The present invention relates to a method and an apparatus for forming composite pellets containing active ingredients of the pharmaceutical type and/or nutritional complements or cosmetics, encapsulated in encapsulating material so as to control the release of the active ingredient in the treatment of humans or animals. The invention also relates to the composite pellets containing said active ingredients.
The practice of encapsulating pharmaceutical and/or nutritional complements in encapsulating materials (generally, but not exclusively, with low melting point), to make composite pellets to be administered, generally orally but also by other means, in therapeutic treatments or to supplement the diet of animals or humans is a well known practice. The encapsulating materials are substantially designed to control the release of the active ingredient (i.e. slowing or accelerating the release of the active ingredient in the best way and where it is truly useful), as well as to reduce the risk, whilst handling, transporting and administering the composite pellets, of polluting the environment with the active ingredient, which is released in the form of a powder and which may mix with other substances. In addition, an encapsulating material may also modify the taste of an active ingredient, to make it more acceptable when taken orally.
Normally, to slow down the releasing action, the encapsulating materials usually used are lipophilic materials which are solid at ambient temperature and have a low melting point. They include beeswax, carnauba wax or other types of wax, stearic acid, monoglycerides, diglycerides, triglycerides or other substances which are not digestible in the stomach but can be chemically attacked only by biliary and pancreatic fluids in the intestine.
Thanks to this property, the pellets containing a pharmacological and/or nutritionally complementing active ingredient are gastro-resistant and the release of the active ingredient may be delayed (an interval as long as two hours may elapse from the time of ingestion to the time the pellets reach the intestine) and/or prolonged (the intestinal fluid requires a certain amount of time in order to chemically attack and disintegrate the encapsulating material, and to reach all of the active ingredient content).
Many situations are known in which the release of the active ingredient must be delayed and prolonged in order to treat diseases in humans or to provide an effective complement to human nutrition.
In the field of animal treatment, the slowed release of the active ingredient may be used to complement with vitamins the nutrition of ruminants such as cattle. In this case, the vitamins must not be made available during the first digestive cycle, when they would be absorbed only by the bacterial flora needed by the animal to digest grass and would not be of any use to the animal itself.
To achieve less pronounced slow-downs, digestible non gastro-resistant materials may be used.
Conversely, to accelerate the release of active ingredients, the encapsulating materials used are usually water-soluble substances such as polymers which may also have low melting points (for example, polyethylene glycols or polyvinylpyrrolidone), and sugars, preferably also with a low melting point (for example, xylitol).
In the context of the present invention, the active ingredient may not only be a pharmaceutical and/or a nutritional complement, but also a cosmetic.
Within the specific field of current pharmaceutical technology, a method known as xe2x80x9cspray-congealing methodxe2x80x9d is used to make composite pellets to be taken orally by humans or animals and consisting of pharmaceuticals and/or nutritional complements as active ingredients encapsulated in a low-melting material which controls the release of the active ingredient. In this method, the low melting temperature material is melted in a tank and maintained in the liquid state while it is uniformly mixed with one or more active ingredients (by means of a stirrer). If the active ingredient is soluble in the low melting temperature material, a solution is obtained, otherwise a suspension is obtained. The liquid mixture thereby obtained is sent to an atomizer or nebulizer and is then sprayed into a chamber that is maintained at ambient temperature or cooled. As they fall inside the cooled chamber, the droplets of melted mixture solidify and collect on the bottom of the chamber in the form of composite pellets.
The liquid atomizers or nebulizers may be of many different types, operating by centrifugal force (i.e. with rotating disks on which the melted mixture is made to fall), by compressed air, by high injection pressure of the melted mixture without using air, or by nebulizing fluid (air, inert gas or liquid).
The droplets of liquid mixture in the chamber may be cooled by maintaining the chamber at least at ambient temperature through cooling coils or by contacting the droplets with jets of cold inert gas (for example, a liquid nitrogen spray).
The method described above has several drawbacks.
In particular, the production of a large batch of pellets requires melting a large quantity of low melting point material and to do so requires a system of considerable size and a long time. Moreover, once the material is melted, the active ingredient must be mixed with it uniformly and in the proper proportions. To avoid variations in the concentration of the active ingredient in the pellets in the same batch, due to inconsistent distribution of the active ingredient (because of poor mixing or the re-depositing of the suspended particles of a non soluble active ingredient), this operation also takes a very long time and requires complex stirring mechanisms.
The mixture must be maintained in the melted state and under conditions of maximum homogeneity until the end of the step of spraying it into the cold chamber. This, too, requires a certain amount of time.
Thus, the mixed active ingredients remain in conditions of relatively high temperature (corresponding to the melting point of the encapsulating material) for a considerable length of time. Considering that low melting point materials generally melt at temperatures over 50xc2x0 C. and that many of them do not melt at temperatures below 80xc2x0 C., the active ingredients may degrade over time, leading to unacceptable variations in the quality of the pellets in a same batch. Many active ingredients are heat sensitive and, if heated for many hours, react and degrade at a rate that increases with increasing temperature (reaction speed approximately doubles for every 10xc2x0 C. of temperature increase).
Therefore, it is virtually impossible to use bioactive ingredients such as yeasts, cells, enzymes, proteins, which are becoming increasingly common both in pharmaceuticals and in nutritional complements for humans as well as animals.
Further, the spray-congealing method also makes it impossible to use encapsulating materials whose melting points are not low, as these require even higher temperatures and, potentially, even longer processing times before they are sprayed than materials with low melting points.
The percentage weight of active ingredient that can be encapsulated in the pellets is generally very low (usually around 30%). Higher percentages of active ingredient (even if mixed in a material with low melting point in the liquid state) would give rise to a material in paste or xe2x80x9csludgexe2x80x9d form. Even in the best of cases, this material could not be suitably atomized and the result would be poor quality pellets with irregular shape and size and with non-uniform composition and with certain amounts of active ingredient being deposited and consequently lost. In the worst of cases, the liquid atomizer or nebulizer would also be obstructed or clogged up.
The jet of droplets of melted material obtained by the atomizers and nebulizers is substantially proportional in length to its flow rate. Given the high speed at which the liquids are emitted by a nebulizer, to obtain high pellet production rates (in the order of a few kilograms per minute) without running the risk that the pellets reach the collection point still in the melted or semi-liquid state, adhering to the sides of the chamber, the chamber must be of considerable size, often with a large, tower-like structure.
High productivity installations, therefore, are bulky and hence can also be extremely costly, if constructed to meet the requirements necessary to comply with the quality standards for the production of drugs or diet supplements for human consumption (for instance, the use of controlled or inert atmospheres, tightness against external pollutants, protection of the environment from toxic spills, the use of stainless or special steel structures, etc.).
For this reason, the spray-congealing method is generally limited to products for animal use (in which the required quality standards described above are less strict), to research laboratories and to small-scale production of drugs and/or nutritional complements also for human consumption where the selling price of the product is so high as to make the use of very expensive equipment economically feasible.
Document U.S. Pat. No. 4,212,837 discloses a method for forming spherical particles of thermoplastic materials where a stream of gas with particles of thermoplastic material dispersed therein is blown from a peripheral region into a jet of hot pressurized gas to form the thermoplastic spherical particles. The document also describes an apparatus which implements the method. The apparatus includes means for discharging a jet of pressurized hot gas from an outlet port and means for ejecting a stream of gas having thermoplastic particles dispersed in it from at least one opening towards the jet of pressurized hot gas. This method is used to make non-composite spherical particles or pellets made from a single thermoplastic material. If applied to the field of the present invention, it presents several drawbacks, as found by the applicant in a number of experiments it has conducted. In particular, the particles ejected against the jet of hot gas tend to be dispersed in all directions by the jet of hot gas, with the consequent risk of prolonged contact of the particles with the heated surfaces of the apparatus. This means that oversize apparatus is required to avoid this problem. Moreover, since heat transfer efficiency is low, the heating time and/or the temperature of the hot gas must be increased. Doing this, however, creates the problem of degrading the active principle.
The aim of the present invention is to overcome the aforesaid drawbacks by providing a highly efficient method for forming composite pellets containing active ingredients encapsulated in encapsulating material so as to control the release of the active ingredients, the method reducing to a minimum the exposure of the active ingredients to high temperature and permitting the use of encapsulating materials whose melting points are not low of active ingredients that are heat sensitive.
Another aim of the present invention is to provide a method for forming composite pellets containing active ingredients encapsulated in encapsulating material so as to control the release of the active ingredient, the method allowing the production of pellets where the percentage weight of the active ingredient is preponderant.
Another aim of the present invention is to provide a method for forming composite pellets containing active ingredients encapsulated in encapsulating material so as to control the release of the active ingredient, the method allowing high productivity and uniformity within the batches of pellets made.
A further aim of the present invention is to provide a method for forming composite pellets containing active ingredients encapsulated in encapsulating material so as to control the release of the active ingredient, the method being suitable for implementation using apparatus of small size and low cost, thereby limiting the cost of the final product.
Yet another aim of the present invention is to provide an apparatus for forming composite pellets containing active ingredients encapsulated in encapsulating material so as to control the release of the active ingredient, the apparatus being suitable for implementing the method according to the invention.
Yet another aim of the present invention is to provide composite pellets containing active ingredients encapsulated in encapsulating material so as to control the release of the active ingredient, each pellet comprising a substantially uniform surface layer, composed mainly of material with a low melting point, and the active ingredient being concentrated mainly in the core of the pellet.
A further aim of the present invention is to provide composite pellets containing active ingredients encapsulated in encapsulating material so as to control the release of the active ingredient, and where the percentage weight of the active ingredient is preponderant.
These aims and others, which shall become more readily apparent in the course of the description that follows, are achieved, in accordance with the present invention, by a method and an apparatus as described in the accompanying claims for forming composite pellets containing active ingredients of the pharmaceutical type and/or nutritional complements or cosmetics, encapsulated in encapsulating material so as to control the release of the active ingredient in the treatment of humans or animals and by the composite pellets made using said method and apparatus.