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    • 专利摘要:
    The invention relates to the use of leaves containing 1,25-dihydroxyvitamin D3 glycoside for the preparation of a single peroral administration composition with a specific gravity of at least 1.25 kg / l which has a delayed release of 1.25-dihydroxyvitamin D3 glycoside, to prevent a symptom selected from a decreased appetite, causes paralysis of both in an animal after giving birth.
    公开号:BE1019408A5
    申请号:E2010/0340
    申请日:2010-06-03
    公开日:2012-07-03
    发明作者:Maurice Verschaeve
    申请人:Emma Nutrition；
    IPC主号:
    专利说明:

    Use of 1,25-dihydroxyvitamin D3 glvcoside in lactating animals.
    Hypocalcemia is a metabolic disease that mainly occurs in milk-producing animals such as cows, dairy cows, sheep, goats, but also in horses. The disease mainly occurs in older, highly productive dairy cows that have already calved several times. Although hypocalcaemia mainly occurs as subclinical hypocalcaemia in the early postpartum phase and during the lactation period a few weeks after calving, the period in which it manifests can vary from a few weeks before to a few weeks after calving. The lactation cycle of a dairy cow begins immediately after calving and extends for approximately 10 months of the year.
    The first symptoms of hypocalcemia are a loss of mental alertness and decreased appetite. Changes can occur within a relatively short period of a few minutes, up to a longer period of several hours. Prompt treatment of the animal is recommended to improve the response. Severe cases of hypocalcemia are known to cause paralysis or milk fever that can lead to paralysis, especially at the back of the animal, and may even lead to the animal's death.
    The occurrence of hypocalcemia is attributed to a low level of calcium in the blood, which mainly occurs around the time of calving. During that period, the amount of Ca needed for colostrum production is much greater than the amount available in the blood, obtained through intestinal uptake and bone mobilization. During the dry period, i.e. a period of about two months prior to calving in which the animal is not milked, the lactation is minimal and the Ca requirement is clearly lower. The cow is then able to absorb sufficient calcium from the intestine. During this dry period, the need for calcium to maintain metabolism and fetal growth remains fairly limited (<30 g), while the amount of calcium in normal diets is considerably higher. As a result, the animal's body responds by reducing the gastrointestinal absorption of calcium. The excretion of hormones responsible for active calcium transport from the intestinal tract and for mobilization from the bones to the blood (parathyroid hormone, 1,25-Dihydroxy-Vitamin D) is therefore also done to a minimal extent during this period. Lactation is induced around calving and the calcium requirement increases considerably. Milk production then has a peak 4 to 6 weeks after calving. Large amounts of calcium are transported from the blood to the mammary gland, which greatly reduces the amount of calcium in the blood. If the concentration falls below 1.8 mMol / l, some cows may show symptoms of hypocalcemia. The start of lactation puts the balance in the Ca housekeeping to the test and despite hormonal regulation, which results in the activation of vitamin D dependent mechanisms, a certain deficiency of Ca (hypocalcaemia) occurs in every cow . Hypocalcaemia usually occurs within 72 hours of calving. Most cows have a natural defense mechanism, which enables them to provide sufficient calcium supply independently from the intake of calcium through absorption from the intestine and resorption from the skeleton. However, in 5-20% of the cows, recovery of the Ca balance is not achieved through the intervention of the parathyroid hormone and they develop milking disease or hypocalcemia.
    In cows suffering from hypocalcemia, three stages of the disease can generally be recognized
    Disease stage 1: No typical symptoms Observed signs, however, only become apparent when they are observed for about 1 hour: lack of appetite, irritability, restlessness, weakness, weight shift and shifting of the hind legs, the cow shows poor coordination of movements, shaking of the muscles, and shaking, cool the large muscle groups of the animal, mainly a cold hindquarters (or back) of the animal.
    Disease stage 2: takes 1 to 12 hours. The cows cannot stand, but lie down with the legs under the body, head turned sideways to the body. The affected animals eyes were slow and listless. The digestive system is inactive, the heart rate increases to values above 100 beats per minute (bpm) and the body temperature decreases.
    Disease stage 3: A further loss of consciousness (finally: coma) is observed. A further increase in heart rate to values that can reach 120 bpm and a further reduction in body temperature. Untreated cows can die within 12 hours of the start of the first clinical symptoms.
    Various methods have been developed for the treatment of hypocalcemia. Examples include intravenous (IV) administration of calcium that gives recovery in the short term; IV administration of a Ca / Mg infusion the day after calving; injecting a synthetic vitamin D preparation to stimulate Ca uptake in the gut, which is banned by many countries despite its good results; administering vitamin D2 via the mouth or administration via injection into the muscles of vitamin D3 or dihydrotachysterol. The disadvantage is that these substances still have to be metabolized and that they are not stable in the organic environment. It is also true that only a small proportion of the substances administered are converted to the active metabolite 1,25-dihydroxyvitamin D3, which means that very large quantities must be administered before a therapeutic concentration of the active metabolite is built up. Another method focuses on controlling the anion-cation balance of the ration in the final weeks before calving. High anionic rations, which mainly contain chloride and sulfur, appear to be able to reduce the percentage of milk disease by lowering the pH of the blood and thus increasing the uptake of Ca from the bones and feed.
    EP1162890 describes a method for preventing hypocalcemia in a milking animal, wherein for at least a part of the dry period feed is administered containing an effective amount of a compound, which absorption of calcium from drinking water and / or from the ration of the animal reduces by binding the free calcium contained in the gastrointestinal tract. Because the free calcium cannot be absorbed by the animal, the natural calcium-regulating defense mechanism is stimulated. Examples of suitable calcium binding compounds are oxalic acid, sodium oxalate, phytic acid, a phytate, mineral clay, zeolites, and others. However, this method requires strict organization and good nutrition for the cows that are dry.
    Gerloff, et al., "Dry Cow Feeding and Metabolic Problems," 46th Minnesota Nutritional Conference and Monsanto Technical Symposium, September 16-18, 1985 suggest avoiding excessive calcium and phosphorus intake in the period prior to calving to prevent of milk fever. Jorgensen, NA, "Combatting Milk Fever, Journal of Dairy Science, Vol. 57, No. 8, 1973, pp. 933-944 provides an overview of known methods for treating milk fever. Examples include low-fat prepartal diets calcium content, regulating the calcium / phosphorus ratio, administering acidic foods, administering mineral acids or ammonium chloride in the prepartum, administering 90 to 100 g of calcium chloride daily for a short period, administering large doses of vitamin D or 25 in the prepartum -hydroxycholecalciferol Howard, Ed., "Current Veterinary Therapy I: Food Animal Practice," WB Saunders Co., Philadelphia, 1981, pp. 340-343 describes the antepartum administration of vitamin D2 and a vitamin D3 metabolite antepartum to reduce the prevention or occurrence of milk fever The oral administration of 90 to 100 g of calcium chloride during two or three days of antepartum is also described.
    It is known from US-A-4,931,290 to reduce the risk of milk fever after calving by administering the animal, every calving time, with an effective dose of (1) an water-soluble calcium salt, (2) an effective amount of a complexing agent for complexing phosphorus to a water-insoluble phosphorus complex, and (3) about 17 mg of magnesium or an equivalent metal. Ca administration and phosphorus binding in an insoluble complex have the effect of maintaining serum calcium levels at a level that prevents severe milk fever. The dosage may also contain vitamin D3. The dose is administered in the form of a powder, tablet, capsule or bolus. It is proposed to administer the first three doses in the first 30 hours after calving, such as immediately after calving and after 12 and 24 hours, and typically followed by additional doses 36, 48, and 72 hours after calving. The repeated administration after calving, however, disadvantages the comfort and well-being of the animal and requires intensive monitoring by the livestock farmer. An additional disadvantage is that the vitamin D3 is insufficiently metabolised.
    US 2006/270640 describes the transvaginal administration of 1 [alpha] hydroxyvitamin D3 or 1,25-dihydroxyvitamin D3 for the treatment of hypocalcemia, in particular for the treatment of conditions such as intrapartum astasia, which is a major cause of death for cows. Where vitamins D, A and E are fat-soluble, only a particular vitamin D derivative can be absorbed from the vagina to a sufficient extent to prevent milk fever. However, this method is uncomfortable for the animal.
    In "Using Solanum glaucophyllum as a source or 1,25-dihydroxyvitamin D to prevent hypocalcemia in dairy cows", Horst et al., Acta fat; scand. Suppl. 98-2003, hypocalcemia is combated with leaves of Solanum glaucophyllum containing gelatin boluses. (Sg) The gelatin boluses were administered to cows who were already fed a diet with a lower cation-anion balance Boluses made from gelatin have the property of dissolving relatively quickly in the stomach, and usually release their active ingredients within a period of time 12-hour Solanum glaucuphyllum (Sg) is a plant that contains high amounts of 1,25-dihydroxyvitamin D3 glycoside.This publication describes several experiments with these gelatin boluses.The final conclusion is that the best results were obtained by a staged administration of the Solanum glaucophyllum leaves, whereby a bolus was administered daily from 5 days prepartum to 7 days postpartum containing 2 g Sg, from day 8 to day 14 a bolus containing 1 g Sg was administered daily, and from day 15-21 the daily bolus still contained 0.5 g. Although good results were obtained with this method, the method is unpleasant for the animal as it was administered a bolus daily, and for the caretaker of the animals, as the daily administration of the boluses is a labor-intensive activity and, in addition, the day of prepartum difficult to predict.
    Although various means and methods have been developed for the prevention and treatment of hypocalcaemia, there is still a need for an agent capable of effective remedy of hypocalcaemia, both in the early phase where hypocalcaemia manifests itself as decreased appetite, as well as in the later phase where paralysis may occur. Moreover, there is a need to provide the animal and the caregiver with the greatest possible comfort.
    The object of the present invention is therefore to prevent in a milk-producing animal a symptom selected from decreased appetite, paralysis or a combination of both, in the period after calving or giving birth to young animals, in a manner that provides optimum comfort to the animal and to the caregiver. Preventing or avoiding these effects is of great importance to dairy farmers in terms of both work and emotional burden, as well as in the commercial area, as they have a strong influence on milk production by animals.
    This is achieved according to this invention by using leaves from plants containing 1,25-dihydroxyvitamin D3 glycoside to prepare a single peroral administration composition in the form of a tablet or a bolus to prevent a symptom selected from a reduced appetite , paralysis or a combination of both in an animal after calving, wherein said composition contains: - a substance or material that is slowly dissolved or physically eroded in the stomach, in which material or material the leaves are encapsulated, causing a delayed release of 1 25-dihydroxyvitamin D3 glycoside is effected, wherein the substance or material is selected from the group - one or more metals or metal compounds such that the composition acquires a specific weight which causes it to sink to the bottom of the stomach after uptake into the stomach , and remains there.
    Preferably the leaves are from Solanum glaucophyllum. Namely, the inventor has determined that 1,25-dihydroxyvitamin D3 glycoside is also absorbed into the blood almost immediately upon oral administration. Glycoside is metabolically cleaved in the gastrointestinal tract, after which the 1,25-dihydroxyvitamin D3 is bioavailable in the animal to ensure an increased intestinal calcium uptake by the blood. The biological effect of 1,25-dihydroxyvitamin D3 glycoside occurs shortly after ingestion and ensures that the natural defense mechanism of the animal is stimulated shortly after ingestion. 1,25-dihydroxyvitamin D3 glycoside is metabolized by cleavage of the glycoside and goes directly to the intestine where it can be absorbed by the blood, in contrast to vitamin D3 as such. By administering the composition prior to lactation, at a time when the animal still has a good appetite and the Ca deficiency is not yet established, the animal has the ability to build up a good resistance, so that the risk of occurrence is a Decreased appetite and paralysis symptoms associated with hypocalcaemia after calving can be minimized at an early stage. The delayed release of the 1,25-dihydroxyvitamin D3 glycoside ensures that the optimal gastrointestinal Ca uptake is spread over a longer period of time. This is important since the loss of appetite and paralysis symptoms can also occur at a slightly later stage, i.e. a few days to a few weeks after calving. The composition of this invention can be administered perorally in any desired manner, but is preferably administered through the mouth with a firing mechanism to ensure that it ends up directly in the stomach.
    The composition of this invention preferably has a specific gravity of at least about 1.25 kg / l whereby, after admission into the stomach, it sinks to the bottom of the stomach, in particular to the bottom of the stomach stomach or rumen, and there remains present, with minimal risk of mixing with the feed that is chewed. Thus optimum delivery of 1,25-dihydroxyvitamin D3 glycoside to the gut is guaranteed. Preferably, however, the composition has a specific weight that is at least 1.5 kg / l, more preferably at least 1.75 kg / l. Such a high specific gravity can be obtained, for example, by adding one or more metals or metal compounds to the composition. Examples of suitable metals are iron, iron oxides or other iron compounds. These show a minimal risk of intoxication. Other metals or metal compounds can also be used, such as, for example, zinc powder, copper powder, but their concentration should be chosen such that intoxication is prevented. Preferably, about 20-60% by weight of metal powder is administered to the composition of the present invention, more preferably about 25-55% by weight of metal powder, more preferably about 30-50% by weight of metal powder, more preferably about 35-45 wt% metal powder, most preferably about 40% metal powder. Preferably the metal powder is iron powder.
    Because the active substance is released from the composition in a delayed manner, a single dose can suffice by adequate choice of the dosage of the 1,25-dihydroxyvitamin D3 glycoside. Thanks to the delayed release that is achieved by slowly dissolving or physically eroding the material of the bolus, a similar effect is achieved as with a phased administration of leaves containing 1,25-dihydroxyvitamin D3 glycoside, but with a single administration. The fact that a single peroral administration is sufficient greatly increases the comfort of the animal and the caregiver. The delayed release is achieved not only by the bolus material that is slowly eroding, but also by the 1,25-dihydroxyvitamin D3 being bound to a glycoside structure, which must first be enzymatically cleaved enzymatically in the cow's metabolism and by 1 25-dihydroxyvitamin D3 glycoside must first be released from the leaves.
    For example, splitting off the glycoside group takes an average of 8-12 hours in the rumen flora. This relieves 1,25-dihydroxyvitamin D3. This 1,25-dihydroxyvitamin D3 then becomes available for uptake within 15 minutes - 6 hours. This release of the glycoside further delays the release of the 1,25-dihydroxyvitamin D3.
    Due to the fact that the active substance still contains 1,25-dihydroxyvitamin D3 glycoside in the leaves, a still further delayed release of the active substance is obtained, which constitutes a further advantage for the effect of the single-dose composition.
    This ultimately results in a composition with a stable sustained release that lasts for about 10-12 days, with the release decreasing towards the end. This reduction at the end avoids getting used to the product, so that usually no relapse effect will occur when treatment is stopped, and as such the physiological condition of the animal is kept optimal. Such a delayed release with end-to-end release is not currently known for a single-dose hypocalcemia drug, and thus offers great benefits for both the animal and the caregiver. Due to the single administration and the delayed effect, the milk yield is ensured after delivery, as well as a good condition of the animal. The parathyroid gland can also start slowly and resume production of the parathyroid hormone, ensuring that the entire biological process proceeds as it should.
    Where the known techniques are aimed at increasing the Ca concentration in the blood or stimulating Ca production during the dry period, and thus intervening in the Ca / Mg metabolism of the animal, which can cause undesirable side effects , this invention aims at enabling a more efficient utilization of the free Ca naturally present in the intestine through the diet, without substantially intervening in the Ca / Mg metabolism. This is an important advantage because changing Ca / Mg concentrations can give rise to cramps, among other things.
    The 1,25-dihydroxyvitamin D3 glycoside used in the composition of this invention can be prepared synthetically, but is preferably derived from the plant Solanum glaucophyllum. It is preferably obtained by preparing the leaves of Solanum glaucophyllum, in particular by standardizing the content of 1,25-dihidroxyivitamin D3 glycoside from Solanum glaucophyllum. Large batches of leaves of Solanum glaucophyllum are thoroughly ground and mixed, after which the exact average concentration of 1,25-dihydroxyvitamin D3 glycoside is determined, which applies to the entire amount due to thorough mixing. After this, small amounts of these ground leaves can be weighed to obtain a certain specific amount of 1,25-dihydroxyvitamin D3 glycoside per dose (or bolus) with fairly good precision. In this way a constant and accurate amount of 1,25-dihydroxyvitamin D3 glycoside in the bolus can be ensured. This Solanum glaucophyllum blend of leaf particles containing 1,25-dihydroxyvitamin D3 glycoside is commercially available as a composition that typically contains about 20 ppm of 1,25-dihydroxyvitamin D3 glycoside (20 mg per kg).
    To facilitate administration and to maximize the comfort of the animal, the composition is preferably administered in the form of a powder, granulate, tablet, pill, bolus or gelatin bolus, the use of the bolus being preferred.
    In case the composition is administered as a bolus, tablet, pill or gelatin bolus, it is preferably administered through the mouth using a firing device so that it is ensured that the composition ends up in the net stomach or rumen, and minimizes the risk of ruminating is being held. Due to its high density, the bolus remains at the bottom of the retinal stomach or rumen after ingestion with a low risk of ruminating and the 1,25-dihydroxyvitamin D3 glycoside is delayed from the retinal stomach or rumen. The tripe is the first stomach with a capacity of approximately 200 liters. Normally the bolus will stay in this stomach, although in some cases the bolus can also move to the second stomach, the stomach stomach. Whether the bolus stays in the net stomach or in the rumen makes virtually no difference to the effect. Because of the physiological structure of the stomachs of ruminants such as in the cow, it is very unlikely that the bolus will move to a third stomach. If the bolus were to be controlled and ruminated by the animal, it is not yet problematic as the cow ruminates the food into small pieces and these small pieces end up in the bottom of the net stomach or tripe and further disintegrate there.
    The inventor has determined that the bolus, due to its high density, after ingestion, remains at the bottom of the net stomach or rumen, with a small risk that the bolus is brought back to the mouth during ruminating and, moreover, much faster than anticipated. 25-dihydroxyvitamin D3 would release glycoside from the leaves. The weight and dimensions of the bolus can be varied within wide limits, but are preferably adjusted to the weight of the animal, such that a single administration is sufficient.
    The dose of 1,25-dihydroxyvitamin D3 glycoside administered to the animal is preferably at least 460 pg, preferably at least 550 pg. This dose is chosen such that the amount of 1,25-dihydroxyvitamin D3 glycoside administered is sufficient to achieve the preventive effect. This dose is chosen such that the amount of 1,25-dihydroxyvitamin D3 glycoside administered is sufficient to ensure that the amount of Ca resorbed daily from the gastrointestinal tract is at least a part of the normal daily amount, preferably at least the normal daily amount. A dosage of 450 to 500 pg spread over a minimum of 10 days results in an average release of a maximum of 50 pg per day. If Solanum glaucophyllum extracts are used instead of the leaves, or if synthetic 1,25-dihydroxyvitamin D3 is administered, release is slowed down, which is disadvantageous. There is no biological cleavage of the glycoside. After all, if there is no delayed release, or a less delayed release, the window for therapeutic administration becomes very narrow with a single administration. The active substance will be released much faster than with the delayed release. As a result, the bolus will need to be delivered at a specific exact time before calving, which must be precisely determined. If this is not done, there is a risk that the active substance will be released too soon or too late. However, since the delivery is difficult to determine precisely, there is a high chance that such a bolus will not be delivered at the right time. In this case or in the event that something should accidentally go wrong in the delayed release of the active substance from the composition and a larger amount of the 1,25-dihydroxyvitamin D3 glycoside is released in one go, there are indeed no direct negative consequences for the animal, but the protective effect may disappear partially or completely.
    Delayed release of 1,25-dihydroxyvitamin D3 glycoside is achieved by encapsulating the 1,25-dihydroxyvitamin D3 glycoside in a material or substance that is slowly dissolved or physically eroded in the stomach. For this purpose useful compounds are selected from the group of a fat, for example castor oil, which can be wholly or partially cured by hydrogenation, or a derivative of a fat, but also a protein, a polysaccharide, a cellulose, a gum, a glycol and derivatives of these compounds can suitably be used. Castor oil that has been hydrogenated and highly compressed usually works for 10 to 12 days. It is important that the hydrolysis rate of the substance is low enough to ensure a delayed release of the active substance. It is also important that the melting point of the substance is quite high, preferably around or above 88 ° C. This is also important in the production of the composition, since the substance is mixed with the leaves and other ingredients in a molten state. A preferred embodiment of such a process is further described below. Preferably, fully hydrogenated castor oil is used. This substance is extremely suitable for producing a sustained-release composition of 1,25-dihydroxyvitamin D3 glycoside, given the optimum rate at which the material physically erodes. This substance can also be very well compressed in combination with, for example, iron powder, which is used to aggravate the composition. In addition to the castor oil, magnesium stearate is also preferably added as a lubricant when compressing the composition. If desired, the composition may be encapsulated with the 1,25-dihydroxyvitamin D3 glycoside in a membrane, for example a membrane of the aforementioned compounds or a plastic film that is biodegradable in the stomach, such as a polyester, for example polylactid acid. The compounds that control delayed release of the 1,25-dihydroxyvitamin D3 glycoside are preferably chosen such that release continues for a period of at least 3 days, preferably at least 5 days. Release will usually stop within a period of 20 days after administration, preferably within a period of 10 days.
    Preferably, the shape and size of the bolus are also determined as a function of the material or substance selected for the bolus, such that the aforementioned periods of release of the active substance are obtained. In a preferred embodiment of the bolus in which hardened or hydrogenated castor oil with some magnesium stearate is used as the slowly eroding material, the bolus can for instance have a length of 80 mm with a thickness and a width of 25 mm each, preferably with rounded shapes and / or to reduce the risk of injury.
    The composition may further also contain 1,25-dihydroxy vitamin D3 glycoside metabolites.
    The composition of this invention is preferably intended for peroral administration, preferably shortly before calving but sufficiently long before calving to ensure optimum Ca uptake as long as there is an increased Ca requirement. Preferably the composition or bolus is administered at least 1 day before calving, more preferably 1 to 2 days before calving.
    In a useful embodiment, the composition of this invention contains adjuvants that may support or enhance the effect of the composition, such as, for example, other vitamins or derivatives thereof, e.g., vitamins A, B12, CD, E, K, niacin, thiamin, choline, biotin, folic acid, ribovlavin, pantothenic acid, one or more minerals, for example cobalt, copper, manganese, selenium, zinc, or a carrier for the 1,25-dihydroxyvitamin D3. Use of a carrier can be useful in improving dispersibility in the other components of the composition. Examples of suitable carrier materials are dietary fiber, kelp.
    The composition of this invention is suitable for use in milk-producing animals, for example cows, sheep, goats, horses, donkeys, etc.
    This invention also relates to the use of 1,25-dihydroxyvitamin D3 glycoside to prepare a composition with a specific gravity of at least 1.25 kg / l which causes a delayed release of 1,25-dihydroxyvitamin D3 glycoside for the purpose of increase intestinal calcium intake by an animal's blood after and around calving.
    Another aspect of the invention relates to the use of 1,25-dihydroxyvitamin D3 glycoside containing composition as described above to prevent a symptom selected from a decreased appetite, paralysis or a combination of both in an animal after calving.
    Still another aspect of the invention relates to the use of 1,25-dihydroxyvitamin D3 glycoside-containing composition as described above for increasing intestinal calcium uptake by an animal's blood after calving.
    The invention further relates to a composition, in a form suitable for peroral administration in the form of a tablet or bolus, for preventing a symptom selected from decreased appetite or paralysis symptoms or a combination thereof associated with calving in an animal, which leaves of plants containing at least 460 pg, preferably at least 550 pg 1,25-dihydroxyvitamin D3 glycoside in those leaves, as well as a substance or material that is slowly dissolved or physically eroded in the stomach, in which substance or material the leaves are encapsulated, wherein the substance or material is selected from the group of a fat or a derivative thereof, for example a soap or a stearate, a protein, a polysaccharide, a cellulose, a gum, a glycol, and derivatives of these compounds which are useful are for delayed release of the 1,25-dihydroxyvitamin D3 glycoside, and thereby one or more metals or metal compounds such that the assembly assumes a specific weight which, after being absorbed into the stomach, drops to the bottom of the stomach and remains there.
    The fat derivative is preferably castor oil, preferably at least in part, but most preferably high to fully hydrogenated or hardened castor oil.
    Useful compositions usually take the form of a granulate, granules, a tablet, a pill, a bolus, a gelatin or a premix with other useful substances. Useful compositions may also be in the form of a powder, granulate or pill or bolus contained in a package that is preferably porous to allow diffusion of the gastric juice to the contents of the pouch for dissolving 1,25-dihydroxyvitamin D3 glycoside on the one hand and, on the other hand, to allow diffusion of the dissolved 1,25-dihydroxyvitamin D3 glycoside to the outside.
    The composition may further contain other useful ingredients such as, for example, at least one other vitamin or mineral, for example vitamins A, B12, C, E, K, niacin, thiamin, choline, biotin, folic acid, ribovlavin, pantothenic acid, one or more minerals, for example cobalt, copper, manganese, selenium, zinc, or a carrier for the 1,25-dihydroxyvitamin D3.
    The invention is further illustrated with reference to the examples below.
    The natural glycoside form of 1,25-dihydroxyvitamin D3 as used in preferred embodiment offers unique stability and water-soluble properties for increased activity. This shape is also heat resistant up to 100 ° C.
    This preferred embodiment of a bolus makes it possible to administer a single treatment, shortly before calving. Prolonged release of the active ingredient for a period of 10-12 days corresponds to a phased administration as described in the prior art. In the prior art, however, different gelatin bolus must be administered, which releases the active ingredient over a period of about 12 hours, while the present invention achieves the same effect with a single bolus.
    EXAMPLE
    Before producing the bolus, the leaves of Solanum glaucophyllum are ground and standardized. This means that the leaves are ground and mixed in large quantities, into one uniform lot. After this, the average concentration of the 1,25-dihydroxyvitamin D3 present in the leaves is determined as accurately as possible. Starting from this concentration, the 1,25-dihydroxyvitamin D3 is then dosed in individual portions by weighing a specific amount of ground leaves and also mixing them again. Given the thorough mixing and crushing of the batch of leaves, it can be assumed that the concentration of 1,25-dihydroxyvitamin D3 in the mixture is fairly constant, so that the balanced doses of the leaves also have the same and previously known amount of 1, 25-dihydroxyvitamin D3.
    A bolus with a weight of 70.2 g was placed in a porous nylon bag with pores of 37 µm, which was prepared from, inter alia, 18.4 g of hydrogenated castor oil (obtained under the trade name Cutina® HR PH from COGNIS and 23, 3 g Panbonis® supplied by HERBONIS, a composition of grounded and standardized Solanum glaucophylum leaves, containing on average 20 ppm 1,25-dihydroxyvitamin D3 glycoside, which corresponded to an average daily release of 38-46 pg of the active ingredient 1.25 - dihydroxyvitamin D3 glycoside, over 10-12 days, furthermore the bolus contained 27.6 g of iron powder and 0.9 g of magnesium stearate.The iron powder only serves as a ballast and serves to weigh the bolus so that it remains on the bottom of the stomach of the animal The magnesium stearate is a component that, together with the castor oil, serves as a lubricant to compress the powder obtained.
    In the production of the bolus itself, the iron powder was mixed with the Sonanum glaucophyllum leaves and heated to 85 ° C. The hydrogenated castor oil (E498) was also heated to above its melting point of 88 ° C. E498 is the E number of castor oil. E numbers means a list of additives that are authorized by the European Union in foodstuffs suitable for human consumption. Subsequently, these products were mixed together at this high temperature. After thorough mixing, the mixture was cooled to 15 ° C. The mixture of Sonanum glaucophyllum leaves, iron powder and castor oil was cooled to 15 ° C, after which it was then finely ground to a powder form. The magnesium stearate (E571) was then added and mixed with the rest.
    The final mixture was pressed into a bolus in a heavy compression machine, with a mold in the form of a bolus and this with the correct and required compression pressure. The composition of the bolus had a specific gravity of 1.75 kg / l. The composition was strongly pressed into a substantially cylindrical bolus with a length of 80 mm, a thickness of at most 25 mm, more preferably about 23 mm and a width of 25 mm, with rounded ends.
    An analysis of the bolus composition gave the results in units of weight given in Table 1.
    Table 1.
    The bag with the bolus was hung in the rumen of 15 cows, who had already calved a minimum of 3 times, and therefore had an increased risk of the occurrence of hypocalcemia, loss of appetite and paralysis. Every day at the same time, the pouch was removed from the rumen, rinsed with water and weighed after draining.
    During the first 4 days, it was observed that the bolus weight increased due to absorption of rumen fluid. After this period the weight decreased again. The bolus was almost completely resorbed after 14 days. The evolution of the weight of the bolus as a function of time is shown in Table 3.
    No loss of appetite was found in any of the cows, nor did paralysis occur. The Ca blood concentrations in the period before calving and at least 2 days after calving remained stable. The effect on blood parameters was measured in 9 cows that had calved 3 and more times before. Table 2 shows the calcium level in the blood of the cows with a first blood sample when using the bolus 1-2 days before calving and with a second blood sample 24 hours after calving. Cow 1 and 2 did not receive a bolus. 2.2 mmol / l Ca is assumed to be the optimum calcium content for the blood plasma of dairy cows.
    Table 2.
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    Cow 2 was treated after the 2nd sampling, because disease symptoms such as a starting paralysis were observed. In this cow, a Ca content of 2.93 mmol / l was measured in the blood 24 hours after this treatment.
    Table 3 shows the kinetics of the bolus. The weight of the bolus is shown here as a function of the number of days that the bolus is present in the rumen. Figure 1 shows graphically the development of the weight of the bolus (m) expressed in grams as a function of the number of days (N) that the bolus was present in the rumen.
    Bolus kinetics and disintegration in the rumen:
    Table 3

    From these experiments it is clearly demonstrable that the bolus according to the present invention increases the calcium concentration in the blood, whereby the frequency of the occurrence of hypocalcemia will be reduced.
    权利要求:
    Claims (15)
    [1]
    Use of leaves from plants containing 1,25-dihydroxyvitamin D3 glycoside for the preparation of a single peroral administration composition in the form of a tablet or a bolus to prevent a symptom selected from a reduced appetite, paralysis or a combination of both in an animal after birth or calving, said composition comprising: - a substance or material that is slowly dissolved or physically eroded in the stomach, in which substance or material the leaves are encapsulated, causing a delayed release of 1.25- dihydroxyvitamin D3 glycoside is effected wherein the substance or material is selected from the group consisting of a fat or a derivative thereof, a protein, a polysaccharide, a cellulose, a gum, a glycol and derivatives of these compounds which are useful for the delayed releasing the 1,25-dihydroxyvitamin D3 glycoside, and - one or more metals or metal compounds such that the composition is a s body weight, which causes it to sink to the bottom of the stomach after it has been absorbed in the stomach and to remain present there.
    [2]
    Use according to claim 1 wherein the leaves are from Solanum glaucophyllum.
    [3]
    Use according to claim 1 or 2, wherein the composition has a specific weight of at least 1.5 kg / l.
    [4]
    Use according to any of claims 1 to 3, wherein in the single administration composition at least an amount of leaves containing 0.460 mg of 1,25-dihydroxyvitamin D3 glycoside is administered to the animal as a single dose.
    [5]
    Use according to claim 4, wherein the amount of leaves contains 0.550 mg of 1,25-dihydroxyvitamin D3 glycoside.
    [6]
    The use according to any of claims 1 to 4, wherein the composition contains an at least partially cured or hydrogenated castor oil.
    [7]
    Use according to any of claims 1 to 6, wherein the composition is intended for administration at least 1 day prior to calving, preferably 1 or 2 days prior to calving.
    [8]
    Use according to any one of claims 1 to 7, wherein the composition further comprises one or more components selected from the group of vitamins A, B12, C, E, K, niacin, thiamin, choline, biotin, folic acid, ribovlavin, pantothenic acid, one or more minerals, selected from the group of cobalt, copper, manganese, selenium, zinc.
    [9]
    9. A composition for preventing a symptom selected from loss of appetite or paralysis, or a combination thereof associated with childbirth or calving in an animal which, in a form suitable for peroral administration in the form of a tablet or bolus, contains leaves of plants with contains at least 0.460 mg of 1,25-dihydroxyvitamin D3 glycoside in those leaves, as well as a substance or material that is slowly dissolved or physically eroded in the stomach, in which substance or material the leaves are encapsulated, the substance or material being chosen from the group of a fat or a derivative thereof, a protein, a polysaccharide, a cellulose, a gum, a glycol and derivatives of these compounds which are useful for the delayed release of the 1,25-dihydroxyvitamin D3 glycoside, and thereby one or more metals or metal compounds such that the composition acquires a specific weight which causes it to reach the bottom of the stomach after uptake into the stomach and remains there.
    [10]
    The composition of claim 9 wherein the leaves contain at least 0.550 mg of 1,25-dihydroxyvitamin D3 glycoside.
    [11]
    The composition of claim 9 or 10, wherein a fat derivative is selected and wherein the fat derivative is an at least partially cured or hydrogenated castor oil.
    [12]
    The composition of any one of claims 9 to 11, wherein the composition is contained in a package that is porous.
    [13]
    The composition of any one of claims 9 to 12, wherein the composition is in the form of a bolus.
    [14]
    A composition according to any one of claims 9-13, wherein the composition further comprises at least one vitamin or mineral.
    [15]
    15. Use to prevent a symptom selected from a reduced appetite, paralysis or a combination of both in a post-delivery animal, of a single peroral administration composition in the form of a tablet or bolus, containing the composition - leaves from plants containing 1,25-dihydroxyvitamin D3 glycoside, - a substance or material that is slowly dissolved or physically eroded in the stomach causing a delayed release of 1,25-dihydroxyvitamin D3 glycoside, into which substance or material the leaves are encapsulated, wherein the substance or material is selected from the group consisting of a fat or a derivative thereof, a protein, a polysaccharide, a cellulose, a gum, a glycol and derivatives of these compounds which are useful for delayed release of the 1.25 -dihydroxyvitamin D3 glycoside, and - one or more metals or metal compounds such that the composition acquires a specific gravity after uptake or administration in the stomach, sinks to the bottom of the stomach and remains there.
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    同族专利:
    公开号 | 公开日
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    EP0482947A1|1990-10-25|1992-04-29|Castex Products Limited|Pellet comprising a magnesium manganese alloy|
    US5869083A|1995-02-01|1999-02-09|Porter; William Leslie|Bolus for supplying biologically beneficial substances to ruminant animals|
    WO2009129818A1|2008-04-21|2009-10-29|Herbonis Ag|Preparation and use of a plant extract from solanum glaucophyllum with an enriched content of 1,25-dihydroxyvitamin d3 glycosides and quercetin glycosides|
    WO2010143101A1|2009-06-10|2010-12-16|Emma®Nutrition|Use of 1,25-dihydroxyvitamine d3 glycoside in lactating animals.|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    BE200900354|2009-06-10|
    BE200900354|2009-06-10|
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