# Patent

## Title
Methods and compositions for treating lactose intolerance

## Abstract

The invention provides methods and compositions for treating lactose intolerance. In embodiments, the invention provides methods and composition for decreasing symptoms of lactose intolerance by administering to an individual suffering from lactose intolerance increasing doses of lactose using a protocol such that at the end of treatment the individual's symptoms of lactose intolerance are decreased and such that symptoms remain decreased after a period of time.

## Background
CROSS-REFERENCE TO RELATED APPLICATION
This application is a continuation of U.S. patent application Ser. No. 11/632,289, filed Dec. 12, 2007 now abandoned which is a 371 of PCT/US05/26095, filed Jul. 22, 2005 which is a continuation-in-part of U.S. utility patent application Ser. No. 10/710,588, filed Jul. 22, 2004, now abandoned all of which are incorporated herein by reference in their entirety.


BACKGROUND OF THE INVENTION
According to several sources, there are 30 to 50 million people in the world who are lactose intolerant. In the 1960's and 1970's, it was reported that 70% of the adults in the world had lactose intolerance. In 1995, it was reported that 75% of the adults in the world and 25% of the adults in the U.S. were categorized as being lactose intolerant. In 1994, it was reported that 75% of African Americans and Native Americans and 90% of Asian Americans had lactose intolerance. It has also been reported that 30% of adults who are mostly North Western and North American descendants of the Europeans, have adapted to high lactase activity into adulthood. Research concludes that this adaption is genetically controlled, permanent and related to a long tradition of milk and milk products consumption in these regions of the world.
If an individual suspects that he has lactose intolerance, it is potentially harmful for him to restrict his diet since it may result in a nutrition shortage or a failure to detect a more serious disease. Mile and other diary products are major sources for nutrition in the basic American diet. The primary nutrients in milk are protein, calcium, riboflavin, vitamin A, and vitamin D. Calcium is an important part of the recommended daily allowances of vitamins and minerals and any deficiency therein can lead to osteoporosis.
Lactose is not digested when the amount of lactose consumed exceeds the lactase enzyme capacity of the small intestine. Instead, excess undigested lactose passes through the small intestines into the large intestine where it is fermented by a bacteria called colinic flora. The fermentation of the lactose in the large intestine produces hydrogen and methane which can lead to bloating, gas, and diarrhea. These symptoms are caused by a very low activity of lactase in the intestines.
Young children who have lactose intolerance are very rare. The amount of lactase enzyme a body produces generally reaches a maximum immediately after birth and then decreases in the majority of people after their body adjusts during the ages of 3-15. A stool test is used to test lactose intolerance in young children. For young children, the breath test is not as accurate because they usually have a tendency to get dehydrated which can cause diarrhea.
The reasons for an onset of lactose intolerance are generally unknown. However, there is a general belief that by consuming small amounts of lactose frequently over a period of time, lactose intolerance can be improved. Whole milk and chocolate milk appear to be tolerated better than low fat milk because the fat content of whole milk and chocolate milk slows the rate of gastric emptying. Previous attempts at improving the symptoms of lactose intolerance have met with some success. See, e.g., Published U.S. Patent Application No. 0020034496 The present invention builds upon this previous success.
INCORPORATION BY REFERENCE
All publications and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.


DETAILED DESCRIPTION OF THE INVENTION
The invention provides methods, compositions, kits, and business methods for the reduction of symptoms of lactose intolerance. Symptoms of lactose intolerance include gas, bloating, diarrhea, abdominal pain, cramping, and vomiting. The methods and compositions of the invention reduce or eliminate one or more of these symptoms, typically all of the symptoms. A striking aspect of the present invention is that the reduction or elimination of symptoms persists after treatment has concluded. Thus, the present invention need not be used on a continuous basis but rather may be utilized in a discrete time period and then discontinued.
Lactose Intolerance
Lactose Intolerance, otherwise referred to as lactose maldigestion, is the inability to digest a significant amount of lactose, derived from a deficiency of the lactase enzyme in the small intestine. Lactose is the natural sugar in milk and milk products of all mammals. Lactase is the enzyme which splits the milk sugar lactose into its components (i.e., glucose and galactose), and also breaks down the milk sugar into smaller forms that can be processed into the bloodstream. The lactase enzyme is necessary for mammals to digest lactose.
There is an important distinction between lactose intolerance and milk allergies. Lactose intolerance is the inability of the body to digest lactose-containing products due to a deficiency in the lactase enzyme. A milk allergy, however, is a sensitively to the protein in milk, which involves the immune system and does not relate to a deficiency of the lactase enzyme. In humans, a milk allergy is usually experienced only by infants.
Generally, humans develop lactose intolerance from a primary or secondary cause. The primary cause is an onset of loss of lactase that is a permanent condition. This occurs at a variable period after the weaning period. The primary cause is also genetically determined. The secondary cause is generally a temporary condition that occurs as a result of another disease or event that damages the lining of the small intestine where lactase is active. This is usually caused by an acute diarrheal disease, parasitic infection, Cohn's disease, celiac disease, gastrointestinal surgery, or the intake of certain medications.
In addition to the primary and secondary causes, certain human ethnic and racial populations have more of a predisposition for lactose intolerance. In these populations, social and cultural habits and attitudes influence lactose intolerance. Lactose activity can also decrease with age in certain ethnic and racial populations, including those populations which have origins in Europe, the African plains, and the Siberian Steppes. Humans who are most likely to have or develop lactose intolerance include those of Asian, Middle Eastern, North American, African, and Latin American decent.
Lactose intolerance can be tested either indirectly or directly. There are three main ways to test by the indirect method: a hydrogen breath test, a stool acidity test, or a blood glucose test. In the hydrogen breath test, the breath is measured to determine the amount of hydrogen produced after consuming a measured amount of lactose, typically 15 g. The lactose is consumed by drinking a lactose mixture, and the subject exhales into a vacuum-sealed collection tube at three one hour time intervals. A high level of hydrogen in the breath indicates an improper digestion of lactose. In a stool test, the stool is tested to determine the amount of acid. In a blood glucose test, the blood is tested to determine the amount of glucose (sugar) content after administering a predetermined amount of lactose-containing product to the subject. The direct method measures lactose activity in a mucosal biopsy specimen.
People typically have different systems of lactose intolerance. Lactose intolerance may also be psychologically induced. There are also many different variations of lactose intolerance depending on the individual. For example, some individuals cannot have cheese, melted cheese, plain milk, or warm diary containing products like milk in coffee, while others cannot have any diary products at all. Also, most lactose intolerant people are limited as to the amount of special “lactose free” foods they can eat that have been manufactured by specified companies. Some examples of these “lactose free” foods are: Mocha Mix ice cream, Tofutti ice cream and ice cream sandwiches, LACTAID® brand milk, cheese, Tofutti “Better than Cream Cheese”, margarine, and live cultured yogurt. These products are not readily available everywhere.
The use of lactase tablets help lactose intolerant people digest milk and milk products. Each lactase tablet typically hydrolyzes up to 99% of the ingested lactose within 24 hours, and is designed to be ingested with the lactose containing food.
Still other techniques for dealing with lactose maldigestion is to use microgranules containing bioactive compounds or microorganisms. See, e.g., U.S. Pat. No. 5,952,021. The use of an active lactase composition for treatment of lactase deficiency is described in U.S. Pat. No. 3,718,739.
Methods
Methods of the invention include methods of administering lactose in increasing doses to an individual suffering from lactose intolerance. The end result is a reduction or elimination of the symptoms of lactose intolerance in the individual. Methods include the administration of lactose, in increasing doses, for a period of time, to an individual with lactose intolerance. The lactose may be in any form, including liquid or powdered. In some embodiments, other substances are administered in combination with the lactose. “In combination,” as used herein, encompasses simultaneous administration of a substance with lactose, as well as administration before lactose (e.g., before a regimen of increasing doses of lactose begins, or before a dose of lactose during such a regimen), after lactose (e.g., after a regimen of increasing doses of lactose begins, or after a dose of lactose during such a regimen), or any combination thereof. Other substances of use in the methods and compositions of the invention besides lactose include live bacteria, fructooligosaccharides, and buffers, e.g., phosphates.
Methods of the invention also include the administration of lactose in increasing doses, in combination with other treatments for lactose intolerance. Other treatments include any of those described herein, such as the use of lactase, or the use of products containing pre-digested lactose.
The invention further provides methods of decreasing the symptoms of lactose intolerance for an extended period of time after treatment stops. Thus, the methods of the invention include partially, substantially, or completely decreasing the symptoms of lactose intolerance for a period of days, weeks, months, years, or permanently. Such a decrease is accomplished by the methods and compositions described herein.
Individuals who may benefit from the methods and compositions of the invention include individuals suffering from the symptoms of lactose intolerance, as described above. Any degree of lactose intolerance may be treated by the methods of the invention. Symptoms of lactose intolerance include gas, bloating, abdominal discomfort, diarrhea, vomiting, and/or cramping. Effectiveness of treatment may be measured in a number of ways. Conventional measurements, such as hydrogen gas production, stool acidity, or blood glucose, may be used before and after treatment. Alternatively, or in addition, the amount of lactose-containing product that may be consumed before the onset of one or more symptoms may be measured or evaluated before and after treatment. Thus, for example, treatment is considered partially effective if, after treatment, on average less hydrogen is produced with a given dose of lactose.
More commonly, individuals will not precisely test the amount of hydrogen or, e.g., use a blood glucose test to measure effectiveness. Instead, individuals generally have a sense of how much lactose-containing product they may consume, and the types and degree of symptoms experienced after such consumption. “Partial” elimination of symptoms of lactose intolerance is any noticeable or measurable increase in the amount of lactose that may be consumed before the onset of symptoms. “Substantial” elimination of symptoms of lactose intolerance, as used herein, encompasses an effect where at least about twice the amount of lactose may be consumed after treatment before the onset of symptoms as could have been consumed before treatment “Complete” or “substantially complete” elimination of symptoms of lactose intolerance, as used herein, indicates that normal amounts of lactose may be consumed after treatment (i.e., the amount of lactose in a typical diet for the area and/or culture in which the individual normally lives) without symptoms, or with only the rare occurrence of symptoms. Thus, for example, an individual may know that if he or she consumes one half cup (4 oz.) of milk that there will be no, or minimal, symptoms, but if 1 or more cup of milk is consumed, then symptoms such as gas or diarrhea occur. The individual may find that, after treatment, 1 and one-half cups of milk may be consumed but that 3 or more cups cause symptoms. This indicates that symptoms of lactose intolerance were substantially eliminated. Alternatively, the individual may find that after treatment a normal diet for their geographical or cultural region may be consumed with no, or rare, symptoms of lactose intolerance. In that case, symptoms of lactose intolerance were completely eliminated.
Alternatively, effectiveness may be measured by percent decrease in symptoms of lactose intolerance. In this measurement, the severity of a predetermined symptom, or set of symptoms is measured before and after treatment, e.g., using pre and post Likert scale. Exemplary symptoms include gas, bloating, diarrhea, cramping, abdominal pain, and vomiting. Any one, or more than one, of the symptoms may be measured. For example, an individual may be asked to rate one or more symptoms on a scale of increasing severity from 1 to 5. In one embodiment, a set of symptoms is rated, and the ratings are added; for example, gas, bloating, diarrhea, abdominal pain, and cramping may be rated. Percentage decrease in symptoms from before to after treatment may be calculated, and the symptoms of lactose intolerance may be considered eliminated by that percent decrease (e.g., if there is a 50% decrease in symptoms, then symptoms of lactose intolerance is 50% eliminated). See, e.g., Example 2.
In some embodiments, the invention provides a method of decreasing symptoms of lactose intolerance in an individual exhibiting symptoms of lactose intolerance by administering to the individual increasing amounts of lactose for a period of time, wherein one or more symptoms of lactose intolerance are partially, substantially, or completely eliminated. In some embodiments, the symptom(s) of lactose intolerance remains partially, substantially, or completely eliminated for at least about 1 day, 1 week, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 9 months, one year, 18 months, two years, three years, four years, five years, or more than five years after the termination of treatment, or permanently after the termination of treatment. In some embodiments, the invention provides a method of decreasing symptoms of lactose intolerance in an individual exhibiting symptoms of lactose intolerance by administering to the individual increasing amounts of lactose for a period of time, wherein symptoms of lactose intolerance are substantially eliminated for at least about one month after treatment is terminated.
In some embodiments, the invention provides a method of decreasing symptoms of lactose intolerance in an individual exhibiting symptoms of lactose intolerance by administering to the individual increasing amounts of lactose for a period of time, wherein the symptoms of lactose intolerance, measured as described herein, are decreased by an average of about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or about 100%. An “average” decrease is a decrease as measured in a group of individuals exhibiting symptoms of lactose intolerance, such as more than about 2, 3, 4, 5, 10, 20, or 30 individuals. In some embodiments, the decrease of symptoms of lactose intolerance persists or becomes even greater (e.g., 50% decrease to 55% decrease) for at least about 1 day, 1 week, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 9 months, one year, 18 months, two years, three years, four years, five years, or more than five years after the termination of treatment. In some embodiments, the decrease in symptoms is permanent. In some embodiments, the invention provides a method of decreasing symptoms of lactose intolerance in an individual exhibiting symptoms of lactose intolerance by administering to the individual increasing amounts of lactose for a period of time, wherein the symptoms of lactose intolerance, measured as described herein, are decreased by an average of about least about 20% and remain decreased by at least about 20% for at least about one month after treatment is terminated. In some embodiments, the invention provides a method of decreasing symptoms of lactose intolerance in an individual exhibiting symptoms of lactose intolerance by administering to the individual increasing amounts of lactose for a period of time, wherein the symptoms of lactose intolerance, measured as described herein, are decreased by an average of about least about 50% and remain decreased by at least about 50% for at least about one month after treatment is terminated.
The total duration of treatment may be from about two weeks to about 12 weeks, or about four weeks to about ten weeks, or about four weeks to about eight weeks, or about six weeks. During this period of time, the subject is started on a program of taking increasing amounts of the lactose containing product of the invention, optionally along with ingestion of lactose containing food products, and in some embodiments also in combination with other substances, as described herein. In some embodiments, the total duration of treatment is about 15 days to about 90 days, or about 15 days to about 60 days, or about 20 days to about 50 days, or about 20 days to about 40 days, or about 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 days. In some embodiments, the total duration of treatment is about 38 days. In some embodiments, the total duration of treatment is about 42 days. It will be appreciated that these durations are averages, and that individuals using the treatment may vary from the average based on the severity of their symptoms, missing days of treatment, and the like. In some embodiments, the duration of the treatment is based on the individual's symptoms. Thus, an individual may experience a return of symptoms at a given dose of lactose, and may require that they stay at that dose, or a lower dose, until symptoms subside. Thus, in some embodiments, the duration of the treatment is not definitively established at the outset, but continues until the highest dose of lactose is achieved, or until the desired level of lactose tolerance is achieved.
Increasing dosage of lactose may be achieved by increasing the number of doses per day of lactose administered, increasing the amount of lactose per dose, or both. Typically, both strategies are used. Thus, in some embodiments of the invention, lactose is initially administered once per day, at increasing doses, followed by twice per day administration, also at increasing doses. The once per day administration can last for a period of about 6 to 30, or about 10 to 26, or about 14 to 22, or about 16 to 20, or about 18 days, and the twice per day administration can last for a period of about 4 to 28, or about 8 to 24, or about 12 to 20, or about 14 to 28, or about 16 days. In some embodiments, during the twice per day administration, the first dose of lactose is constant while the second dose increases. In some embodiments, lactose may be administered an average of about once per day, twice per day, three, four, five, six, or more than six timer per day, or any combination thereof.
After treatment has concluded, the individual is encouraged to enjoy dairy products at least once every 4-5 days in order to maintain the reduction in symptoms of lactose intolerance.
In some embodiments, the individual self-administers the lactose-containing product. In some embodiments, the lactose-containing product is supplied or recommended by a health professional, e.g., a dietician, nutritionist, nurse, physician, or other qualified health professional. In some embodiments, the lactose-containing product is administered by a health professional and/or results of the program are monitored by a health professional. In some embodiments, the lactose-containing product is labeled as a medical food.
While an individual typically will not require more than one course of treatment, in some embodiments of the invention an individual may have repeated courses of treatment. The course of treatment may be repeated when symptoms of lactose intolerance appear or increase to an undesirable level. Alternatively, the course of treatment may be repeated at regular or predetermined intervals. Thus, treatment may be repeated after about one month, two months, three months, four months, six months, eight months, ten months, one year, 18 months, two years, three years, four years, five years, or more than five years, or any combination thereof (e.g., treatment may be repeated after one year, then every two to five years thereafter). The treatment may be repeated in the same form (e.g., duration, dosage, timing of dosage, additional substances, etc.) as used in the first treatment, or it may be modified. For example, treatment duration may be shortened or lengthened, dosage may be increased more quickly or slowly and/or a higher or lower starting dose of lactose may be used, a different lactose-containing product may be used (e.g., containing more or less of other substances, or fewer or more substances in addition to lactose), and the like.
The starting dose of lactose and the incremental increases in lactose dosage may be any suitable dose size. In some embodiments, the starting dose of lactose is about 0.05 to 4.0 gm, or about 0.1 to about 3 gm, or about 0.2 to about 3.0 gm, or about 0.2 to about 2 gm, or about 0.4 to about 1.6 gm, or about 0.4 to about 1.4 gm, or about 0.6 to about 1.2 gm, or about 0.6 to about 1.0 gm, or about 0.7 to about 0.9 gm, or about 0.8 gm. The incremental increase in lactose dosage can vary, or each increase can be the same, or any combination thereof. The lactose dosage may increase incrementally by about 0.05 to 4.0 gm, or about 0.1 to about 3 gm, or about 0.2 to about 3.0 gm, or about 0.2 to about 2 gm, or about 0.4 to about 1.6 gm, or about 0.4 to about 1.4 gm, or about 0.6 to about 1.2 gm, or about 0.6 to about 1.0 gm, or about 0.7 to about 0.9 gm, or about 0.8 gm. The maximum dose reached in treatment again may be any suitable dose size, depending on the individual being treated and the outcome desired. The maximum dose of lactose may be about 6 to about 60 gm, or about 12 to about 48 gm, or about 14 to about 36 gm, or about 16 to about 36 gm, or about 18 to about 34 gm, or about 20 to about 32 gm, or about 22 to about 30 gm, or about 23 to about 29 gm, or about 24 to about 28 gm, or about 25 to about 27 gm, or about 25.5 to about 26.5 gm, or about 25.5, 25.6, 25.7 gm.
Thus, in some embodiments of the invention, the initial dose of lactose is about 0.8 gm, and the dose is increased by 0.8 gm over time, for example, daily, until a maximum dose of 25.6 gm of lactose is reached. Additional phases of the regimen may include giving various amounts of milk products in which the dosage of lactose may be given in dairy form, before the treatment ends, and the dosage of lactose in the milk products may not be precisely the same as the doses given up to that point; it will be understood that various milk products and brands of milk products may contain varying doses of lactose.
The lactose may be given in any suitable form, i.e., as a powder, such as in capsules or tablets, or powder that may be dissolved in a liquid prior to consumption, or in liquid form, e.g., predissolved in a liquid or in the form of milk. Any grade or form of lactose that is suitable for consumption by the individual being treated, e.g., by humans, may be used. Lactose-containing products useful in the invention are described more fully below.
Additional substances may be given in conjunction with lactose. These substances can enhance the action of the increasing doses of lactose by, e.g., encouraging the growth of bacteria in the gut that alleviate symptoms of lactose intolerance, increasing adhesion of friendly bacteria, or allowing doses of friendly bacteria to more readily pass through the stomach without being destroyed. These substances may be given prior to treatment with lactose, during treatment with lactose, after treatment with lactose, or any combination thereof. If administered during lactose treatment, they may be administered with the dose of lactose being given, or before or after the dose of lactose, or any combination thereof.
Substances of use in the invention in conjunction with lactose include live bacteria, fructooligosaccharides (FOS), and buffers, e.g., phosphates. One or more of these substances may be used in combination with lactose at any suitable time before, during, after treatment, or some combination thereof. Thus, in some embodiments, during some or all of the treatment, lactose is administered in conjunction with live bacteria. In some embodiments, during some or all of the treatment, lactose is administered in conjunction with FOS. In some embodiments, during some or all of the treatment, lactose is administered in conjunction with buffer, e.g., phosphates. In some embodiments, during some or all of the treatment, lactose is administered in conjunction with live bacteria and FOS. In some embodiments, during some or all of the treatment, lactose is administered in conjunction with live bacteria and phosphates. In some embodiments, during some or all of the treatment, lactose is administered in conjunction with FOS and buffer, e.g., phosphates. In some embodiments, during some or all of the treatment, lactose is administered in conjunction with live bacteria, FOS and buffer, e.g., phosphates
Live bacteria, e.g., live cultured bacteria, that may be used in the methods and compositions of the invention include any suitable bacteria for assisting in reduction or elimination of the symptoms of lactose intolerance. Typically such bacteria will be probiotic. Probiotic bacteria favorably alter the intestinal microflora balance, inhibit the growth of harmful bacteria, promote good digestion, boost immune function, and increase resistance to infection. People with flourishing intestinal colonies of beneficial bacteria are better equipped to fight the growth of disease-causing bacteria. Probiotic bacteria such as lactobacilli and bifidobacteria are thought to maintain a healthy balance of intestinal flora by producing organic compounds, such as lactic acid, hydrogen peroxide, and acetic acid, that increase the acidity of the intestine and inhibit the reproduction of many harmful bacteria. Probiotic bacteria also produce substances called bacteriocins, which act as natural antibiotics to kill undesirable microorganisms. Nonexclusive examples of probiotic bacteria that may be used in the methods of the invention include L. acidophilus or lactobacillus acidophilus. Acidophilus, a probiotic, is one of the most important strains of the Lactobacilli family of microflora which inhabit the gastrointestinal tract. These “good” bacteria are involved with immune system function, inhibiting carcinogenesis, metabolism of cholesterol, aging, and nutritional status. Acidophilus and other probiotic bacteria help maintain optimum pH, reduce putrefaction, and reduce endotoxemia. Other lactobacillus bacteria which may be employed include lactobacillus crispatus, lactobacillus casei, lactobacillus rhamnosus, lactobacillus reuteri, lactobacillus fermentum, L. plantarum, L. sporogenes, L. bulgaricus and lactobacillus rhamnosus. Other probiotic bacteria include Bifidobacterium lactis, B. bifidum, B. infantis, Saccharomyces boulardii. The bacteria may be given as part of a food, e.g., in yogurt, or in powdered form. Mixtures of one or more species or strains of bacteria may be used.
In some embodiments, probiotic bacteria, such as L. acidophilus, is given prior to beginning treatment with lactose. In some embodiments, probiotic bacteria, such as L. acidophilus, is given in conjunction with treatment with lactose, for part or all of the treatment with lactose. Thus, in some embodiments, some or all doses of lactose are accompanied by a dose of bacteria, e.g. live cultured bacteria, e.g., L. acidophilus. In some embodiments, bacteria, e.g., L. acidophilus is given initially with the lactose, but then its use is discontinued. For example, the initial one, two, three, four, five, six, seven, eight, nine, ten, or more than ten days of treatment with lactose may include doses of bacteria, with the use of bacteria discontinued after that time. In some embodiments, bacteria, e.g. bacteria in yogurt, or bacteria by themselves, may be given for the first two days of treatment, then the administration of bacteria is discontinued. In some embodiments, probiotic bacteria, either alone or in combination with other substances or treatments are used after the treatment with lactose is terminated. The bacteria may be taken for any suitable period after the termination of treatment with lactose, and may be taken daily or at regular or irregular intervals. Doses may be as described below.
Any suitable dosage of bacteria may be used. Typically, bacteria are given as live cultured bacteria, e.g., in combination with lactose and, optionally, other substances. The dose can be about 1 to about 1000 mg, or about 2 to about 200 mg, or about 2 to about 100 mg, or about 2 to about 50 mg, or about 4 to about 25 mg, or about 5 to about 20 mg, or about 10 to about 15 mg, or about 10, 11, 12, 12.5, 13, 14, or 15 mg. In some embodiments, L. acidophilus is used in a dose of about 12.5 mg. The dose may be given in combination with lactose. In some embodiments, as lactose dose increases, the dose of bacteria increases as well. For example, an initial dose of lactose may be about 0.6 to 1.0 gm, e.g., 0.8 gm, given in combination with about 10-15 mg, e.g., about 12.5 mg, of L. acidophilus. The dose of lactose may be increased incrementally by about 0.6 to 1.0 gm, e.g., 0.8 gm, and the accompanying dose of L. acidophilus may be increased by about 10-15 mg, e.g., about 12.5 mg, of L. acidophilus. 
Fructooligosacharides (FOS), are a non-digestible, soluble-fiber that supports the growth of beneficial bacteria in the intestinal tract, particularly two important strains—l. acidophilus and l. bifidus. These two strains play an essential role in reducing the number of pathogenic bacteria. Additional nutritional properties, such as the effect on colonic pH and stool bulking justify their classification as dietary fibers. In experimental models, it has also been reported that they improve the bioavailability of essential minerals. As a fiber, it is thought to slow digestion and allow the painless reintroduction of lactose into the body. FOS are chain polymers of the sugar fructose that are found in a variety of foods. The sugar units can be linked in a single straight chain or can be a chain with side branches. In many cases small amounts of glucose are also contained in the chain. The length of the fructose chains can vary from source to source. Inulin is an example of a longer chained compound that is considered a FOS. The shorter (lower molecular weight) compounds tend to have a sweet taste. The size and complexity of the FOS molecule gives it desirable characteristics. Although the simple sugars fructose and glucose are quickly absorbed into the body by the intestines, FOS for the most part is indigestible and therefore acts as a non-digestible fiber in the diet. This is because the human does not have the enzymes to break down the FOS as it travels down the digestive tract. When the FOS reaches the large intestine and the colon, the bacteria that are found there start to break down the FOS. These bacteria have the enzymes needed to break down FOS. Bifido bacteria have been reported to use FOS. It is believed that foods that promote bifido bacteria growth are good for the health.
In some embodiments, FOS are given prior to beginning treatment with lactose. In some embodiments, FOS are given in conjunction with treatment with lactose, for part or all of the treatment with lactose. Thus, in some embodiments, some or all doses of lactose are accompanied by a dose of FOS. In some embodiments, FOS are given initially with the lactose, but then their use is discontinued. For example, the initial one, two, three, four, five, six, seven, eight, nine, ten, or more than ten days of treatment with lactose may include doses of FOS, with the use of FOS discontinued after that time. In some embodiments, FOS may be given for the first two days of treatment, then the administration of FOS is discontinued. In some embodiments, FOS, either alone or in combination with other substances or treatments are used after the treatment with lactose is terminated. The FOS may be taken for any suitable period after the termination of treatment with lactose, and may be taken daily or at regular or irregular intervals. Doses may be as described below.
Numerous FOS preparations are known in the art, and any suitable FOS preparation may be used in the methods and compositions of the invention. FOS may be used in a dose from about 1 mg to about 10 gm, or about 1 mg to about 5 gm, or about 2 mg to about 1000 mg, or about 2 mg to about 500 mg, or about 2 mg to about 200 mg, or about 2 mg to about 100 mg, or about 2 mg to about 50 mg, or about 2 mg to about 20 mg, or about 5 mg to about 10 mg, or about 5, 6, 7, 7.5, 8, 9, or 10 mg. In some embodiments, FOS are used in a dose of about 7.5 mg. The dose may be given in combination with lactose. In some embodiments, as lactose dose increases, the dose of FOS increases as well. For example, an initial dose of lactose may be about 0.6 to 1.0 gm, e.g., 0.8 gm, given in combination with about 5-10 mg, e.g., about 7.5 mg, of FOS. The dose of lactose may be increased incrementally by about 0.6 to 1.0 gm, e.g., 0.8 gm, and the accompanying dose of FOS may be increased by about 5-10 mg, e.g., about 7.5 mg, of FOS.
One or more buffers, optionally with a calcium counterion, may also be administered in methods of the invention. Any buffer suitable for consumption by the individual being treated, e.g., human, may be used. The buffer neutralizes stomach acidity which can, e.g., allow live bacteria to reach the gut. Buffers include citrates, phosphates, and the like. Some embodiments of the invention utilize a buffer with a calcium counterion, such as Calcium Phosphate Tribasic. The calcium can serve to restore the calcium that many lactose intolerant individuals are missing in their diet. A recent study demonstrated the ability of calcium phosphate to protect lactobacillus acidophilus from bile. It is an excellent buffering agent and will help neutralize stomach acidity.
In some embodiments, a buffer such as calcium phosphate is given prior to beginning treatment with lactose, e.g., in conjunction with administration of bacteria. In some embodiments, a buffer such as calcium phosphate is given in conjunction with treatment with lactose, for part or all of the treatment with lactose. Thus, in some embodiments, some or all doses of lactose are accompanied by a dose of a buffer such as calcium phosphate. In some embodiments, a buffer such as calcium phosphate is given initially with the lactose, but then its use is discontinued. For example, the initial one, two, three, four, five, six, seven, eight, nine, ten, or more than ten days of treatment with lactose may include doses of a buffer such as calcium phosphate, with the use of the discontinued after that time. In some embodiments, a buffer such as calcium phosphate may be given for the first two days of treatment, then the administration of buffer is discontinued. In some embodiments, a buffer such as calcium phosphate, either alone or in combination with other substances or treatments is used after the treatment with lactose is terminated. The a buffer such as calcium phosphate may be taken for any suitable period after the termination of treatment with lactose, and may be taken daily or at regular or irregular intervals. Doses may be as described below.
Numerous buffers suitable for human consumption are known in the art, and any suitable buffer may be used in the methods and compositions of the invention. Calcium triphosphate is an exemplary buffer and has the advantage that its counterion supplies a nutrient that is often lacking in lactose-intolerant individuals, i.e., calcium. The buffer may be used in a dose from about 2 to about 2000 mg, or about 4 to about 400 mg, or about 4 to about 200 mg, or about 4 to about 100 mg, or about 8 to about 50 mg, or about 10 to about 40 mg, or about 20 to about 30 mg, or about 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 mg. In some embodiments, buffer is used in a dose of about 25 mg. In some embodiments, calcium phosphate is used in a dose of about 25 mg. The dose may be given in combination with lactose. In some embodiments, as lactose dose increases, the dose of buffer increases as well. For example, an initial dose of lactose may be about 0.6 to 1.0 gm, e.g., 0.8 gm, given in combination with about 20-30 mg, e.g., about 25 mg, of buffer, e.g., calcium phosphate. The dose of lactose may be increased incrementally by about 0.6 to 1.0 gm, e.g., 0.8 gm, and the accompanying dose of buffer, e.g., calcium phosphate, may be increased by about 20-30 mg, e.g., about 25 mg, of buffer, e.g., calcium phosphate.
In some embodiments, treatment with lactose, optionally in conjunction with bacteria, FOS, and/or buffer, is used in combination with other treatments to reduce the symptoms of lactose intolerance. Any suitable treatment for the reduction of symptoms of lactose intolerance may be used, e.g., the use of lactase. Lactase may be administered before, during, or after treatment with lactose, or any combination thereof. In some embodiments, especially when symptoms of lactose intolerance are not completely or substantially completely eliminated by lactose treatment, lactase is administered after lactose treatment is terminated. The lactase may be used on an as-needed basis.
In some embodiments, the treatment occurs in phases. One phase utilizes a single administration of lactose per day, generally though not necessarily with food, e.g., dinner. The dose of lactose increases over time. For example, the dose of lactose may increase each day. Another phase, generally following the first phase, utilizes two administrations of lactose per day, again, generally with food, e.g., with breakfast and dinner. Again, during this phase the dose of lactose increases over time, e.g., increasing each day. In some embodiments, the invention includes one phase in which lactose is administered once per day in conjunction with live bacteria. This phase, if used, is generally the first phase of the method. Alternatively, live bacteria may be administered during some or all of the entire period of treatment. For example, in some embodiments, live bacteria are included in a lactose-containing product that is administered to the individual. Typically, during the preceding phases no dairy products are consumed. A final phase of the protocol can involve the gradual reintroduction of dairy into the diet, either with or without the continuing use of the lactose-containing product used in the first phases of treatment. Finally, treatment is concluded and no further ingestion of lactose-containing product is required.
For example, in some embodiments, there are essentially five major phases to the regimen. The first phase relies upon the use of the lactose containing products administration for two days, along with live bacteria, e.g., yogurt containing live cultures. In the second phase, the lactose containing product is taken with food and typically a dinner for a period of about 10 to 30, or about 14 to 24, or about 16 to 20, or about 18 days. In the third phase, the lactose containing product is taken with both dinner and breakfast for another period of about 6 to 18, or about 8 to 16, or about 10 to 14, or about 12 days. For another 2, 3, 4, 5, or 6, e.g., about 4 days thereafter, the lactose containing product is administered with both dinner and breakfast, along with the addition of other diary products. Prior to this time, diary products are not consumed during the first phases, e.g., the first about 34 days of the regimen. This total period, e.g., of approximately 38 days, constitutes the full period in which the lactose containing product is consumed, but more importantly consumed essentially in these time periods. Following the actual administration of the lactose containing product, the regimen includes the actual ingestion of diary products for about at least every few days to maintain and build up the complete tolerance, but without the administration of the lactose containing product. In the first period of time, through the first, e.g., 18 days, the amount of the lactose containing product administered at dinner time increases regularly each day. Thereafter, and in the third period, the amount of the lactose containing product increases regularly each day in combination with a breakfast meal. Moreover, and for the final days, e.g., the final four days, a lactose containing food item, such as milk, also is regularly increased for those 4 days.
Thus, in one embodiment of the invention, a first dose of the lactose containing product is administered in increasing amounts for a 6-week period. On the first and second days of this period, promote bacteria, e.g., in a food containing product also having a live culture bacteria is administered with the lactose containing product. One such food item containing a live cultured bacteria is yogurt. Further, during the third phase during this 6-week period, a second dose of the lactose containing product is administered, typically at breakfast time. An example of the dosing regimen is shown in the following table:












TABLE I







Week
Day
PM-Dosage
AM-Dosage





















1
1
1 tbs + 8 oz yogurt




1
2
1 tbs + 4 oz yogurt



1
3
 1 tbs



1
4
 2 tbs



1
5
 3 tbs



1
6
 4 tbs



1
7
 5 tbs



2
8
 6 tbs



2
9
 7 tbs



2
10
 8 tbs



2
11
 9 tbs



2
12
10 tbs



2
13
11 tbs



2
14
12 tbs



3
15
13 tbs



3
16
14 tbs



3
17
15 tbs



3
18
16 tbs



3
19
16 tbs
 1 tbs



3
20
16 tbs
 2 tbs



3
21
16 tbs
 3 tbs



4
22
16 tbs
 4 tbs



4
23
16 tbs
 5 tbs



4
24
16 tbs
 6 tbs



4
25
16 tbs
 7 tbs



4
26
16 tbs
 8 tbs



4
27
16 tbs
 9 tbs



4
28
16 tbs
10 tbs



5
29
16 tbs
11 tbs



5
30
16 tbs
12 tbs



5
31
16 tbs
13 tbs



5
32
16 tbs
14 tbs



5
33
16 tbs
15 tbs



5
34
16 tbs
16 tbs



5
35
 9 oz milk
 9 oz milk



6
36
10 oz milk
10 oz milk



6
37
11 oz milk
11 oz milk



6
38
12 oz milk
12 oz milk



6
39
Cheese 1 oz



6
40
Cheese 2 oz



6
41
lactose tolerance





achieved



6
42










In the first day of the regimen, the subject ingests 8 ounces of yogurt or other food product containing a live culture bacteria, along with 1 tablespoon of milk, at the dinner meal. As an example and considering the regimen shown in Table I, the subject will ingest 8 ounces of live culture bacterial yogurt on the first day, along with 1 tablespoon of milk with dinner. On the second day, the amount of the yogurt ingested is reduced to 4 ounces, although the administration of the milk remains the same. On the third day, administration of the yogurt is ceased, but the milk remains at 1 tablespoon. During the fourth through the 18th days, the amount of milk ingested with dinner is increased by 1 tablespoon each day until 16 tablespoons are reached on the day 18.
In the third phase of the regimen, and on, it can be seen that both 1 tablespoon of milk is ingested in the morning, with breakfast, and 16 tablespoons of milk are ingested with dinner. From day 16 until day 34, the same ratio of milk with dinner is maintained, but the morning dose increases daily at a rate of a tablespoon per day. In this way, by day 34, the subject is ingesting 32 tablespoons of milk.
It can also be seen that on day 35, ingestion of the lactose containing product is discontinued and in place thereof, milk is ingested, with 9 ounces of milk in the morning and an additional 9 ounces in the evening. The milk amounts are increased incrementally at a rate of an ounce per day, such that, by day 38, the subject is ingesting 12 ounces of milk with breakfast and an additional 12 ounces of milk at dinner.
Finally, on days 39 through 42, cheese is substituted for milk.
It will be recognized that Table I is only a single exemplary 6-week regimen. The actual days can vary, and the quantity of the dosages can similarly be modified according to each particular subject and the reactions encountered by that subject. Even though there may be variations in both the time period and the dosage rates, the concept of increasing the dosages of the lactose containing product for specific time periods is maintained and encompassed by the present invention.
As a simple example of variations in the above-identified regimen, it may be found that the subject is capable of ingesting more than 5 tablespoons of milk by day 7. As a result, the amount of milk ingested by day 7 may be increased to 6 tablespoons, etc. Determination of whether or not the subject is capable of increasing the dosage or the time period depends on whether or not the subject encounters any adverse affects. In the event that the subject does encounter adverse affects, the subject should resort back to the regimen as specified in Table I.
The same alterations can be made in the time intervals between the administration of the lactose containing product and the various other lactose containing food items. Thus, if desired, the subject could potentially alter the amount of the lactose food item every 12 hours. In like manner, that time period could vary to 36 or even 48 hours: As indicated previously, the lactose containing product of the invention may be administered as a pure powder lactose, the latter of which is mixed with water and consumed much in the same manner as a soft drink. The amount of the lactose can also be incorporated in one or more capsules, or otherwise, in the loose granular form, as indicated.
The table following Table II shows an example of a powder lactose regimen:












TABLE II







Week
Day
PM-Dosage
AM-Dosage





















1
1
s + 8 oz yogurt




1
2
s + 4 oz yogurt



1
3
 s



1
4
 m



1
5
 m + s



1
6
2m



1
7
2m + s



2
8
3m



2
9
3m + s



2
10
4m



2
11
4m + s



2
12
5m



2
13
5m + s



2
14
6m



3
15
6m + s



3
16
7m



3
17
7m + s



3
18
8m



3
19
8m
 s



3
20
8m
 m



3
21
8m
 m + s



4
22
8m
2m



4
23
8m
2m + s



4
24
8m
3m



4
25
8m
3m + s



4
26
8m
4m



4
27
8m
4m + s



4
28
8m
5m



5
29
8m
5m + s



5
30
8m
6m



5
31
8m
6m + s



5
32
8m
7m



5
33
8m
7m + s



5
34
8m
8m



5
35
 9 oz milk
 9 oz milk



6
36
10 oz milk
10 oz milk



6
37
11 oz milk
11 oz milk



6
38
12 oz milk
12 oz milk



6
39
Cheese 1 oz



6
40
Cheese 2 oz



6
41
lactose tolerance





achieved



6
42










In the foregoing Table II the designation “s” refers to a single zero sized capsule containing 0.8 gm of pure lactose powder, and this is equivalent to about 1 tablespoon of milk. The designation “m” refers to a double-sized zero capsule, which may be filled with 1.6 grams of lactose powder. The amount of the lactose ingested in any time interval, in accordance with Table II, is substantially identical to that regimen as shown in Table I. However, the form of the lactose is different.
In some protocols, lactose need not be administered with bacteria. Hence, the standard protocol starts with a subject taking 0.8 grams of lactose with a dinner. On days 2-16, the subject increases the dosage of lactose by 0.8 grams, thus they go from having 0.8 grams on day 1, to 1.6 grams on day 2, and 2.4 grams on day 3. On day 17, the subject starts the same process with breakfast, by taking 0.8 grams on day 17, then 1.6 grams on day 18 and so on. While this is going on, the subject continually takes 12.8 grams of lactose with dinner. Finally on day 33, the subject starts to re-introduce dairy products into their daily diet. While the dairy foods may vary, milk is the standard product a subject starts out with. Starting with drinking 6 ounces with breakfast and dinner, the subject gradually drinks 8 ounces, 10 ounces and 12 ounces of milk per day. At day 36, the subject has completed the protocol and may now enjoy dairy products pain-free. No future protocol, supplements or medication is needed for these subjects to consume dairy products.
An example of this dosing regimen is shown below in Table III.












TABLE III





Week
Date
PM-lactose
AM-lactose
PM-Dairy
AM-Dairy






















1
1
.8
grams






1
2
1.6
grams


1
3
2.4
grams


1
4
3.2
grams


1
5
4
grams


1
6
4.8
grams


1
7
5.6
grams


2
8
6.4
grams


2
9
7.2
grams


2
10
8
grams


2
11
8.8
grams


2
12
9.6
grams


2
13
10.4
grams


2
14
11.2
grams


3
15
12
grams


3
16
12.8
grams


3
17
12.8
grams
.8
grams


3
18
12.8
grams
1.6
grams


3
19
12.8
grams
2.4
grams


3
20
12.8
grams
3.2
grams


3
21
12.8
grams
4
grams


4
22
12.8
grams
4.8
grams


4
23
12.8
grams
5.6
grams


4
24
12.8
grams
6.4
grams


4
25
12.8
grams
7.2
grams


4
26
12.8
grams
8
grams


4
27
12.8
grams
8.8
grams


4
28
12.8
grams
9.6
grams


5
29
12.8
grams
10.4
grams


5
30
12.8
grams
11.2
grams


5
31
12.8
grams
12
grams


5
32
12.8
grams
12.8
grams


5
33




 6 oz Milk
 6 oz Milk


5
34




 8 oz Milk
 8 oz Milk


5
35




10 oz Milk
10 oz Milk


6
36




12 oz MiIk
12 oz MiIk









Although the doses shown here have been used and tested, variations in the doses and timing in which they are administered can still result in an effective treatment for increasing tolerance for lactose containing product. For example, the presented doses have been tested on adult subjects. Thus, when applying the protocol of the present invention to younger subjects, the weight of the subject might be a consideration. For example, a subject weighing 50 pounds may not require, and may not be capable of tolerating, the doses set forth in Table 1 at prescribed time in the protocol. As such, the dose administered to the subject may be proportionally scaled down based on his weight. Although the doses are disclosed as being administered with breakfast and dinner, alternatively the order of the doses may be switched, or may be administered at other times of the day with meals such as lunch or snacks (or conceivably with no meals). The program may also be reduced into a shortened or lengthened program. The program can work with an abbreviated 4 week program or it can be lengthened up to a 10 week program. Although the invention has been described for use in humans, it is also capable of being administered to other mammals.
Compositions
The invention also provides compositions for the treatment of the symptoms of lactose intolerance. The compositions contain lactose and one or more of: bacteria, FOS, and/or buffer. Additional ingredients include ingredients to improve handling, preservatives, flavorings and the like.
In some embodiments, the composition contains lactose and bacteria. The lactose will typically comprise more than 50% of the weight of the composition while the bacteria will typically comprise less than about 10%, 5%, 4%, 3%, or 2% of the compositions (all percentages are weight percent unless otherwise indicated). For example, lactose may be present at about 80-99.75% and the bacteria at about 0.25-2.10%, or the lactose may be present at about 89-94% and the bacteria at about 1.2-3.75%. In some embodiments, lactose is present at about 94.01% and bacteria, e.g., L. acidophilus, is present at about 1.47%. If the bacteria and lactose do not make up 100% of the composition, the remaining ingredients may be any suitable ingredients intended for the consumption of the individual, e.g., human, including, but not limited to, FOS and/or buffer, but also including ingredients intended to inhibit clumping and increase portability, such as silicone dioxide and microcyrstalline cellulose, or similar ingredients as are well-known in the art.
In some embodiments, the compositions contain lactose and FOS. For example, lactose may be present at about 80-99.75% and the FOS at about 0.10-1.89%, or the lactose may be present at about 89-94% and the FOS at about 0.40 to about 1.26%. In some embodiments, lactose is present at about 94.01% and FOS is present at about 0.88%. If the FOS and lactose do not make up 100% of the composition, the remaining ingredients may be any suitable ingredients intended for the consumption of the individual, e.g., human, including, but not limited to, bacteria and/or buffer, but also including ingredients intended to inhibit clumping and increase pourability, such as silicone dioxide and microcrystalline cellulose, or similar ingredients as are well-known in the art.
In some embodiments, the compositions contain lactose and buffer, e.g., calcium phosphate tribasic. For example, lactose may be present at about 80-99.75% and the buffer at about 0.50-4%, or the lactose may be present at about 89-94% and the buffer at about 1.2 to about 3.75%. In some embodiments, lactose is present at about 94.01% and buffer is present at about 2.94%. If the buffer and lactose do not make up 100% of the composition, the remaining ingredients may be any suitable ingredients intended for the consumption of the individual, e.g., human, including, but not limited to, bacteria and/or FOS, but also including ingredients intended to inhibit clumping and increase pourability, such as silicone dioxide and microcyrstalline cellulose, or similar ingredients as are well-known in the art.
In some embodiments, the compositions contain lactose, bacteria (e.g., L. acidophilus), and FOS. For example, lactose may be present at about 80-99.75%, bacteria at about 0.25-2.10%, and the FOS at about 0.10-1.89%, or the lactose may be present at about 89-94%, bacteria at about 0.91-1.95% and the FOS at about 0.40 to about 1.26%. In some embodiments, lactose is present at about 94.01%, bacteria at about 1.47%, and FOS is present at about 0.88%. If the bacteria, FOS and lactose do not make up 100% of the composition, the remaining ingredients may be any suitable ingredients intended for the consumption of the individual, e.g., human, including, but not limited to buffer, but also including ingredients intended to inhibit clumping and increase pourability, such as silicone dioxide and microcyrstalline cellulose, or similar ingredients as are well-known in the art.
In some embodiments, the compositions contain lactose, bacteria, and buffer. For example, lactose may be present at about 80-99.75%, bacteria at about 0.25-2.10%, and the buffer at about 0.50-4%, or the lactose may be present at about 89-94%, bacteria at about 0.91-1.95% and the buffer at about 1.2 to about 3.75%). In some embodiments, lactose is present at about 94.01%, bacteria at about 1.47%, and buffer is present at about 2.94%. If the bacteria, buffer and lactose do not make up 100% of the composition, the remaining ingredients may be any suitable ingredients intended for the consumption of the individual, e.g., human, including, but not limited to, FOS, but also including ingredients intended to inhibit clumping and increase pourability, such as silicone dioxide and microcyrstalline cellulose, or similar ingredients as are well-known in the art.
In some embodiments, the compositions contain lactose, FOS, and buffer. For example, lactose may be present at about 80-99.75%, FOS at about 0.10 to about 1.89%, and the buffer at about 0.50-4%, or the lactose may be present at about 89-94%, FOS at about 0.40 to about 1.26%, and the buffer at about 1.2 to about 3.75%. In some embodiments, lactose is present at about 94.01%, FOS at about 0.88%, and buffer is present at about 2.94%. If the FOS, buffer and lactose do not make up 100% of the composition, the remaining ingredients may be any suitable ingredients intended for the consumption of the individual, e.g., human, including, but not limited to, bacteria, but also including ingredients intended to inhibit clumping and increase pourability, such as silicone dioxide and microcyrstalline cellulose, or similar ingredients as are well-known in the art.
In some embodiments, the compositions contain lactose, bacteria, FOS, and buffer. For example, lactose may be present at about 80-99.75%, bacteria at about 0.25 to about 2.10%, FOS at about 0.10 to about 1.89%, and the buffer at about 0.50-4%, or the lactose may be present at about 89-94%, bacteria at about 0.91 to about 1.95%, FOS at about 0.40 to about 1.26%, and the buffer at about 1.2 to about 3.75%. In some embodiments, lactose is present at about 94.01%, bacteria at about 1.47%, FOS at about 0.88%, and buffer is present at about 2.94%. If the bacteria, FOS, buffer and lactose do not make up 100% of the composition, the remaining ingredients may be any suitable ingredients intended for the consumption of the individual, e.g., human, including, but not limited to, ingredients intended to inhibit clumping and increase pourability, such as silicone dioxide and microcyrstalline cellulose, or similar ingredients as are well-known in the art.
Additional ingredients include ingredients to improve handling, preservatives, flavorings and the like. In some embodiments, the compositions include microcrystalline cellulose and silicone dioxide.
In embodiments that include lactose, bacteria (e.g., L. acidophilus), buffer (e.g., calcium phosphate tribasic), microcrystalline cellulose and silicone dioxide, proportions and weights are as shown in the Table IV, below. As will be appreciated, weights are merely exemplary, and may be varied. For example, in some embodiments, the weight of lactose is 800 mg (0.8 g) and the other weights may be adjusted accordingly:











TABLE IV








Alternative





Percentage
Percentage
Exemplary


Ingredients
Weight
Range
Range
Percentage




















Lactose
3,200.00
mg
  80-98.5
89-94
94.01


Buffer, e.g., Calcium Phosphate
100.00
mg
0.5-4.0
 1.2-3.75
2.94


Tribasic


Bacteria, e.g., Lactobacillus
50.00
mg
0.25-2.10
0.91-1.95
1.47


Acidophilus


Fructooligosacchrides (FOS)
30.00
mg
0.10-1.89
0.40-1.26
0.88


Handling agent, e.g.,
20.00
mg
0.95-1.15
0.18-0.92
0.59


Microcrystalline Cellulose


Handling agent, e.g., Silicon
4.00
mg
0.04-0.32
0.08-0.19
0.12


Dioxide









Compositions of the invention include any suitable form, including liquid or powder. Powdered compositions may be as pure powder, or may be in the form of capsules, tablets, or the like. Powder may be packaged in bulk (e.g., in a container containing sufficient lactose and/or other substances for one individual to follow an entire course of treatment with increasing doses of lactose, or a portion of a course of treatment), or as individual packets (e.g., packets containing a single dose of lactose plus other components, or packets containing the dose of lactose and other components needed for a particular day of a lactose treatment regimen). If packaged in bulk, the powder may be in any suitable container. The container may also include one or more scoops or similar serving devices of a size or sizes appropriate to measure and serve one or more doses of lactose and, optionally, other ingredients included in the powder. Liquid compositions contain lactose and, optionally, other ingredients, in a suitable liquid, e.g., water or buffer. Liquid compositions may be provided in bulk (e.g., in a container containing sufficient lactose and/or other substances for one individual to follow an entire course of treatment with increasing doses of lactose, or a portion of a course of treatment), or as individual containers, such as cans, bottles, soft packs, and the like (e.g., containers containing a single dose of lactose plus other components in suitable liquid, or containers containing the dose of lactose and other components needed for a particular day of a lactose treatment regimen). The container may also include one or more measuring cups or similar serving devices of a size or sizes appropriate to measure and serve one or more doses of lactose and, optionally, other ingredients included in the liquid.
Kits
In a further aspect, the invention provides kits for the treatment of the symptoms of lactose intolerance. The kits include lactose in suitable packaging for use by an individual in the treatment of symptoms of lactose intolerance. Any of the compositions described herein may be packaged in the form of a kit. A kit may contain an amount of lactose and, optionally, other ingredients as described herein, sufficient for an entire course of treatment, or for a portion of a course of treatment. Thus, in some embodiments, a kit may include sufficient lactose for the first, second, third, fourth, fifth, and sixth weeks of treatment, or additional weeks of treatment if used, or any combination thereof. Doses of lactose may be individually packaged, or the lactose may be provided in bulk, or combinations thereof. Thus, in some embodiments, a kit provides, in suitable packaging, individual doses of lactose that correspond to dosing points in a treatment regimen, wherein the doses are packaged in one or more packages intended for use in the treatment of symptoms of lactose intolerance. For example, a kit may contain doses of lactose, as described herein, for a treatment program, where the lactose is taken in increasing doses, so that individual packets of lactose are increasing in amount of lactose contained in the packet, from lower doses intended for use at the start of the program to higher doses as the program progresses. As doses are provided for later points in the program, two or more doses per day may be provided, each in its individual packet. Each packet may be labeled to indicate the day and time of day that it is intended to be taken, or the packaging containing the packets may be so labeled, or both. A “packet,” as used in this context, is any individual container that contains lactose, whether the lactose is in solid or liquid form, and can include a packet that contains powder, tablets, or pills, or a packet that contains a liquid.
In some embodiments, the lactose may be provided in bulk in a single container, or in two, three, four, five, or more than five containers (e.g., where each container contains enough lactose for a particular week of a treatment program). If more than one bulk container is provided, the bulk containers may be suitably packaged together to provide sufficient lactose for all or a portion of a treatment protocol. The container or containers can be labeled with a label indicating information useful to the individual performing the treatment protocol, such as dosing schedules.
The lactose may be packaged with other suitable substances, such as bacteria, FOS, and/or buffer, as described herein. The other substance or substances may be packaged separately from the lactose, or mixed with the lactose, or combinations thereof. Thus, in some embodiments, kits of the invention include a powder or liquid containing all the ingredients intended to be used in a course of treatment or a portion of a course of treatment, e.g., lactose and bacteria, FOS, and/or buffer. In some embodiments, lactose is packaged in one package or set of packages, and additional components, such as bacteria, FOS, and/or buffer, are packaged separately from the lactose.
Kits may further include written materials, such as instructions, expected results, testimonials, explanations, warnings, clinical data, information for health professionals, and the like. In some embodiments, the kits contain a label or other information indicating that the kit is only for use under the direction of a health professional, such as a dietician, nutritionist, nurse, physician, or other appropriate health professional. In some embodiments, the kits contain or include information, such as a label, designating the material within as a medical food.
In one embodiment, the invention provides a kit that includes a container of powder, where the powder includes lactose, and additionally FOS, bacteria, and/or buffer, and a label on the container that indicates proper dosage and schedule of use for the powder. The container may further include scoops or other measuring and/or serving devices. In one embodiment, the invention provides a kit that includes a container of liquid, where the liquid includes lactose, and additionally FOS, bacteria, and/or buffer, and a label on the container that indicates proper dosage and schedule of use for the liquid. The container may further include measuring and/or serving devices.
Business Methods
The invention also provides business methods for marketing compositions and methods for the treatment of the symptoms of lactose intolerance. In some embodiments, the invention provides a method of doing business that includes marketing a composition for the treatment of symptoms of lactose intolerance wherein the treatment is by administering increasing doses of lactose according to any of the methods described herein, optionally in combination with other substances such as FOS, bacteria, and buffers In some embodiments, the composition is part of a kit, as described herein. The methods may further include producing such compositions or kits. The marketing may be directly to the consumer, or to suitable health professionals, or combinations thereof. The methods of marketing used in these embodiments of the invention include, but are not limited to, print, television, or radio commercials, infomercials, internet advertising, testimonials, word of mouth, telemarketing, and the like.
EXAMPLES
Example 1
The standard regimen starts with each subject of a group taking 0.8 grams of lactose with dinner each evening. On days 2-16, the dosage of the lactose is increased by 0.8 grams, such that on day 2, the subject takes 1.6 grams, and on day 3, takes 2.4 grams. This process continues until day 16. On day 17, the subject starts the same process with breakfast by consuming 0.8 grams of the product on day 17 and 1.6 grams on day 18. This process continues elevating at the same rate. Simultaneously therewith, the subject is taking 12.8 grams of the lactose containing product with dinner.
On day 33, each subject starts a reintroduction of diary products into their daily diet. While the diary products may vary, milk is typically the standard product, at least as a starting point. When milk is used, the subject starts with 6 ounces with breakfast and dinner, and gradually increases to 8 ounces, 10 ounces, 12 ounces of milk per day. On day 36, the subject has completed the entire regimen and is able to consume dairy products thereafter with decreased lactose intolerant symptoms. An example of this dosing regimen is shown below in the Table.















Week
Date
PM-lactose
AM-lactose
PM-Dairy
AM-Dairy






















1
1
.8
grams






1
2
1.6
grams


1
3
2.4
grams


1
4
3.2
grams


1
5
4
grams


1
6
4.8
grams


1
7
5.6
grams


2
8
6.4
grams


2
9
7.2
grams


2
10
8
grams


2
11
8.8
grams


2
12
9.6
grams


2
13
10.4
grams


2
14
11.2
grams


3
15
12
grams


3
16
12.8
grams


3
17
12.8
grams
.8
grams


3
18
12.8
grams
1.6
grams


3
19
12.8
grams
2.4
grams


3
20
12.8
grams
3.2
grams


3
21
12.8
grams
4
grams


4
22
12.8
grams
4.8
grams


4
23
12.8
grams
5.6
grams


4
24
12.8
grams
6.4
grams


4
25
12.8
grams
7.2
grams


4
26
12.8
grams
8
grams


4
27
12.8
grams
8.8
grams


4
28
12.8
grams
9.6
grams


5
29
12.8
grams
10.4
grams


5
30
12.8
grams
11.2
grams


5
31
12.8
grams
12
grams


5
32
12.8
grams
12.8
grams


5
33




 6 oz Milk
 6 oz Milk


5
34




 8 oz Milk
 8 oz Milk


5
35




10 oz Milk
10 oz Milk


6
36




12 oz Milk
12 oz Milk









It is again pointed out that the doses can be varied in the actual times of application. Thus, as a simple example, the regimen can be used with the subject starring out at a breakfast time and increasing the dosages on the 17th day at dinner time. Alternatively, other times of the day could be used. Moreover, the quantities can vary, depending on the physical conditions of the user. Thus, and particularly in the case of children, dosages can be reduced.
Example 2
A double-blind study of the ability of the lactose-based compositions and methods of the invention was made in order to determine reduction of the symptoms of lactose intolerance. More specifically, the study was conducted to determine whether graduated and controlled administration of lactose-containing product of the invention to subjects who have been confirmed as having lactose intolerance was effective in order to determine if the regimen of the invention was effective in relieving then lactose intolerant symptoms. For this purpose, a double-blind randomized study was conducted with the subjects following the 38-day regimen with a placebo, or otherwise, the lactose-containing product, itself.
Eight-six persons were pre-screened to determine lactose intolerance. Each of these subjects was between the ages of 18 and 55 and recruited from the Los Angeles area. A pre-Likert scale and a post-Likert scale was used to determine the severity of five particular symptoms of lactose intolerance. Each subject was recruited through advertisements posted in local newspapers in the greater Los Angeles area, as well as the worldwide web. Over 190 subjects were pre-screened for this study. Each subject rated symptoms of bloating, abdominal pain, cramps, diarrhea, and nausea. A ranked scale was used, with 1 indicating no symptoms, 2 indicating slight symptoms, 3 indicating mild symptoms, 4 indicating moderate symptoms, and 5 indicating severe symptoms. The maximum possible score was 20. A score of 14 or higher with no information suggesting milk allergy, irritable bowel symptoms, or pregnancies, allowed each subject to participate.
Each of the subjects were paired by age group and gender. Most members of each pair of subjects began the program within two days. One member of the pair randomly received a supply of the lactose-containing product, while the other received a placebo. This placebo was similar in appearance to the actual lactose-containing product. Detailed instructions for administration were given to each participant. In short, each subject was instructed to take the powdered formula, as well as the powdered placebo, and mix same with water for ingestion. Particular preparation dispensed to each subject was unknown both to the subject and the dispensing individual. A record of each was kept by a third party.
In conducting the study, the regimen described in Example 1 was used. Also, the lactose-containing product of the Table IV of ingredients in the Compositions section, above, was used and particularly that product identified as having the exemplary percentages. Each subject was contacted once a week for the first two weeks, and then each week thereafter, in order to check on their progress. Directions were provided on a personal basis if changes were needed. During the entire program, 5 extra days were included, and each subject was asked to follow this 42-day program until completion. On days 35-37, each subject consumed a measured amount of milk with breakfast and dinner. On day 38, the subjects were asked to incorporate at least 16 ounces of diary product into their diet for the next 5 days. Upon completion, each subject again rated their symptoms using the same Likert scale which was used in the pre-screening procedure. Subjects were again asked for another rating of symptoms after one month of completion of the program.
The data collected from the symptom score sheets was analyzed. Participants provided ratings for five symptoms of lactose intolerance on a 0 (no symptom) to 4 (severe symptom) sale. Data collection was successful. The total symptom scale provided scores ranging from 0 to 20, Data were collected pre-treatment for 73 individuals and 64 individuals (87.7%) completed the program and provided data at the conclusion of that program. Completion rates were 88.9% for those assigned to the group receiving the lactose product and 86.9% for those assigned to the placebo group. 61 individuals provided data between one and two months following completion of the program.
SUMMARY OF RESULTS
Data are summarized for all individuals that provided information for two or more data points (Table, below). At the pre-treatment measurement point, members of the two groups provided statistically equivalent ratings of their symptoms for lactose intolerance (t=0.95, n.s.)1. At the post-treatment measurement point, the group receiving the lactose-containing product provided symptom ratings that, in total, were 54.6 percent lower than their original ratings, while the placebo group ratings declined by 34.1 percent. At post-treatment, analyses (analysis of covariance employing the pre-treatment ratings as the covariate) indicated that the respondents receiving the lactose-containing produced reported a significant decline in symptoms relative to the placebo group (F=8.81, p>0.01). Approximately one month later, participants were contacted again. At that point, the individuals receiving the lactose-containing product provided symptom ratings that were 56.6 percent lower than then original ratings, while the placebo group ratings declined by only 23.3 percent. Again, these results were significantly different
(F=18.32, p>0.001):














TABLE V












1-month




Pre-Treatment

Post-Treatment

follow-up



N
Mean (s.d.)
N
Mean (s.d.)
N
Mean (s.d.)






















Lactose
32
14.1(2.6)
32
3.7(5.6)
29
 3.3(5.8)


Placebo
32
14.9(3.5)
32
8.1(6.2)
32
10.3(5.6)









As well, the percentage of respondents with a decline of 10 or more points on the total ratings were examined. As would be expected, the results were similar. For the post-treatment measuring point, 71.9 percent of the Lactose group, but only 37.5 percent of the placebo group reported symptom declines of 10 points or greater on the rating scale (χ2=7.63, p>0.01)2. One month later, the observed differences had increased, and 79.3 percent of the Lactose group but only 18.8 percent of the placebo group reported a symptom rating scale decline of at least 10 points (χ2=22.37, p>0.001).
Summary of Pairs with 3 Data Points (−26)
In this section, data are summarized for the 26 matched pairs of individuals that provided information for all 3 data points (Table below). At the pre-treatment measurement point, the two groups were statistically equivalent on their symptom rating scale totals (t=1.19, n.s.). At the post-treatment measurement point, the group receiving the lactose-containing product reported significantly lowered symptom severity relative to the placebo group (t=2.36, p>0.05). In addition, 73.1 percent of the group receiving the lactose-containing product versus 38.5 percent of the placebo group reported a symptom decline of at least 10 points on the rating scale, and this result was also statistically significant (χ2=6.33, p>0.05). At the final measurement point, the group receiving the lactose-containing product provided symptom ratings that, in total, were 54.1 percent lower than their original ratings, while the placebo group ratings declined by only 26.3 percent. Analyses (a matched-pair t-test) indicated that the matched respondents receiving the lactose-containing product reported significantly lowered symptom severity relative to the placebo group (t=3.67, p>0.01). In addition, 76.9 percent of the group receiving the lactose-containing product versus 23.1 percent of the placebo group reported a symptom decline of at least 10 points on the rating scale, and this result was also statistically significant (χ2=15.08, p>0.001).
The summary of the data for 3 data points is set forth in the Table below:














TABLE VI












1-month




Pre-Treatment

Post-Treatment

follow-up



N
Mean (s.d.)
N
Mean (s.d.)
N
Mean (s.d.)






















Lactose
26
13.8(2.5)
26
3.9(6.0)
26
3.7(6.1)


Placebo
22
14.9(3.7)
26
7.9(6.3)
26
9.7(5.7)









The present study confirmed the occurrence of decrease of symptoms when lactose intolerant subjects ingested a formulated lactose-containing product for 38 days and showed a decrease in the severity of all symptoms when they were challenged with a lactose load (8, 10, and 12 oz glass of milk) after metabolic adaptation compared with pre-adaption severity. Post one month data demonstrated the same degree of improved symptoms as subjects continued to incorporate dairy products into their diets.
It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes

## Claims

1. A composition for ameliorating the symptoms associated with lactose intolerance, the composition comprising: a lactose reduced dairy product and an effective amount of a probiotic selected from the group consisting of the genus Lactobacillus, the genus Bifidobacterium and mixtures thereof, and a fiber, wherein the lactose reduced dairy product has reduced lactose content and is selected from the group consisting of a yogurt containing pre-digested lactose, an ice cream containing pre-digested lactose and a margarine containing pre-digested lactose; wherein the probiotic is present in an amount of from about 1 mg to about 1000 mg of the composition; and wherein the fiber comprises a fructo-oligosaccharide.

2. The composition of claim 1, wherein the fiber further comprises inulin.

3. The composition of claim 1, wherein the fiber is about 0.1 to about 1.26% of the composition.

4. The composition of claim 1, wherein the probiotic is present in an amount of about 2 mg to about 50 mg of the composition.

5. The composition of claim 1, wherein the probiotic is present in an amount of about 4 mg to about 25 mg of the composition.

6. The composition of claim 1, wherein the fiber is present in an amount of from about 1 mg to about 10 g of the composition.

7. The composition of claim 1, wherein said lactose reduced dairy product is the ice cream containing pre-digested lactose.

8. The composition of claim 1, wherein said lactose reduced dairy product is the yogurt containing pre-digested lactose.

9. The composition of claim 1, wherein said lactose reduced dairy product is the margarine containing pre-digested lactose.

10. The composition of claim 1 wherein the probiotic is a member of the genus Lactobacillus.

11. The composition of claim 1 wherein the probiotic is a member of the genus Bifidobacterium.

12. A method for treating lactose intolerance in a human subject in need thereof, the method comprising: administering a composition comprising a lactose reduced dairy product and an effective amount of a probiotic selected from the group consisting of the genus Lactobacillus, the genus Bifidobacterium and mixtures thereof, and a fiber wherein the lactose reduced dairy product has reduced lactose content and is selected from the group consisting of a yogurt containing pre-digested lactose, an ice cream containing pre-digested lactose, and a margarine containing pre-digested lactose; wherein the probiotic is present in an amount of from about 1 mg to about 1000 mg of the composition; and wherein the fiber comprises a fructo-oligosaccharide.

13. The method of claim 12, wherein said lactose reduced dairy product is the ice cream containing pre-digested lactose.

14. The method of claim 12, wherein said lactose reduced dairy product is the yogurt containing pre-digested lactose.

15. The method of claim 12, wherein said lactose reduced dairy product is the margarine containing pre-digested lactose.