder was obtained.

The product of the present invention is a mixture of disease-preventing constituents having a molecular weight which is generally at least 20,000 daltons. The mixture is characterized by an improved transportability of disease-preventing constituents across a gastrointestinal tract of an animal compared to man-made immunoglobulin formulations when orally administered. The product of the present invention also includes disease-preventing constituents which are transferrable to an animal. It is known that the disease-preventing constituents include immunoglobulins made by the female animal against pathogenic antigens when exposed to a pathogen either by natural exposure or by vaccination. Immunoglobulin types include but are not limited to immunoglobulin G (IgG) , immunoglobulin M (IgM) , and immunoglobulin A (IgA) . Immunoglobulin constituents of the product of the present invention are not necessarily present in the same proportion as constituents in the natural colostrum. This is because a portion of the immunoglobulin constituents are not retained in the ultrafiltration step.

The fraction of protein included in the product of the present invention which is IgG is demonstrated by measuring specific activity. Specific activity is described as the percent IgG compared to total protein concentration. Specific activity of natural bovine colostrum falls within a range of 15 to 30 percent. In one example, specific activity of a product of the present invention, made with bovine colostrum, is 35-70 percent. The product of the present invention is however not limited to the specific activity of this bovine colostrum example.

The quantity of immunoglobulin specific for an antigen of a pathogen against which the female animal is immunized is measured by relative antibody potency. The measurement is relative because immunoglobulins present in the antibody preparation are compared to another antibody preparation. An example of relative antibody potency transferred from the disease-preventing mixture of the present invention to the blood sera of newborn animals is illustrated in the Figure and described in Example 2.

Exam le 2 The Figure depicts the relative antibody potency levels against K99 antigen positive Escherichia coli in blood sera of 30 bovine calves studied. The abscissa of the Figure enumerates the response of each calf in the study. The ordinate of the Figure quantifies the relative antibody potency in each serum sample. Calves were 24-hours old when serum samples were collected. Ten of the calves received no ultrafiltered bovine colostrum. These calves were in a control group. Twenty calves were treated with ultrafiltered bovine colostrum containing immunoglobulins against Escherichia coli bearing the K99 pilus antigen. Serum samples represented in the Figure were taken 8-16 hours after oral administration of the ultrafiltered bovine colostrum. Calves were challenged with the K99 antigen positive Escherichia coli pathogen 2-hours after administration of the product of the present invention. The Figure illustrates that the ultrafiltered bovine colostrum containing relative antibody potency against K99 antigen positive Escherichia coli was rapidly absorbed across the gastrointestinal tract of the calves into the calves' sera. In one embodiment, the product of the present invention is an ultrafiltered bovine colostrum having constituents to prevent infection of human beings or other non-bovine animals by non-bovine pathogens. These constituents are extracted from natural bovine colostrum. These constituents are originally made by female bovines that have been exposed to a human or non- bovine pathogen and have mounted an immunological response. A non-bovine animal ingesting a dose of the ultrafiltered bovine colostrum product of the present invention is passively immunized against human or non- bovine pathogens. It is not known how long this state of passive immunity persists if the ingestion is a single dose. This feature of the product of the present invention is illustrated in Example 3.

_Examp_le ? Piglets received an oral administration of ultrafiltered bovine colostrum containing IgG against the bacterium Streptococcus mutans. Ultrafiltered bovine colostrum IgG against the Bacterium Streptococcus mutans was used in order to provide a sensitive and verifiable marker of serum uptake of the ultrafiltered colostrum because newborn piglets do not typically contain immnoglobulins of antibody potency for Streptococcus mutans. Administration occurred within the first 24 hours after birth. The quantities of Streptococcus mutans IgG specific for immunoglobulins administered to a set of piglet groupings were 0 grams (control group), 10.0 grams, 1.0 grams, and 0.1 grams. Samples of blood sera were taken from piglets at regular intervals from the date of farrowing to a time 5 weeks later. The results, displayed in Tables 1, 2, and 3 show that immunoglobulin from the ultrafiltered bovine colostrum was present in the piglets' sera even after 5 weeks.

Table 1

Table 2

A complete enumeration of constituents of the product of the present invention is not known. Depending upon the species of the female animal, the product includes, in addition to IgG, immunoglobulin M (IgM) and immunoglobulin A (IgA) in various concentrations. It is not known whether the mixture contains constituents which influence cell-mediated immunity of a recipient. Table 4 sets forth physical and chemical features of a spray dried product of the present invention derived from bovine colostrum: Table 4

The present invention includes a method for administering the product of the present invention to an animal. In one preferred embodiment, the product is administered to a newborn animal. The administration is oral and is performed within the first 12 hours of the newborn's life. A single administration of the product of the present invention passively immunizes a newborn. The newborn is immunized against the same pathogens to which the female animal is immunized. The single dosage of ultrafiltered concentrated colostrum of the present invention does not interfere with the newborn's IgG uptake in subsequent natural colostrum feedings. Natural colostrum is absorbed by treated newborn animals to the same degree as by untreated newborn animals.

In a case where bovine newborns (calves) are orally treated with the product of the present invention before ingesting natural colostrum, the treated calves have neither enhanced nor diminished absorption of IgG from subsequent natural colostrum feedings. The product of the present invention does not then interfere with absorption of the IgG from natural colostrum across the gastrointestinal tract of a newborn bovine animal. In one embodiment, a single dose of the powdered or liquid product of the present invention is pre-packaged. In the case of the powdered product, the single dose of the powder is prepackaged with a volume of a diluent. Alternatively, multiple doses are packaged with multiple volumes of diluent. The powder and diluent are separated by a barrier within the package. To mix, the diluent is squeezed in a manner to break the barrier and mix with the powder. Once the diluent volume is mixed with the powdered product, the mixture is fed to a newborn animal. To feed, for example, the animal's mouth is held open and the mixture is poured into its mouth. Alternative feeding methods include but are not limited to by bottle, syringe or stomach tube.

The oral administration of the product of the present invention confers an immunological benefit which is obtained and concentrated from the colostrum of the immunized female animal. The immunized animal does not have to be the newborn's mother. This is a significant advantage of the product of the present invention o the natural process of a newborn ingesting only its mother's colostrum. With the present invention, a newborn's immunity to infectious disease no longer depends upon the disease and vaccination history of its mother. In the case of bovines, a single oral administration of the product of the present invention immunizes a newborn against pathogens causing scours or other types of gastrointestinal disorders. Immunization occurs even if the newborn's natural source of colostrum contains no such disease preventing constituents.

The process and product of the present invention achieve a result which is unexpected in light of what is known in the art. Prior to the present invention, those skilled in the art commonly assumed that for acceptable immunoglobulin transfer across a non-human newborn's gastrointestinal tract to occur an antibody mixture had to have a complement of low molecular weight constituents and be of relatively low specific activity. A mixture containing only higher molecular weight proteins and immunoglobulins was believed to cause gastric upset in the newborn. The product of the present invention, which does not include a complement of low molecular weight constituents, and has a high specific activity but does not cause gastric upset, is contrary to the commonly held belief.

A demonstration of efficacy in the form of conferring passive immunity of the mixture of the present invention to an animal is described in Example 4.

Example 4 A mixture containing immunoglobulins directly against Escherichia coli antigen was prepared by the method of the present invention and was tested in 30 newborn calves. Twenty calves were administered a single dose of a reconstituted mixture. In subsequent feedings, these animals received colostrum. Ten calves in the control group received only normal colostrum. All 30 calves were challenged by oral administration with a virulent strain of K99 antigen positive Escherichia coli and were monitored for a period of 5 days. The results were that the calves treated with the mixture faired significantly better in all areas evaluated when compared to the control animals. The use of the mixture substantially reduced the time interval for shedding Escherichia coli from 43/50 study days for the control group to 27/100 days for the group receiving the mixture of the present invention. More importantly, the death rate in the group receiving the product of the present invention was reduced to 10 percent (90 percent survival) from 70 percent (30 percent survival) in the control group.

Although the present invention has been described with reference to preferred embodiments, workers skilled in the art will recognize that changes may be made in form and detail without departing from the spirit and scope of the invention.

Claims

WHAT IS CLAIMED IS:

1. A method for producing a disease preventing mixture derived from a natural colostrum obtained from an immunized female animal postpartum, the method comprising: pooling the natural colostrum of the female animal; ultrafiltering the natural colostrum to remove components with a molecular weight of less than 20,000 daltons.

2. The method of Claim 1 wherein the natural colostrum pool includes the first six milkings of the female animal postpartum.

3. The method of claim 1 wherein a fraction of casein proteins are removed prior to ultrafiltration.

4. The method of claim 1 wherein a fat fraction is removed prior to ultrafiltration.

5. The method of Claim 1 wherein the pooled natural colostrum is subjected to heat treatment prior to ultrafiltration.

6. The method of Claim 1 wherein the pooled natural colostrum is subjected to heat treatment following ultrafiltration.

7. The method of Claim 1 wherein the natural colostrum which has been ultrafiltered is dried to make a powder.

8. The method of claim 1 wherein the powder is packaged with a volume of diluent, separated by a breakable package barrier.

9. The method of Claim 1 wherein the natural colostrum which has been ultrafiltered is concentrated to a protein concentration on a dry weight basis in a range of 50 to 90 percent.

10. The method of claim 1 wherein the natural colostrum is bovine.

11. The method of claim 10 wherein the natural bovine colostrum contains at least one disease- preventing constituent against at least one bovine pathogen.

12. The method of claim 11 wherein the be -ine pathogen is Escherichia coli.

13. The method of claim 10 wherein the natural bovine colostrum contains at least one disease preventing constituent against at least one non-bovine pathogen.

14. The method of claim 13 wherein the non-bovine pathogen is a human pathogen.

15. The method of claim 1 wherein the ultrafiltered colostrum is orally administered to an animal.

16. The method of claim 15 wherein the animal is a newborn.

17. The method of claim 16 wherein the newborn is not more than 24 hours old.

18. A product produced by the process of claim 1.

19. A product extracted from natural colostrum comprising: an array of disease-preventing constituents having an average molecular weight which is at least 20,000 daltons.

20. The product of claim 19 wherein the disease- preventing constituents are immunoglobulins.

21. The product of claim 20 wherein the immunoglobulins have a measurable relative antibody potency.

22. The product of claim 19 wherein the disease- preventing constituents have protective immunological properties which are transportable across a recipient's gastrointestinal tract upon oral administration.

23. The product of claim 19 wherein the disease- preventing constituents have protective immunological properties which are transferable to a nursing infant.

24. The product of claim 22 wherein the protective immunological properties are transferrable with a single oral administration to a nursing infant.

25. The product of claim 21 wherein the measurable relative antibody potency is against a pathogen infecting the animal's gastrointestinal tract.

26. The product of claim 25 wherein the pathogen infecting the animal's gastrointestinal tract is Escherichia coli.

27. The product of claim 19 wherein the array of disease-preventing constituents is dried.

28. The product of claim 27 wherein the dried array of disease-preventing constituents has a moisture within a range of 0-10 percent.

29. The product of claim 27 wherein the dried array of disease-preventing constituents has a protein concentration of at least 50 percent.

30. The product of claim 19 wherein the array of disease-preventing constituents is extracted from a bovine colostrum.

31. The product of claim 21 wherein the measureable relative antibody potency is against a bovine pathogen.

32. The product of claim 31 wherein the bovine pathogen is K99 antigen positive Escherichia coli.

33. The product of claim 21 wherein the measureable relative antibody potency is against a porcine pathogen.

34. The product of claim 21 wherein the relative antibody potency is against a human pathogen.

35. The product of claim 32 wherein the human pathogen is Streptococcus mutans.

36. The product of claim 25 wherein the dried array of disease-preventing constituents is discretely packaged with at least one volume of diluent, separated by a breakable package barrier.