KR20050105491A - Dosage form having a saccharide matrix - Google Patents

Abstract

The present invention provides a non-compressed fast-dispersing solid dosage form suitable for oromucosal administration of a pharmaceutically active substance comprising (a) a first matrix forming agent in the form of maltodextrin having a dextrose equivalent (DE) of between 1 and 20,(b) a second matrix forming agent in the form of sorbitol, and (c) the active substance.

Description

DOSAGE FORM HAVING A SACCHARIDE MATRIX

The present invention relates to non-compressed, fast dispersing solid dosage forms suitable for the administration of pharmaceutically active substances, and for the preparation of compressed rapid dispersible tablets.

Allergies are a major health problem in countries with a western lifestyle. Moreover, the prevalence of allergic diseases is increasing in these countries. Allergies are not generally considered a life-threatening illness, but asthma causes a significant number of deaths each year. An exceptional outbreak of about 30% in teenagers represents a significant loss of quality of life, working days and money, and is a good basis for classification among the major health problems in the Western world.

Allergies are a complex disease. Many factors contribute to the sensitisation event. There is still a defined sensitivity of the individual among them, as the interaction between some genes is still insufficiently understood. Another important factor is allergen exposure above the threshold. Several environmental factors can be important for sensitization, including pollution, infant infections, parasitic infections, intestinal microorganisms, and the like. Once an individual becomes sensitive and an allergic immune response occurs, the presence of only minor amounts of allergens is effectively manifested as a symptom.

The natural course of allergic disease is usually accompanied by exacerbation at both levels. Firstly, the development of the disease is accompanied by the development of the disease and the intensity of the disease, for example from hay fever to asthma. Secondly, the spread of offensive allergens often occurs with an allergic multi-reaction. Chronic inflammation leads to a general weakening of mucosal defense mechanisms leading to unspecified stimulation and eventually destruction of mucosal tissue. Infants may be primarily sensitive to foods such as, for example, milk that causes eczema or gastrointestinal disease; Most often, however, they naturally deviate from these symptoms. These infants are at risk of developing respiratory allergies later in their lives.

The most important allergen source is found among the most widespread particles of any size in the air we breathe. These sources are very common and include grass pollen and dust mite droppings, both of which are responsible for about 50% of all allergies. Among the most important factors are, for example, animal dandruff such as cat and dog dandruff, other pollen such as wormwood pollen, and very small fungi such as Alteraria. However, on a regional basis, other pollen, such as birch pollen in northern and central Europe, hives in eastern and central America, and cedal pollen in Japan, can prevail. For example, insects and foods such as bee and wasp venom each account for about 2% of all allergies.

Allergies, such as, for example, type I hypersensitivity, are caused by inappropriate immune responses to external nonpathogenic substances. Important clinical manifestations of allergies include asthma, hay fever, eczema and gastrointestinal diseases. Allergic reactions peak within 20 minutes upon contact with an immediate and offensive allergen. Moreover, allergic reactions are specific in the sense that certain individuals are sensitive to certain allergens. On the other hand, the individual does not necessarily show an allergic reaction to other substances known to cause allergic diseases. Phenotypes of allergies are characterized by the presence of allergen specific antibodies of IgE in the expressed inflammation and circulation of the mucous membranes of target organs and on the surface of mast and basophilic cells.

When an antibody binds to a high affinity IgE specific receptor on the surface of mast cells and basophils, an allergic attack is initiated by the reaction of an allergen specific IgE antibody with an external allergen. Mast cells and basophils contain preformed mediators such as, for example, histamine, tryptase, and other substances released upon cross-linking of IgE antibodies bound to two or more receptors. IgE antibodies are cross linked by simultaneous binding of one allergen molecule. Thus, it follows that foreign substances with only one epitope do not initiate an allergic reaction. Cross-linking of IgE bound to receptors on the surface of mast cells is also responsible for attracting eosinophils, allergen-specific T-cells, and other types of cells to the place of allergic reactions. Leads to the release of signaling molecules. These cells, which interact with allergens, IgE and effector cells, lead to renewed rapid symptoms that occur 12 to 24 hours after allergen contact.

Allergic disease management includes treatment, including diagnostic and prophylactic treatment. Diagnosis of allergies involves the identification of allergen specific IgE and the identification of allergen sources. In many cases, careful recall may be sufficient for the diagnosis of allergies and for the identification of unpleasant allergen source materials. Most often, however, the diagnosis is supported by objective means such as a skin prick test, blood test, or irritation test.

Treatment choices fall into three main categories. The first choice is allergen avoidance or reduction of exposure. Allergen avoidance is evident for example in the case of food allergens, while it may be difficult or expensive for house dust mite allergens, or may be impossible for pollen allergens. The second and most widely used treatment option is the prescription of medications according to conventional symptoms such as anti-histamines and steroids. Symptomatic drugs are safe and efficient; However, they do not change the original cause of the disease, and they do not control the spread of the disease. The third treatment option is a specific allergy vaccination that in many cases reduces or alleviates allergic symptoms caused by the allergen in question.

Conventional specific allergy vaccination is a common treatment for allergic diseases. It interferes with the underlying immune mechanism, causing continuous improvement of the patient's immune status. Therefore, the protective effect of certain allergy vaccinations extends beyond the treatment period as opposed to symptomatic drug treatment. Some patients undergoing the treatment are healed, and moreover, most patients experience a reduction in the intensity of the disease and the symptoms they are experiencing, or at least a deterrent to the worsening of the disease. Thus, certain allergic vaccinations have a prophylactic effect that reduces the risk of developing hay fever into asthma and reduces the risk of developing new sensitivity.

The immune mechanisms that underlie successful allergy vaccination are not known in detail. Certain immune responses, such as the production of antibodies to certain pathogens, are known as adaptive immune responses. This response is distinct from the innate immune response, which is an unspecific response to a pathogen. Allergy vaccines are certain to deal with adaptive immune responses. And it includes cells and molecules with antigen specificity, such as T-cells and B-cells that produce antibodies. B-cells cannot mature into cells that produce antibodies without help from T-cells of corresponding specificity. T-cells that participate in the promotion of allergic immune responses are mainly Th2 type. The establishment of a new balance between Th1 and Th2 cells has been stated to be beneficial and central to the immune mechanisms of certain allergic vaccinations. Whether this is caused by a decrease in Th2 cells, a change from Th2 to Th1 cells, or up-regulation of Th1 cells is controversial. Recently, regulatory T-cells have been specified as important for the mechanism of allergy vaccination. According to this model, regulatory T-cells, for example Th3 or Th1 cells, downregulate both Th1 and Th2 cells of the corresponding antigen specificity. Despite these ambiguities, the active vaccine should generally have the ability to stimulate allergen specific T-cells, preferably TH1 cells.

Certain allergy vaccinations, despite their advantages, are not widely used primarily for two reasons. One reason is the discomfort associated with traditional vaccination programs, including vaccination arterial injections repeated over several months. Another reason is more important, the risk of allergic side reactions. Conventional vaccination against infectious pathogens is performed efficiently using single or several high dose immunotherapy. However, this strategy cannot be used for allergic vaccination because a pathological immune response is already in progress.

Therefore, certain conventional allergy vaccinations are performed using a number of subcutaneous immunotherapy applied over an extended period of time. The process is divided into two phases: up dosing and maintenance. In the up dosing step, increasing the dosage is typically applied over a 16 week period, beginning with a small dosage. Once the recommended maintenance dose has been reached, this dose is typically applied for the maintenance phase, which is injected every 6 weeks. After each injection, the patient is usually extremely rarely life-threatening, but should remain under doctor's care for 30 minutes due to the risk of irritable side reactions. In addition, hospitals should be equipped to support first aid. Vaccines based on other routes of administration should not only promote wider use, but also eliminate the risk for allergic side reactions inherent in current subcutaneous basal vaccines, possibly allowing direct vaccination at home. There is no doubt that it should be reduced.

Attempts to improve vaccines against certain allergic vaccinations have been undertaken for over 30 years and include a variety of approaches. Some approaches have dealt with the allergens themselves by changing the IgE reactivity. Other approaches addressed this route of administration.

The immune system is accessible through the oral cavity and sublingual administration of allergens is a known route of administration.

Conventional allergy vaccines using the oral mucosal route consist in increasing the daily dose of allergen solution. In comparison, a given maintenance dose of treatment (accumulated) exceeded the maintenance of comparable subcutaneous administration by a factor 5-500. Obvious drawbacks of this formulation and route of administration are problems associated with precise and constant self-administration of the correct dose by the patient (multiple drops must be given the uniformity of the individual drops, the application site accuracy). In addition it is necessary to refrigerate the drug and include a preservative in the formulation.

Netien et al .: "Galenica 16-Medicaments homeopathiques" ed. 2, 1986, pp. 77-99 disclose compressed tablets of liquid solutions or conventional lactose, saccharose or mixtures thereof injected onto solid particulates (granules) for sublingual administration of medicaments such as allergens. However, these formulations are associated with serious weaknesses, such as infusion procedures.

DD-A-0 107 208 discloses a process for preparing conventional compressed tablets containing allergens. After administration, the tablet is dissolved by saliva and then allergens are absorbed through the oral mucosa. The formulations contain undesirable paraffins and fatty acids, as well as excipients that are insoluble in water, ie talcum, because they leave an unpleasant residue in the mouth of the patient. Moreover, friction during the tableting process can be detrimental to the physical stability of the allergen.

EP 278 877 discloses sublingual pharmaceutical compositions in which solid supports such as, for example, saccharose / lactose are coated with a solution of allergens. The resulting formulation is claimed to disintegrate quickly but not immediately. However, no method of achieving the object has been disclosed. Moreover, the formulation includes reducing sugar in the form of fructose, which is likely to react with allergens.

In order to ensure that as many doses of any allergen as possible are provided to the oral mucosa and to maximize the contact time with the mucosa of the further degraded product, it is very important that the formulation collapses immediately upon contact with the saliva of the oral cavity. Rapidly dispersed solid dosage forms which release the active ingredient easily in the oral cavity are known in the art.

U. S. Patent No. 4,371, 516 discloses pharmaceutical formulations containing active ingredients which disintegrate rapidly in water. The pharmaceutical formulation comprises an open matrix network of carrier materials, which disintegrates within 10 seconds.

As disclosed in WO 00/61117, freeze-dried fish gelatin based carriers are designed to release the active ingredient immediately upon contact with saliva when administered orally. Vaccines against hay fever are mentioned as active ingredients.

As disclosed in WO 00/44351, freeze-dried modified starch carriers are designed to release the active ingredient immediately upon contact with saliva when administered orally. Vaccines against hay fever are mentioned as active ingredients. The modified starch carrier may be pre-gelatinized starch with dextrin.

WO 99/21597 discloses rapidly disintegrating formulations of vaccines and adjuvants for oral use.

WO 02/13858 discloses fast dissolving pharmaceutical compositions containing vaccines in the form of "cake" which dissolve rapidly for oral use. The purpose of WO 02/13858 seems to be to provide vaccines of virus or bacteria that remain intact in the gastrointestinal tract. This is accomplished by incorporating antacids such as calcium carbonate into the cake to protect the antigen against the acidic contents of the stomach.

WO 00/51568 discloses rapidly disintegrating compacted low friability tablets designed to dissolve in the oral cavity in contact with saliva in less than 30 seconds while forming susceptible suspensions.

US-A-5,648,093 discloses non-compressed solid formulations that disperse quickly. As a specific example, a formulation consisting of maltodextrin, mannitol and xanthan gum is disclosed.

WO 91/09591 (Example 25) describes the preparation of a placebo carrier matrix by solid-state dissolution, wherein the matrix consists of maltodextrin (DE10), mannitol and xanthan gum.

US-B2-6 337 082 describes sugar-based matrices for use in food products comprising maltodextrins, gelling agents and sugars having a DE of less than 40, preferably 20-40 and optionally 10-20. Explain. The gelling agent can be, for example, xanthan gum or gelatin. Sorbitol is mentioned in a long list of suitable sugars. It is specified that the matrix can be dispersed immediately in water to form a suspension. The matrix is formed in a process involving simultaneous rapid heating and applied physical forces. The resulting matrix has the form of particles, chips, flakes or acicular bodies. The examples refer to specific compositions of maltodextrin, sorbitol, and food ingredients having a DE of 36, which are made by spinning to form a matrix of white narrow flakes.

WO 00/57856 discloses fast-dispersion formulation pharmaceuticals for dosing after contact with the oral mucosa, wherein the formulation comprises between 50% and 99% of the carrier and possibly diluents. Maltodextrins having a DE of 3-50 as carriers are mentioned in the long list of compounds. Sorbitol is referred to as a diluent in a long list of compounds.

Summary of the Invention

The present invention

Next Steps and i.a. It is related to:

Non-compressed, fast-dispersing solid dosage forms suitable for oral mucosal administration of pharmaceutically active substances

(a) a first matrix former in the form of maltodextrin having 1 to 20 dextrose equivalents (DE),

(b) a second matrix former in the form of sorbitol, and

(c) an active substance.

Formulations according to the invention comprise a substrate which forms one or more additional matrices.

Formulations according to the invention, and the substrates forming the additional matrix here, are monosaccharides, disaccharides, or trisaccharides.

The formulation according to the invention, and the substrate on which the additional matrix is formed, is mannitol.

Formulations according to the invention further comprise polyethylene glycol (PEG).

Formulations according to the invention, wherein maltodextrins, comprise 3-40% (w / w), preferably 10-35 (w / w) and more preferably 15-25% (w / w) of the administration solution. Present in quantities.

Formulations of the present invention wherein sorbitol is present in an amount of 0.01-10% (w / w), preferably 0.05-5% (w / w) and more preferably 0.1-2-2% (w / w) Exists as.

Formulations of the Invention wherein PEG is in an amount of 1-20% (w / w), preferably 2-15% (w / w) and more preferably 3-10% (w / w) of the administration solution exist.

Formulations according to the invention, wherein the active substance is an allergen.

The present invention is based on the surprising findings that it is possible to use maltodextrin as the substrate to form the base matrix in a rapidly disperse, uncompressed formulation, instead of a substrate that forms a conventional base matrix, such as gelatin and starch. Since maltodextrin is partially hydrolyzed, maltodextrin has an advantage over starch that dissolves or disperses more quickly. At the same time, non-compressed solid formulations using maltodextrin as the substrate forming the matrix are active from formulations which are not highly undesirable for some active substances such as allergens and degradation of the active substance during manufacture, filling, transportation, processing and storage. It has been surprisingly found to have sufficient mechanical strength to remain stable and unchanged to avoid release of the material.

Moreover, even at very small contents, it has been surprisingly shown that sorbitol strongly increases the mechanical strength of the formulation.

Uncompressed, fast disperse formulations designed to release the active ingredient almost immediately in contact with saliva are well suited for the delivery of allergens to the oral mucosa. However, a priori use of this particular formulation for allergens is associated with serious problems. Solid formulations of this kind are mainly characterized by low mechanical strength compared to compressed tablets because of the inherent properties of a non-compressed matrix, which is almost wafer-like and brittle. This may cause the release of residual particles containing allergens during the handling of the formulation by the patient. Since allergens can elicit an allergic reaction or induce an allergic reaction in a susceptible person (ie, dose dependent sensitivity or allergic reaction), this is particularly detrimental when the active ingredient is an allergen. For example, the maximum allowable levels for environmental pollution in the form of allergens in dust are specified according to the allergen in question as low as 2 micrograms of major allergen per gram of house dust (allergy, principles and Actual (1993, 4th edition), Mosby-Year book, Vol. I page 520.

Non-compressed, fast dispersing solid dosage forms can be prepared in situ, which are prepared by removing liquid from a solidified system comprising a substrate, the active ingredient and other suitable excipients forming the matrix.

Due to the removal of the solvent from the solidified system of the active ingredient and the matrix forming excipient in the in situ manufacturing process, ie in the final container, for example a blister pack, the formulation is sealed and thus coated to prevent the release of residues from the formulation. It is impossible to do. Moreover, coating the formulation is not possible because it jeopardizes the immediate release properties of the formulation.

Therefore, there is a need for fast disperse solid formulations containing allergens, which rapidly release the allergens in the oral cavity and where the formulations have mechanical firmness at the same time, ideally from the formulation to the surroundings during the handling of the formulations by the patient. There is no residue released.

There is also a need for a fast dispersing solid dosage form containing allergens to have sufficient chemical stability of the active ingredient to allow for manufacturing, shipping, storage and handling of patients in particular.

It has now been surprisingly found that the preparation of low crushed, non-compressed, fast disperse solid formulations containing allergens is indeed possible, which is sufficiently robust and does not release harmful amounts of residue after handling by the patient. Moreover, it has been surprisingly found that such formulations are really stable at room temperature. These findings are of great importance for the handling procedures of the final product. In manufacturing plants, during storage or in storage at pharmacies, cold storage is often associated with high unit costs, since the refrigeration plant must be closely monitored and investment in reliable refrigeration plants is very expensive. Moreover, in view of patient compliance, it is desirable to allow the formulation to be stored at room temperature. The European pharmacopeia monograph for allergen products specifies that the moisture level should not exceed 5% for freeze-dried products (eg allergen extracts in vials). It has surprisingly been found that even formulations according to the invention having a moisture content above the required maximum level of 5% are stable at room temperature. Without being bound by theory, it can be explained by the fact that excipients in rapid dispersion solid dosage forms bind to the residual water in the formulation and reduce the water activity of the allergen vaccine formulation. Thus, by reducing the water activity of the preparation, it is possible to obtain a stable preparation without degradation of the allergen, even if the water content defined for the allergen extract in the vial is higher than the maximum level of 5%.

The stability of the solid dosage form to ensure sufficient shelf life of the final product can be measured in terms of the physical and chemical properties or individual components of the solid dosage form.

Water activity is one important factor that contributes to the shelf life of a product. It is well known that the water activity of a product affects the growth of bacteria as well as the stability, efficacy and consistency of the drug. Protein stability is also significantly affected by water activity because of its relatively fragile nature. Most proteins must remain in shape to remain active. Maintaining low water activity levels helps prevent or encourage changes in form, and it is of great importance to ensure that proteins are stable in the form of allergens. In addition, the hydrolysis of proteins caused by enzymes or not is affected by water activity.

Moisture activity measurements are performed using methods known to those skilled in the art, such as, for example, cooling mirror dew point method, relative humidity with sensors that change electrical resistance or capacitance, or by using lithium chloride electrodes.

The water activity of the preferred solid formulations does not exceed 25% and is preferably 0.1% to 20%, more preferably 0.5 to 15%, more preferably 2 to 8% and most preferably 4 to 7%.

The water content of the solid dosage forms measured according to the method described in Example 1 preferably does not exceed 25%, preferably 0.1% to 20%, more preferably 0.5 to 15%, more preferably 2 to 8%, most preferably 4-7%.

Several laboratory tests may be used to characterize allergens. The most widely used techniques are sodium dodecyl polyacrylamide gel electrophoresis (SDS-PAGE), isoeletric focusing (IEF), cross-linked immunoelectrophoresis (CIE) and Rocket Immuno Electrophoresis (RIE). Quantification of individual allergens can be performed by various quantitative immunoelectrophoretic (QIE), Radial Immune Diffusion (RIE) or immunosorbent assays (ELISA) linked to enzymes. have. Determination of the total efficacy of allergens is most often performed by radio allergosorbent test (RAST), (LIA) or related techniques. ELISA-based techniques can also be used.

Guidance on acceptable limits generally applied to tests that measure bioefficiency can be found in, for example, Note for Guidance on Allergen Product; Meicinal product CPMP_BWP_243_96 is found in European institutions for evaluation.

For the purposes of the present invention, the stability of the active ingredient, for example allergens, is assessed by measures of efficacy of the allergen, such as total allergen activity and the main allergen content.

"Initial allergen activity" or "initial content of at least one major allergen" of a solid formulation means the value after completion of the preparation of the solid formulation.

The loss of total allergen activity according to the method described in Example 1 is preferably less than 50% of the total initial activity, more preferably less than 30% of the total initial activity, even more preferably less than 20% of the total initial activity. Most preferably less than 15% of the total initial activity.

The classification of allergens as major allergens may require some testing. If at least 25% of patients show strong IgE binding (3 points), and 50% of patients show at least moderate binding (2 points), allergens are generally classified as major allergens and the binding is CRIE (CRIE strong binding). I.e., IgE-binding, CRIE moderate binding, ie binding after 3 days, CRIE weak binding, ie binding after 10 days) seen on the x-ray film after one day). Strong IgE binding from at least 10% of patients classifies allergens as intermediate allergens and apparently specific binding from less than 10% of patients is classified as minor allergens. Other methods can also be used, for example, to measure IgE binding of IgE-blots.

The loss of the allergen content of at least one major allergen according to the method described in Example 1 is preferably less than 50% of the total initial content, more preferably less than 30% of the total initial content, even more preferably the total initial Less than 20% of the content, most preferably less than 15% of the initial content.

In one embodiment of the solid allergen formulation the loss of total allergen activity according to the method described in Example 1 is less than 50% of the total initial activity.

In another embodiment of the solid allergen formulation the loss allergen content of the at least one major allergen according to the method described in Example 1 is less than 50% of the initial content.

The formulations of the present invention are preferably stable in that they do not change significantly after preparation in terms of physical and chemical properties such as, for example, the efficacy of the allergen, the mechanical robustness and the properties of the sensory organs to ensure a sufficient shelf life of the final product. .

Therefore, the stability of solid formulations is preferably controlled by additional parameters such as fracture properties, tensile strength, mechanical robustness such as maximum load to fracture, stability of physical properties, ie sensory properties such as dispersion time and visible appearance of the formulation. Is evaluated.

These can be evaluated, for example, by measuring the maximum load for fracture of the present invention or by the tensile strength of the solid formulation. As is apparent from the equation in which the tensile strength can be calculated, the tensile strength value is obtained depending on many parameters. And it is susceptible to changes such as, for example, the thickness or diameter of the solid dosage form and will contribute to the change of the measured values. It is therefore believed that the maximum load on fracture is a much more accurate parameter for the evaluation of the robustness of the solid dosage unit of the present invention.

Solid formulations need to have a constant resistance to external forces to ensure that they are sufficiently robust during storage and when handled by a patient, while at the same time solid formulations must disintegrate rapidly in the oral cavity.

In another embodiment of the invention the solid dosage form is preferably 1.1 N / mm ² Has a tensile strength of less than 0.8 N / mm ² . Typically, formulations have a tensile strength of 0.2-0.5 N / mm ² . The lower the tensile strength, the lower the mechanical strength and the stability of the formulation, which disperses faster.

Preferably, the fast dispersing formulations disintegrate immediately or rapidly in contact with saliva to ensure maximum exposure of allergens to immunized tissues of the mucosa before swallowing. In a preferred embodiment the solid dosage form is less than about 90 seconds, preferably less than 60 seconds, preferably less than 30 seconds, more preferably less than 20 seconds, more preferably less than 15 seconds, even more preferred The following disintegrates intraorally in less than 10 seconds, even more preferably less than 5 seconds, most preferably less than 2 seconds.

In a preferred embodiment of the invention, the composition of the invention is a fast dispersible solid formulation comprising a solid network of allergens and any water soluble or insoluble matrix. The network is obtained by sublimating the solvent from the composition in the solid state, the composition comprising a solution of allergens and the matrix. More preferably the network is obtained by freeze drying.

Excipient

In a preferred embodiment of the invention, the formulation further comprises one or more excipients in addition to the matrix forming agent.

Pharmaceutically acceptable excipients which form part of the matrix in the fast-dispersing solid dosage forms according to the invention are adjuvants, antacids, diluents, enhancers, tacky agents, flavors, taste masking agents, preservatives, antioxidants, surfactants, viscous enhancers , Excipients, pH modifiers, sweeteners and the like. Such excipients are all selected according to conventional pharmaceutical practice in a manner understood by those skilled in the art of formulating allergen vaccines.

In a preferred embodiment of the invention, the formulation contains a protein stabilizer. Examples of protein stabilizers are eg PEG300. PEG400. PEG600. PEG1000. PEG1500. PEG3000. Polyethylene glycol (PEG) such as PEG3050, PEG4000, PEG6000, PEG20000 and PEG35000; Amino acids such as glycine, alanine, arginine; Monosaccharides, disaccharides, and trisaccharides such as trihalose and sucrose; Polyvinyl alcohol (PVA); Polyoxyethylene sorbitan fatty acid esters (polysorbates, tweens or spans); Human serum albumin (HSA); Bovine serum albumin (BSA). Preferably, PEG is used as protein stabilizer. In addition to being protein stabilizers, it is believed that PEG imparts elastic properties to the matrix of the formulation.

Suitable colorants include red, black, and yellow iron oxides and FD & C dyes such as FD & C Blue 2 and FD & C Red 40. Suitable spices include peppermint, raspberry, licorice, orange, lemon, grapefruit, caramel, vanilla, cherry and grape flavors, and combinations thereof. Suitable pH modifiers include citric acid, tartaric acid, phosphoric acid, hydrochloric acid and maleic acid. Suitable sweeteners include aspartame, acesulfame K and taumatic. Suitable taste masking agents include sodium bicarbonate, ion-exchange resins, cyclodextrin containing compounds, adsorbates or microencapsulated actives.

Supplements are generally used to enhance the uptake of allergens as well as to improve the immune-stimulatory properties of the allergens.

In one embodiment of the invention at least one adjuvant is embodied in the formulation according to the invention. Examples of suitable adjuvants include aluminum salts, fragments of non-toxic bacteria, cytokines, chlorea toxins (and their detoxified fragments), chitosan, homostable E. coli (and detoxified) Fragments), bacterial products such as saponins, lipopolysaccharides (LPS), and muramyl dipeptide (MDR), liposomes, CpG (immunogenic DNA sequences), lactide / glycolide homo (Copolymer in the form of a microparticular polymer or the like). The use of supplements in allergen vaccines is often convinced by the fact that the allergen in question cannot penetrate the barrier through which it will pass. The adjuvant may therefore act as an absorption enhancer or they may act as immunostimulators. However, the use of adjuvant may be associated with significant weaknesses such as immune response, systemic lupus erythematosus or mucosal barrier ability and thus unintended stimulation of various mechanisms of allowing the passage of harmful substances. Further from the industrial point of view, the addition of supplements further constitutes additional production and material costs in addition to the great demand for documentation of drug registration.

In another preferred embodiment of the invention the rapid dispersion solid dosage forms according to the invention do not comprise adjuvant.

It has also surprisingly been found that solid formulations, for example, do not require incorporation of adjuvant into rapid disperse solid formulations to enhance the immune stimulating properties of the allergens in question which may cause specific immune responses.

Non-compressed, fast dispersing solid dosage forms according to the invention may be mucoadhesive to some extent on their own, but in one preferred embodiment of the invention, to increase the contact time of the formulation with the mucous membranes of the oral cavity. It may be necessary to add mucoadhesive excipients to the formulation. Suitable mucoadhesive excipients include polyacrylic polymers such as carbomers and carbomer derivatives; Cellulose derivatives such as hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and sodium carboxymethylcellulose; Natural polymers such as gelatin, sodium alginate, pectin and glycerol.

Substrate Forming Matrix

In a preferred embodiment of the invention, maltodextrins have a DE between 1 and 15, more preferably between 1 and 10.

In a preferred embodiment of the invention the agents forming another matrix are monosaccharides, disaccharides, trisaccharides. Examples of monosaccharides, disaccharides, and trisaccharides include mannose, glucose, galactose, mannitol, mannose, galactitol, erythritol, inositol, threitol, trehalo Trehalose, sucrose, maltose, maltrotriose, lactose, palatinose and lactulose.

In a preferred embodiment of the formulation of the invention, the additional matrix forming substrate is mannitol.

Other matrix forming substrates for use in accordance with the invention include animal or plant proteins such as gelatin, soybeans, wheat and psyllium seed proteins; Gums such as acacia, guar and pellets; Polysaccharides such as starch and modified starch; Cyclic sugars such as cyclodextrins; Algiates; Carboxymethylcellulose; Carrageenans; And substances derived from polysaccharide complexes such as polypeptides / proteins or gelatin-acacia complexes.

Other matrix forming substrates for use according to the invention include inorganic salts such as sodium phosphate, sodium chloride and aluminum silicate; And amino acids having 2-12 carbon atoms such as glycine, L-alanine, L-aspartic acid, L-glutamic acid, L-hydroxyproline, L-isoleucine and L-phenylalanine.

As mentioned above, the present invention offers the possibility of preparing a quick dispersion uncompressed formulation using maltodextrin as the primary matrix forming substrate and sorbitol as the secondary matrix forming substrate.

Moreover, the present invention offers the possibility of preparing a rapidly disperse uncompressed formulation in a matrix consisting of maltodextrin, sorbitol and monosaccharides, disaccharides and trisaccharides. Therefore, in another preferred embodiment of the invention, the matrix is free of matrix forming agents other than maltodextrin, sorbitol and monosaccharides, disaccharides and trisaccharides. In particular, the matrix is preferably free of polymeric matrix formers and more specifically the matrix is preferably free of gelatin and / or starch and / or gums.

The total dry matter content of the dosage solution is preferably greater than 20% (w / w), more preferably greater than 30% (w / w), more preferably greater than 40% (w / w), more preferably Greater than 50% (w / w) and most preferably greater than 60% (w / w). The total dry matter content of the dosage solution will depend on the dimensions of the tablet to be produced.

Pharmaceutically active substances

The pharmaceutically active substance used in the formulation of the present invention may be any active substance that can be administered via the oral mucosal route. Oral mucosal administration is difficult to administer via the intestinal mucosa when rapid administration is desired and / or due to, for example, difficulties in transporting the active substance across the mucosa and / or degradation of the active substance through the gastrointestinal system. It is appropriate in place.

Examples of suitable active materials include, but are not limited to:

Analgesics and anti-inflammatory agents: aloxiprin, auranov, azapropazone, benorylate, diflunisal, etodolac, fenbufen, Fenoprofen calcim, flurbiprofen, ibuprofen, indomethacin, ketoprofen, meclofenamic acid, mefenamic acid (mefenamic acid), nabumetone, naproxen, naproxen, oxaprozin, oxyphenbutazone, phenylbutazone, pyroxicam, sulindac .

Insecticides: albendazole, bephenium hydroxynaphthoate, cambendazole, dichlorophen, ivermectin, mebendazole, jade Oxamniquine, oxfendazole, oxantelembonate, praziquantel, pyrantel embonate, thiabendazole.

Anti-arrhythmic agents: amiodarone HCl, disopyramide, flecainide acetate, quinidine sulphate.

Anti-bacterial agents: benethamine penicillin, cinoxacin, ciprofloxacin hydrochloric acid (ciprofloxacin HCl), clarithromycin, clofazimine, cloxazilin, dimeclocycline (demeclocycline), doxycycline, erythromycin, ethionamide, ethionamide, imipenem, nalidixic acid, nitrofurantoin, ripampicin, ripampicin, spiramycin spiramycin, sulphabenzamide, sulphadoxine, sulphamerazine, sulphacetamide, sulphacetamide, sulphadiazine, sulphafurazole, sulphamethoxazole , Sulfapyridine, tetratracycline, trimethoprim.

Anticoagulants: dicoumarol, dipyridamole, nicoumalone, phenindione.

Antidepressants: amoxapine, cyclazindol, maprotiline hydrochloric acid (maprotiline HCl), mianserin hydrochloric acid (mianserin HCl), nortriptyline hydrochloric acid (nortriptyline HCl), trazodone HCl, trizo Trimipramine maleate.

Antidiabetics: acetohexamide, chlorpropamide, glibenclamide, glibenzamide, gliclazide, glipizide, tolazamide, tolbutamide .

Antiepileptics: beclamide, carbamazepine, clonazepam, ethotoin, metoin, mesuximide, methylphenobarbitone methylphenobarbitone, oxcarbazepine, paramethadione, phenacemide, phenobarbitone, phenobarbitone, phenytoin, phensuximide, primidone, sulciamine sulthiame, valproic acid.

Antibacterial agents: amphotericin, buttoconazole nitrate, clotrimazole, econazole nitrate, fluconazole, flucitosine, and gliofulvin griseofulvin, itraconazole, ketoconazole, ketoconazole, miconazole, natamycin, nystatin, sulconazole nitrate, terbinafine HCl, Terconazole, thioconazole, and undecenoic acid.

Antigout agents: allopurinol, probenecid, sulfinpyrazone.

Antihypertensives: amlodipine, benidipine, darodipine, dilitazem HC1, diazoxide, felodipine, guanabenz acetate acetate, indoramin, isradipine, minoxidil, minoxidil, nicardipine HC1, nifedipine, nimodipine, phenoxybenzamine H1 phenoxybenzamine HC1), prazosin hydrochloric acid (prazosin HCL), reserpine, terazosin HC1.

Antimalarial agents: amodiaquine, chloroquine, chlorproguanil HC1, halophantrin HC1, mefloquine HC1, proguanil H1 proguanil HC1), pyrimethamine, quinine sulphate.

Antimigraine Controls: dihydroergotamine mesylate, ergotamine tartrate, methisulzide maleate, pizotifen maleate, sumatriptan succinate succinate).

Anti-muscarinic agents: atropine, benzexol HC1, biperiden, ethopropazine HCl, hyoscine butyl bromide , Hyoscyamine, mefenzolate bromide, orphenadrine, oxyphencylcimine HCl, tropicamide.

Antitumor and immunosuppressive agents: aminoglutethimide, amsacrine, azathioprine, busulphan, chlorambucil, cyclosporin, dacarbazine ), Estramustine, etoposide, lomustine, melphalan, mercaptopurine, methotrexate, mitomycin, mitotan , Mitoxantrone, procarbazine HC1, tamoxifen citrate, testolactone.

Antiprotozoal: benznidazole, clioquinol, decoquinate, diodohydroxyquinoline, diloxanide furoate, dinitolmide, pearl Furzolidone, metronidazole, nimorazole, nitrofurazone, olidazole, tinidazole.

Antithyroid agents: carbimazole, propylthiouracil.

Anti-anxiety, sedative, sleeping and neurosuppressive agents: alprazolam, amylobarbitone, barbitone, betazepam, bromazepam, bromperidol, Brotizolam, buttobarbitone, carbromal, chlordiazepoxide, chlormethiazole, chlorpromazine, chlorpromazine, clobazam, clo Tiazepam, clozapine, diazepam, droperidol, ethinamate, flunanisone, flunitrazepam, fluopromazine , Flupenthixol, decanoate, fluphenazine decanoate, flurazepam, haloperidol, lorazepam, lormetazepam , Medazepam, meprobamay (meprobamate), metaqualone, midazolam, nitrazepam, oxazepam, pentobarbitone, perphenazine pimozide, prochlor Ferrazine (prochlorperazine), sulpiride, temazepam, thioridazine, triazolam, zopiclone.

β-blockers: acebutolol, alprenolol, atenolol, atenolol, labetalol, metoprolol, nadolol, oxprenolol, pindolol pindolol), propranolol.

Cardiac muscle contractors: amrinone, digitoxin, digoxin, inoximone, lantoside C, medigoxin.

Corticosteroids: beclomethasone, betamethasone, budesonide, cortisone acetate, desoxymethasone, dexamethasone, dexamethasone and fludrocortisone (fludrocortisone acetate), flunisolide, flucortolone, fluticasone propionate, hydrocortisone, methylprednisolone, prednisolone, prednisone prednisone ), Triamcinolone.

Diuretics: acetazolamide, amiloride, bendlofluazide, bumetanide, chlorothiazide, chlorthalidone, etathalicone Seeds (ethacrynic acid), prusemide, metolazone, spironolactone, triamterene.

Enzyme: Anti-Parkinson's disease: bromocriptine mesylate, lysuride maleate.

Gastrointestinal: Bisaccodyl, cimetidine, cisapride, diphenoxylate HCl, domperidone, famotidine, loperamide, mesalazine (mesalazine), nizatidine, omeprazole, ondansetron hydrochloride (ondansetron HCL), ranitidine hydrochloride (ranitidine HCL), sulfasalazine.

Histamine H, receptor antagonists: arivastine, astemizole, cinnarizine, cyclizine, cyproheptadine HCl, dimenhydrinate, Flunarizine hydrochloride (flunarizine HCl), meclozine hydrochloride (meclozine HCl), oxatomide, terfenadine, triprolidine.

Lipid modulators: bezafibrate, clofibrate, fenofibrate, gemfibrozil, probucol.

Local Anesthetics:

Neuromuscular agent: pyridostigmine.

Nitrate and other antianginal agents: amyl nitrate, glyceryl trinitrate, isosorbide dinitrate, isosorbide mononitrate, pentaerythritol Tetranitrate (pentaerythritol tetranitrate).

Nutritional Supplements: Betacarotene, Vitamin A, Vitamin B2, Vitamin D, Vitamin E, Vitamin K.

Opioid analgesics: codeine, dextropropyoxyphene, diamorphine, dihydrocodeine, meptazinol, methadone, morphine, morphine, nalbuphine (nalbuphine), pentazocine.

Oral Vaccines: Vaccines designed to prevent or reduce symptoms of the following diseases, not typical but exclusive lists: influenza, tuberculosis, meningitis, hepatitis, whooping cough, polio, tetanus, diphtheria, malaria, cholera, herpes, typhoid fever, HIV, AIDS, measles, Lyme disease, traveler's diarrhea, type A, B and C infections, otitis media, dengue, rabies, parainfluenza, rubella, yellow fever, dysentery, veterans, schistosomiasis, Q-fever, hemorrhagic fever, Argentina Hemorrhagic fever, bone cancer, Chagas disease, urinary tract infections, pneumococcal disease, mumps, and Chikungunya.

Vaccines that prevent or reduce the symptoms of syndromes of the following diseases, which are not representative but exclusive lists of causative organisms:

Vibrio species, Salmonella species, Bordetella species, Haemophilus species, Toxoplasmosis gondil, Cytomegalovirus, Chlamydia species, Streptococcal Species, Norwalk virus, Escherichia coli, Helicobacter pylori, Rotavirus, Neisseria gonorrhae, Neisseria meningiditis, Adenovirus, Epstein bar virus (Epstein Barr Virus), Japanese Encephalitis Virus, Pneumosystis carini, Herpes Simplex, Clostridia spp., Respiratory Syncytial Virus, Klebsielia spp., Shigella species, Pseudomonas aeruginosa, Parvovirus, Campylobacter species, Rickettsia species, Varicella zoster, Yersinia spp., Ross River Virus, J. Seed. J. C. Virus, Rhodococcus equi, Moraxella catarrhalis, Borrelia burgdorferi and Pasteurella haemolytica.

Vaccines have been prescribed for non-infectious immunomodulatory diseases such as topical and systemic allergies such as hay fever, asthma, rheumatoid arthritis and Carcinomas.

Coccidiasis, Newcastle disease, endemic pneumonia, feline leukemia, atrophic rhinitis, alone, foot and mouth disease, swine, pneumonia, and other diseases and other infections and autoimmune diseases affecting pets or breeding animals.

Proteins, Peptides and Recombinant Drugs: Insulin (hexamolecular / dimeric / monomeric), glucagon, somatotropin, polypeptide or derivatives thereof (preferably molecular weight up to 1000-300,000), calcitonin And synthetic modifications thereof, enkephalins, interferons (especially alpha-2 interferons for the treatment of common colds), LHRH-like analogs (nafarelin, buserelin, zolidex), GHRH (hormone releasing growth hormone), secretin, bradykin antagonist, GRF (growth release factor), THF, TRH (thyroid stimulating hormone releasing hormone), ACTH analog, IGF (insulin-like growth factor) ), CGRP (calcitonin gene related peptide), atrial sodium excretion peptide, vasopressin and analogs (DDAVP, lypressin), factor VII, G-CSF (granulocyte-colonizing stimulating factor), EPO (erythropotin ( erythropoitin)).

Sex hormones: clomiphene citrate, danazol, ethinyloestradiol, methroxyprogesterone acetate, mestranol, methyltestosterone, noretheti Norethisterone, norgestrel, oestradiol, conjugated oestrogens, progesterone, stanozolol, stiboestrol, testosterone ), Tribolone.

Spermicide: nonoxynol 9.

Stimulants: amphetamine, dexamphetamine, dexfenfluramine, fenfluramine, mazindol, pemoline.

In a preferred embodiment of the invention the pharmaceutically active substance is an allergen. In the remainder of this paragraph and in most other parts of the description, the invention is described with respect to this embodiment of the invention.

According to the present invention allergen vaccines are provided in rapid disperse solid formulations which dissolve rapidly in the oral cavity upon contact with saliva, thus bringing allergens in close contact with immune-related tissues of the mucosa and allowing the allergens to handle them. In a preferred embodiment of the invention the allergens according to the invention are naturally occurring proteins reported to induce allergies, for example IgE modulates their post-exposure response to certain individuals. Examples of naturally occurring allergens include pollen allergens (trees, grasses, weeds, and grass pollen allergens), insect allergens (suction factor, saliva and poison allergens, for example mite allergens, cockroach and small beetle allergens, maximus) Venom allergens), animal hair and dandruff allergens (eg from dogs, cats, horses, rats, mice, etc.), and food allergens. Important pollen allergens from trees, grasses and grasses are the necks of the toxonomic family of Fagales, Oleales, Pinales and Platanaceae, for example, birch Tula (Betula), Alder (Alnus), Hazel (Corylus), Cypress (Carpinus) and Olive (Olea), Cedal (Cryptomeria) (Cryptomeria and Juniferus) and plataneas, including the weeping tree (Platanus), for example, the genus Lolium, Phleum, Poa, cynodon The tree of Poales, including the crests and trees of Cynodon, Dactylis, Holcus, Palaris, Secale, and Sorghum, for example Asterales and Ulticals, including the herb of the genus Ambrosia, Artemisia, and Parietaria from the neck of es). Other important inhaling allergens are storage mites such as the dermatophagoides and Euroglyphus necks, such as Lepidoglyphys, Glycyphagus and Tyrophagus. Coming out of house dust mite. For example, cockroaches such as Blatella, Periplaneta, Chironomus and Ctennocepphalides, small beetles and fleas, and mammals such as cats, dogs and horses. Stinging or biting insects, such as those from the necks of the taxa of the Hymenoptera, including honeybees (superfamily honeybees), wasps (honeyweeds), and ants (hyperaceae) These are from poison allergens, including those derived from the fields.

In a more preferred embodiment of the invention allergens are Bet v 1, Aln g 1, Cor a 1 and Car b 1, Que a 1, Cry j 1, Cry j 2, Cup a 1, Cup s 1, Jun a 1, Jun a 2, jun a 3, Ole e 1, Lig v 1, Pla l 1, Pla a 2, Amb a 1, Amb a 2, Amb t 5, Art v 1, Art v 2, Par j 1, Par j 2, Par j 3, Sal k 1, Ave e 1, Cyn d 1, Cyn d 7, Dac g 1, Fes p 1, Hol l 1, Lol p 1 and 5, Pha a 1, Pas n 1, Phl p 1, Phl p 5, Phl p 6, Poa p 1, Poa p 5, Sec c 1, Sec c 5, Sor h 1, Der f 1, Der f 2, Der p 1, Der p 2,, Der p 7 , Der m 1, Eur m 2, Gly d 1, Lep d 2, Blo t 1, Tyr p 2, Bla g 1, Bla g 2, Per a 1, Fel d 1, Can f 1, Can f 2, Bos d 2, Equ c 1, Equ c 2, Euq c 3, Mus m 1, Rat n 1, Apis m 1, Api m 2, Ves v 1, Ves v 2, Ves v 5, Dol m 1, Dil m 2 , Dol m 5, Pol a 1, Pol a 2, Pol a 5, Sol i 1, Sol i 2, Sol i 3, and Sol i 4, Alt a 1, Cla h 1, Asp f 1, Bos d 4, Supplent hybrids derived from Mal d 1, Gly m 1, Gly m 2, Gly m 3, Ara h 1, Ara h 2, Ara h 3, Ara h 4, Ara h 5 or their molecular proliferation hufflant hybrids).

In the most preferred embodiment of the present invention the allergen is grass pollen allergen or dust mite allergen or urticaria allergen or cedar pollen or cat allergen or birch allergen.

In another embodiment of the present invention, the fast dispersing solid dosage form is a grass group 1 and grass group 5 allergen or a tick group 1 and group 2 allergens derived from the same allergic source or derived from different ticks and grass species, respectively, Weed antigens such as short and large hives allergens, other fungal allergens such as alternaria and cladosporium, birch, hazel, hornbeam, oak and alder allergens It consists of at least two different types of allergens derived from the same tree allergens, food allergens such as peanuts, beans and milk allergens.

The allergens incorporated into the fast disperse solid dosage form may be in the form of extracts, purified allergens, modified allergens, recombinant allergens or mutants of recombinant allergens. Allergenic extracts naturally contain one or more isoforms of the same allergen, whereas recombinant allergens typically represent only one isoform of the allergen. In another preferred embodiment the allergen is recombinant allergen. In a more preferred embodiment the allergen is a naturally occurring low IgE-binding mutation or a recombinant low IgE-binding mutation.

The allergens may be present in equal-molar amounts or the ratio of allergens may vary preferably up to 1:20.

In another embodiment of the invention the low IgE binding allergens are allergens according to WO 99/47680, WO 02/40676 or WO 03/096869 A2.

Formulation

Formulations of the present invention are preferably produced by lyophilization.

Preferably the pH is adjusted before solidification of the matrix containing allergens and solutions to prevent degradation of allergens, precipitation and to ensure a stable product. The optimal pH for the various allergens in solution is almost over the entire pH range, such as their isoelectric point (pl). Mixtures of allergen-like extracts have equal optimum conditions for solubility and stability, determined by factors such as the concentration of the individual allergens in the extract. Therefore, individual determination of the feasible range of pH for formulation according to the invention can be envisaged. The optimal pH for the allergen in question is determined by conducting accelerated stability studies for formulations with different pH. The design of such studies is known to those skilled in the art of allergen vaccine formulation.

Preferably, the pH of the dosage solution containing the allergen extract should be adjusted to between 3.5 and 10, more preferably between 4 and 9 and most preferably between 6 and 9.

In addition, the ionic strength may be a parameter that primarily affects the stability of the freeze-dried solid formulation through the effect of the freeze-drying process. It is also known that precipitation is affected at high ionic strengths. Therefore, optimum conditions should be made by measurements well known to those skilled in the art. Preferably the ionic strength of the extract is in the range of 1 to 1500 μS / cm, more preferably in the range of 300 to 800 μS / cm, most preferably about 500 μS / cm, and for the matrix and allergen containing the system, Is preferably in the range of 1 to 2000 µS / cm, more preferably in the range of 500 to 1500 µS / cm.

Typical increasing dose desensitization, in which the dose of allergen in the form of a rapidly disperse solid dosage form, increases to a certain maximum, alleviates the symptoms of allergy. The preferred trend of unit dosage of the formulation is 150-1000000 SQ-u / formulation, the more preferred trend is 1000-250000 SQ-u / formulation, and even more preferred is 1500-125000SQ-u / formulation, the most preferred trend. Is 1500 ~ 75000SQ-u / formulation.

In another embodiment of the invention, the formulation is a repeating single-dose, preferably in the range 1500-1750SQ-u / formulation.

In a further embodiment of the invention the allergen formulation dissolved in saliva is not swallowed up to 3 minutes after administration, for example, to allow sufficient contact time for absorption across the mucosa in the mouth.

In a further preferred embodiment, the allergen formulation is not diluted in the oral cavity by inhalation of a fluid such as water until after 5 minutes.

The fast disperse solid dosage forms according to the invention can be prepared and packaged in disposable single dose blister packs as described in US 5,729,958 and US 5,343,762. Examples of suitable blister packs are All Aluminum Blister packs, eg, blister packs made of polypropylene, blister packs made of PVC, and PVC / PVdC laminates. For example, a blister pack sealed with aluminum laminated with polished kraft paper, Aclar® or Triplex®.

In one embodiment of the present invention, the rapid dispersion formulation is made and packaged in a blister pack formed of a PVC / PVdC laminate and sealed with aluminum laminated with polished kraft paper. In another embodiment, the blister pack is placed in a sachet of a suitable size, consisting of aluminum laminated with polished kraft paper.

In another embodiment, the rapid dispersion formulation is packaged in a blister pack sealed with aluminum formed of aluminum and laminated with polished kraft paper.

In a further embodiment, the rapid dispersion formulation is packaged in a multilayer blister pack sealed with aluminum, for example, formed of a five layer aluminum laminate and laminated with polished kraft paper.

In another embodiment, the rapid dispersion formulations are blisters sealed with aluminum that are made of aluminum laminate and laminated with polished kraft paper, such as, for example, child-resistant packs, to make it difficult for children to open. Are packed in packs.

Non-compressed rapid dispersing solid dosage forms are generally characterized by low mechanical strength compared to compressed tablets due to the inherent properties of such non-compressed formulations. This results in the release of allergen-containing residual particles after removal from the blister pack and during treatment of the formulation by the patient. In most situations this is absent or of primarily cosmetic importance. However, this is particularly harmful when the active substance is an allergen, since a small amount of allergen can elicit an allergic reaction in a potential person or a sensitive person. In general, exposure is in the range of 10 μg / year for major allergen proteins accumulated for pollen allergens or dust mite allergens, for example, which is sufficient to provide sensitivity or symptoms.

After dealing with the solid dosage form, the allergen can initiate contact with a target organ such as the airways or the eye and elicit a response in an allergic person. One formulation may contain as many allergens as a person is exposed for more than one year depending on the nature of the exposure. It is possible to induce eye symptoms in allergic patients using conjunctival allergen attack. Based on this attack study, one can assess how many allergen extracts are needed to induce conjunctival symptoms. In a population of patients with severe grass-pollen induced hay fever, the minimum dose of grass pollen extract that causes conjunctival symptoms has been suggested to be 3000 SQ-U / ml × 0.05ml = 150SQ-U (median) (SRDurham). , SMWalker, EMVarga, MRJacobson, F.O'Brien, W.Noble, SJTill, QAHamid, and KT Nouri-aria.Long-term clinical efficacy of grass-pollen immunotheraphy.N.Engl.J.Med 341 (7): 468-475, 1999).

Therefore, in one embodiment of the formulations of the invention, less than 500 SQ-U, more preferably less than 250 SQ-U, most preferably less than 150 SQ-U are released from each solid formulation during manual treatment.

In order to ensure that allergens containing residues from the formulation are not released to the surroundings after opening the blister pack, the crushability of the formulation is preferably as low as possible without risk of release of the allergen from the formulation after oral administration.

In a preferred embodiment of the invention after removal of the formulation the residual content of dust in the blister pack is 2% of the total allergen content, preferably 0.5% of the total allergen content of the solid formulation and more preferably the total allergen content of the solid formulation. 0.2%, most preferably 0.1% of the total allergen content of the solid dosage form.

Typically the crushing test of the compressed tablets is carried out in Pharmacopeia E.P. 2.9.7 and USP <1216>, where the loss of weight will be assessed as a parameter of the intact formulation. Therefore, the intact of the current formulation will be assessed by visual testing and measurement of tablet weight after undergoing the method. Optionally, due to the low weight of the formulations according to the invention the weighing can be replaced by the immunological test specification for this allergen.

It has been found that the use of a modified crush test is a useful tool for evaluating that the compositions are most stable with regard to firmness and mechanical strength. In one embodiment, the crushability of the solid formulation, measured by the amount of allergen released, is less than 500 SQ-U per solid formulation, more preferably solid, in any suitable crush test that exerts sufficient external force on the composition to be tested. Less than 250 SQ-U per formulation, most preferably less than 150 SQ-U per solid formulation. In a more preferred embodiment, the crushability measured by the amount of allergen released is less than 500 SQ-U per solid dosage form, more preferably less than 250 SQ-U per solid dosage form, in the crush test conducted according to Pharmacopeia. Preferably less than 150 SQ-U per solid dosage form. In a more preferred embodiment, the crushability measured by the amount of allergen released is less than 500 SQ-U per solid formulation, more preferably less than 250 SQ-U per solid formulation, most preferably in a test comprising the following steps: Less than 150 SQ-U per solid dosage form;

a) placing individual units of solid dosage form contained in a blister pack unit sealed in a device suitable for crushability measurement,

b) move it at the right speed for the right amount of time,

c) remove the sealed solid dosage unit,

d) opening the sealed solid dosage unit, emptying the unit content in the container and placing the rapid dispersion dosage unit and any residues in the container,

e) removing the solid dosage unit from the vessel, ignoring any lost residues in the vessel;

f) conducting an allergen specific assay for the residue to determine the allergen content in the residue and

g) Optionally calculate the percentage of allergen content in the residue of the total allergen content of the solid formulation unit.

 In a preferred embodiment of the crushing method the unit is rotated 100 times at 25 ± 1 rpm and the content of allergen is measured by ELISA test.

Moreover, oral formulations preferably have an attractive appearance. Therefore, as part of quality control, it is preferred that the fast disperse solid dosage forms according to the invention be visually inspected for parameters such as color, shape, irregularity, defects and the like.

To ensure optimal approval of the patient, it is desirable for the patient to recognize the formulation as comfortable when the formulation is in the mouth and dissolution is allowed.

Since allergens are highly bio-active in allergic patients, i.e. even at small doses, it is necessary to ensure that the content of allergens is constant during treatment, for example to ensure that the response pattern experienced by the patient is repeated when the same dose is administered. desirable. Preferably the change in the allergen content of the unit in the blister pack is within ± 10%, preferably within ± 7% and most preferably within ± 5% compared to the dose set.

The blister pack may contain a conceivable number of fast dispersing solid formulations. In a preferred embodiment the blister pack contains 1-100 solid formulations and more preferably 5-35 solid formulations. The blister pack may also be packaged in a suitable container according to any particular dosage form required to desensitize a patient.

The invention also relates to a method for producing a fast dispersing non-pressed solid dosage form according to claim 1, wherein the method

Preparing an aqueous solution of a dosage form consisting of a pharmaceutically active substance and an excipient suitable for maltodextrin and optionally one or more additional matrix formers,

The solution is introduced into a depression of the multilayered blister sheet,

Freezing and freeze-drying the seated sheet using standard conditions of shelf temperature and chamber pressure.

Moreover, the present invention relates to a method for obtaining a fast dispersing, non-compressed allergen vaccine solid dosage form suitable for oral mucosal administration.

1) to produce a rapidly dispersed, non-compressed solid allergen vaccine formulation,

2) determine the crushability of the formulation in the assay, the assay

a) placing the solid dosage form contained in the sealed blister pack unit into a device suitable for crushability measurement,

b) moving it at a suitable speed for a suitable time;

c) removing the sealed solid dosage unit,

d) opening the sealed solid formulation and emptying the unit in the vessel / placing the rapid dispersion formulation in the vessel,

e) removing the solid formulation from the container while leaving a lossy residue in the container,

f) performing an immunochemical allergen specific analysis on the residue to detect the amount of allergen content in the residue,

g) calculating the percentage of allergen content in the residue compared to the total allergen content of the solid formulation unit, and

h) detecting that the formulation meets the requirements for low crushability,

3) Repeat steps 1) and 2) until the requirements for formulation are met.

process

The fast disperse solid dosage forms according to the invention can be prepared by sublimation according to the method described in US Pat. No. 4,371,561. Thus, the solidification solution of allergens and matrix forming excipients undergo sublimation. The sublimation process is preferably carried out by freeze-drying the solution. The solution is contained in the depression of the blister pack during the freeze-drying step to produce a solid form of the desired shape. The blister pack can be frozen using liquid nitrogen or solid carbon dioxide. After the freezing step, the freezing solution in the blister pack is depressurized and, if necessary, subjected to controlled application of heat to assist in sublimation of the solvent.

Clinical allergic manifestations and symptoms may vary depending on the various and sensitive individuals and the allergy applied. Common are symptoms such as edema, pruritus, redness and symptoms of tears and runny nose (rhinitis conjunctivitis), symptoms of upper and lower respiratory tracts such as wheezing, cough, shortness of breath, eczema, urticaria and pruritus. Other symptoms such as fatigue are also experienced. Treatment for symptoms is aimed at reducing the severity of symptoms or reducing the need for other drugs given to or affecting them in parallel. Drugs for symptoms include antihistamines, such as H1 and H2 receptor antagonists, intranasal and invasive corticosteroids, non-steroidal anti-infective drugs, and codeh decontradtans, such as adrenoceptor agonists. Treatment and alleviation of one or more symptoms or reduction of the need for other drugs is a further object of the present invention.

The present invention therefore relates to a method for the prevention or treatment of a disease comprising the administration of an effective amount of oral mucosa of the formulation according to the invention.

More specifically, the present invention relates to a method for the prevention and treatment of allergies or alleviation of allergic symptoms comprising the administration of an effective amount of oral mucosal of an allergen vaccine formulation according to the invention.

The invention also relates to a pharmaceutically active substance for the preparation of a fast dispersing non-press solid formulation according to the invention.

More particularly, the present invention relates to a fast dispersing non-compression solid formulation according to the invention for oral mucosal protection or treatment of a disease.

More particularly, the present invention relates to a fast dispersing non-compression allergy vaccine solid dosage form according to the invention for oral mucosal protection, treatment of allergies or alleviation of allergic symptoms.

The invention furthermore relates to the use of pharmaceutically active substances for the preparation of rapid dispersion or non-compression solid formulations according to claim 1 for the prevention of oral mucosa or the treatment of diseases.

More particularly, the present invention relates to the use of allergens for the preparation of rapid dispersion or non-compressed allergen vaccine solid dosage forms according to claim 1 for oral mucosal protection or treatment of allergies or alleviation of allergic symptoms.

Sublingual immunotherapy can be considered as a method of inducing resistance, including mucosal vaccination. The mucous membrane of the mouth is rich in dendritic cells with strong potential for antigen presentation. It is believed that dendrites process allergens and then migrate to local lymph nodules that direct allergen-inducing peptides to allergen-specific T-cells. During sublingual immunotherapy, it is believed that this dendritic cell-T cell interaction allows T-cells to have regulatory potential or increases the ratio of allergen-specific Th1 cells to allergen-specific Th2 cells. Many of the immunological parameters monitored during allergy vaccination, alone or in combination, may be markers suitable for the effectiveness or efficacy of the treatment. These include global or mucosal antibody reactions such as specific lgA, lgG and lgE antibodies; Cytokine levels such as INF gamma, IL-2, IL-4, IL-5, IL-10 IL-12 and TNF alpha in blood or mucosal secretions; Activity, chemotaxis, proliferation, signaling, cytokine production and other responses of regulatory T-cells, Th1 cells, Th2 cells, CD8 cells, other T cell subsets or B-cells or NK cells, and CD markers, such as Effector cell functions such as expression of cell surface markers such as CD4, CD8, CD23, CD25, CD62L, CLA, beta7, CCR9, CD69, CD45RO, CCR3, CXCR5, total histamine content of basophil cells; Eosinophils, basophilic cells, lymphocytes, monocytes in blood, tissue or secretion; Eosinophils, basophils, lymphocytes, monocyte modulator release, cytokine production, activity, chemotaxis, proliferation, signaling and other responses.

In a preferred embodiment, the formulations according to the invention have the property that one or more immunological changes can be found: increased allergen specific lgG response, increased allergen specific lgA response, reduced allergen specific lgE response, side effects Almost none; Reduced allergen specific effector response of eosinophils, basophils, lymphocytes and / or monocytes; Induction of T cells with regulated potential, increased ratio of allergen Th1 cells to allergen Th2 cells, induction of other cells with regulated potential, reduced allergen specific Th2 response.

Allergies are also known diseases in animals, especially breeding or pets. It is known in the art that they are exposed to numerous allergen sources, including grass, dust mites, and parasites. Hematopgagus, or vampire insect invasion, is known to cause a hypersensitivity reaction known as flea allergic dermatitis (FAD). In a preferred embodiment of the invention allergens for animal vaccines are ectoparasites (e.g. fleas, ticks, mosquitoes, flies), enteroparasitic poisons (e.g. dirophyllaria filaments or e.g. filamentous filaments) and house dust And allergens originated or metastasized from ticks. Most preferred are from fleas such as dog fleas and cat fleas, from true mites such as river mites, from mite to mites such as Amblyomma, soft mites and back mosquitoes. Saliva allergen.

Formulations Containing Microcapsules

Pyer's patches are a collection of lymph nodules located in the walls of the small intestine, large intestine and appendix and are an important part of the body's defense against the attachment and passage of other foreign objects to the infectious agent and the body. Fire collection is also known as vesicular lymphoid aggregates. Similar vesicle lymphoid aggregates can be found in the respiratory tract, rectum, nasal cavity, oral cavity, pharynx, genitourinary system, large intestine, and other mucosal tissues of the body. The tissue is generally called mucosal related lymphoid tissue (MALT).

Pharmaceutically active substances formulated into microcapsules with appropriate size and appropriate physico-chemical properties can be effectively absorbed by using Fire aggregation and MALT.

Thus, a further aspect of the invention relates to formulations wherein at least a portion of the active substance is in the form of microcapsules embedded in the matrix and the microcapsules comprise the first encapsulating agent and the active substance. Without being bound by theory, it is believed that with respect to many active substances, especially allergens, it is possible to obtain the intended therapeutic effect by microcapsules, which is allowed to be absorbed by MALT or to derive its effect through MALT. In a preferred embodiment of the invention, the active agent is present in the matrix both in the form of microcapsules and in the form of molecules in direct contact with the matrix. In this embodiment, it is believed that the active substance is allowed to be absorbed and / or obtained its effect through two different mechanisms, namely through MALT and through immune system stimulation obtained by free allergens, thus enhancing the therapeutic effect Obtained in comparison with the situation, wherein the active substance is formulated as a microcapsule or by directly binding to a matrix.

In addition to the enhanced therapeutic effect, the use of microcapsules includes the benefit of protecting the pharmaceutical active from degradation during the production and storage of the formulation and during the administration of the active to the patient. As described in more detail elsewhere herein, it is particularly important when the active material is allergin. The use of microcapsules to protect substances acting on sensitive organisms from degradation is well known. Typically, materials acting on living organisms are encapsulated in many protective wall materials, which are generally naturally polymerizable. The agent to be encapsulated may be coated with a single wall (microcapsules) of the polymerizable material or may be homogeneously dispersed within the polymerizable matrix (microspheres). "Encapsulation" or "microencapsulation" is interpreted correspondingly). The amount of material inside the microcapsules can vary as needed, ranging from small amounts up to 95% of the microcapsule composition. The diameter of the microcapsules is preferably less than 20 μm, more preferably less than 15 μm, even more preferably less than 10 μm and most preferably in the range of 1 to 10 μm.

Moreover, the use of microcapsules includes the advantage of preventing the active substance from being released from the formulation. As described in more detail elsewhere herein, this is particularly important when the active substance is an allergen.

The encapsulating agent may be a biodegrading agent, preferably a polymerizing agent. Preferably the first encapsulant is poly-lactide, poly-lactide-poly (ethylene glycol), poly (DL-lactide-co-glycolide), poly (glycolide), copolyoxalate, polycapro Lactone, poly (lactide-co-caprolactone), poly (esteramides, polyorthoesters and poly (8-hydroxybutyric acid), and polyanhydrides, most preferably poly (DL Other examples of encapsulating agents include poly (butyl-2-cyanoacrylate), poly (3-hydroxybutyrate) and polyanhydride copolymers of fumaric acid and sebacic acid, poly ( FA: SA) In addition, suitable encapsulating agents for use according to the invention include, but are not limited to, animal or vegetable proteins such as, for example, gelatin, dextrins and soybeans, wheat and gold flame seed proteins; acacia, guar, agar and agar. Pellets; polysaccharides; starches and modified starches, algins Acid salts; carboxymethylcellulose; carrageenan; dextrin; pectin; synthetic polymers such as polyvinylpyrrolidone; and polypeptides / proteins or polysaccharide complexes, such as gelatin-acacia complexes. Preferably, the encapsulating agent is selected to render the microparticles hydrophobic It is believed that the hydrophobic microparticles are more readily absorbed by the MALT or are allowed to elicit its effect through the MALT.

In a preferred embodiment of the invention, the microcapsule-containing formulations are formulated as tablets, ie cohesive formulations. In another preferred embodiment, the microcapsule-containing formulation is formulated into granule compositions suitable for preparing granule compositions, eg compressed tablets. In addition, the formulations of the present invention are formulated into granular compositions, such as granule compositions suitable for the manufacture of compressed tablets, when the pharmaceutically active substance is present in direct binding to the matrix former.

The invention also relates to compressed tablets comprising the granular composition of the invention.

The present invention also relates to an aqueous solution for preparing a fast-dispersing solid composition suitable for oral mucosal administration of a pharmaceutically active substance.

(a) a first matrix former in the form of maltodextrin having a dextrose equivalent (DE) of 1-20, and

(b) a microcapsule comprising a first encapsulation matrix former and an active substance.

First of all, the present invention

Preparing a microcapsule comprising a first encapsulation matrix former and a pharmaceutically active substance,

 Preparing aqueous solutions of microcapsules and maltodextrin and optionally one or more additional matrix formers and appropriate excipients,

Spray-freezing the dosing solution to produce primary granules, and

A method for producing a formulation according to the invention comprising the step of freeze-drying primary granules to produce secondary granules.

Justice

The term "maltodextrin" refers to partially hydrolyzed starch having a dextrose equivalent (DE) of 1-20.

The term “fast dispersing formulation” refers to less than about 90 seconds, preferably less than 60 seconds, preferably less than 30 seconds, more preferably less than 20 seconds, even more preferably less than 10 seconds, even more preferred in the oral cavity. The following refers to formulations which degrade in less than 5 seconds, most preferably in the oral cavity and in less than about 2 seconds.

The term "stable" refers to a formulation in which the loss of the content of at least one major allergen according to the method described in Example 1 of the allergen is less than 50% of the initial content.

"Low crushability" refers to the amount of remaining material that is lost from a formulation when the formulation is forced from the outside. Solid formulations are sufficiently friable and transported, stored and processed when the residual material loss is less than 500 SQ-units per solid formulation, preferably less than 150 SQ-units per solid formulation of the total allergen content of the formulation. It is robust. For the purposes of the present invention, crushability can be measured by the method according to the invention or by a modified method according to the European Pharmacopeia.

"Non-compressed" refers to a solid dosage form, which is prepared by removing liquid from a solidified system comprising a matrix former, an active ingredient and other suitable ingredients which become a solid matrix comprising allergens.

A “solid dosage form” is a dosage form, which is neither liquid nor powder, for example when it is administered orally, it is a tablet or granule composition.

"Tensile strength" is calculated according to the following equation,

σ = 3Wa × 9.8Nmm-2 / 2d2b

Where w = maximum load to fracture (kgF)

a = distance between supports

        d = thickness of the fast dispersing solid formulation (mm)

        b = diameter of the fast dispersing solid formulation in mm

"Maximum load for cleavage" means the maximum force required to break a unit in a three-point bend test using a suitable machine (eg CT5, Engineering System, 1 Loach Court, Radford Bridge Road, Nottingham NG8 1NA). do.

"Oral mucosa" refers to a formulation placed under the tongue or elsewhere in the oral cavity such that the active ingredient contacts the mucous membrane of the oral cavity or pharynx of the patient.

"Monosaccharide" refers to an organic molecule containing six carbons and is in the form of a ring or a linear molecule. "Disaccharide" refers to a saccharide comprising a combination of two monosaccharides. "Trisaccharide" refers to a saccharide comprising a combination of three monosaccharides.

"Dosing solution" refers to a non-solid mixture of solvent, matrix former, active agent, and any other excipient to be solidified.

"Allergen" refers to an allergen, a naturally occurring protein or mixture of proteins known to induce an IgE mediated response after repeated exposure to an individual. Examples of naturally occurring allergens include pollen allergens (wood, grass and herb and grass pollen allergies), mite allergens (e.g. house dust mites and shed mites), and insert allergens (suction, saliva and venom allergens) And animal allergens, fungal allergens and food allergens from saliva, hair and dandruff, such as, for example, dogs, cats, horses, rats, mice. The allergens may be in the form of allergen extracts, purified allergens, modified allergens or recombinant allergens or recombinant mutant allergens, allergen fragments of 30 amino acids or more or combinations thereof.

SQ-Units: SQ-units are measured according to Alk Abelo A / S's “SQ Bioefficacy” -standardization method, with 100,000 SQ units equal to the standard subcutaneous maintenance dose. Generally, 1 mg extract contains between 100000 and 1000000 SQ units, depending on the allergen source from which they originate and the manufacturing process used. The exact amount of allergen can be measured by immunoassay, ie total major allergen content and total allergen activity. In the field of expertise, there is no internationally accepted standardization law. Therefore, if extracts of other origin are to be used, they should be standardized on Alk Abelo A / S extracts, which is a process well known to those skilled in the art. The topic is "Allergic Extracts" (H. Ipsen et al, Chapter 20 in Allergy, principle and practise (Ed. S. Manning) 1993, Mosby Year Book, St. Louis and Lowenstein H. (1980) Arb Paul Ehrlich Inst 75: 122).

"Uniformity of contents" means a change in dosage unit from a given dosage.

"Water content" means the content of residual water in solid dosage units measured quantitatively using Karl Fischer titration. This method is based on the principle that a given amount of 12 results in the conversion of the same amount of water (European Pharmacopoiea 2.5.12).

As used herein, "water activity aw" is water that is effective in the sample. Water activity measurements are carried out using methods known to those skilled in the art, for example using a cooling mirror dew point method, a sensor with varying electrode resistance or capacity, or using a relative humidity using a lithium chloride electrode: aw can be calculated according to will be.

aw = p / ps = ERP (%)

here,

p = partial pressure of water vapor on the product surface

ps = partial pressure of water vapor against pure water at saturation pressure or product temperature

ERH = Equilibrium Relative Humidity

Abbreviation:

API: Active Protein Ingredients

ELISA: Enzyme Linked Immunosorbent Assay

DDT: Dithiothreitol

HRP: Hose Radish Peroxidant

LIA: Magic Light Especially IgE Test

LITE-pharmaceutical: fluorescently labeled anti-gE

PMP: Paramagnetic particle

SDS-PAGE: Sodium Dodecyl Sulfate Poly-acrylamide Gel Electrophoresis

TMB: tetramethylbenzidine

Example  One

Grass extract

Grass pollen extracts were obtained from Ipsen and Lowensten (1983) Jour. Allergy. Clin. Immunol. Prepared according to the method described in 72.2, page 150-159. In summary, turf pollen was extracted in ammonium hydrogen carbonate for 20 hours at 5 ° C. The particulate matter was removed by centrifugation and the supernatant was dialyzed against water (three times), lyophilized and stored for storage until reconstitution.

Solid formulation

Manufacturing Method:

1.MQ water is added to a beaker with a magnetic stirrer.

2. If necessary, add mannitol and sorbitol and dissolve under stirring.

3. If necessary, add maltodextrin and PEG and dissolve under stirring.

4. If necessary, add allergen extract.

5. If allergen is present, adjust pH to pH = 7-8 with hydrochloric acid (2N) or sodium hydroxide (2N).

6. Administer 250 μl of solution into pre-molded blister packs. The solution is dosed at ambient temperature.

7. After administration, the filled blister pack is cooled at -80 ° C. The unit was freeze-dried using standard conditions of shelf-temperature and chamber pressure.

Brief description of the method

Visual inspection: All units are visually observed for defects, for example to identify color, shape, irregularity and acceptable appearance.

Degradation: Testing is currently conducted as described in European Pharmacopoeia or the current USP.

Water content: The residue was measured using Karl Fischer titration. The method provides quantitatively the water content in a sample based on the principle that a given amount of I _{2 results} in the conversion of the same amount of H ₂ O.

Furtherance

code Mannitol Maltodextrin Sorbitol Allergen extract A 3 w / w% 5 w / w% - 0.002 w / w% B 3 w / w% 5 w / w% 0.1 w / w% 0.002 w / w% C 3 w / w% 5 w / w% 1 w / w% 0.002 w / w%

The amount of * API depends on the reconfiguration factor of the particular batch API.

Analysis test result code Water content decomposition Visual examination A 4.5% 1 sec Very difficult to remove one piece of solid unit from blister pack B 4.4% 1 sec Very difficult to remove one piece of solid unit from blister pack C 3.8% 1 sec Very difficult to remove one piece of solid unit from blister pack

It has been shown the possibility to produce freeze-dried solid formulations with various contents of mannitol, maltodextrin, allergen extracts, with or without sorbitol. All formulations degraded in one second time.

Example  2

code Mannitol Maltodextrin Sorbitol A 3 w / w% 5 w / w% - B 3 w / w% 5 w / w% 0.1 w / w% C 3 w / w% 5 w / w% 1 w / w%

Analysis test result code Water content decomposition Visual examination A 4.6% n.m. Unable to remove one piece of solid unit from blister pack B 4.6% n.m. Unable to remove one piece of solid unit from blister pack C n.m. n.m. Unable to remove one piece of solid unit from blister pack

It was only possible to remove the 3 solid uni- ties from the blister pack, which is why the overhaul is based on 3 units.

It has been shown that it is possible to produce freeze-dried solid formulations having various contents of mannitol, maltodextrin and / or sorbitol.

Example  3

code Mannitol Maltodextrin Sorbitol PEG 6000 A 5 w / w% 10 w / w% 0.1 w / w% - B 10 w / w% 20 w / w% 0.1 w / w% - C 10 w / w% 20 w / w% - - D 5 w / w% - 0.1 w / w% 5 w / w% E 10 w / w% - 0.1 w / w% 10 w / w% F 10 w / w% - - 10 w / w%

Analysis test result code Water content decomposition Visual examination A n.m. n.m. Unable to remove one piece of solid unit from blister pack B 5.1% 3 sec Very difficult to remove one piece of solid unit from blister pack C n.m. n.m. Very difficult to remove one piece of solid unit from blister pack D n.m. n.m. Unable to remove one piece of solid unit from blister pack E n.m. n.m. Unable to remove one piece of solid unit from blister pack F n.m. n.m. Unable to remove one piece of solid unit from blister pack

It has been shown that it is possible to produce freeze-dried solid formulations with varying amounts of mannitol and / or maltodexstream and / or sorbitol and / or PEG. Formulations comprising mannitol, maltodextrin and sorbitol had a degradation time of 3 seconds.

Example 4

code Mannitol Maltodextrin Sorbitol PEG 6000 A 5 w / w% 20 w / w% 0.1 w / w% - B 5 w / w% 20 w / w% 0.1 w / w% 3 w / w% C 5 w / w% 35 w / w% 0.1 w / w% - D 5 w / w% 35 w / w% 0.1 w / w% 3 w / w% E 5 w / w% 35 w / w% 0.2 w / w% - F 5 w / w% 35 w / w% 0.2 w / w% 3 w / w%

Analysis test result code Water content decomposition Exterior A n.m. 5 sec One piece of solid unit can be removed from the blister pack B n.m. 2 sec Unable to remove one piece of solid unit from blister pack C n.m. 81 seconds One piece of solid unit can be removed from the blister pack D n.m. 58 seconds One piece of solid unit can be removed from the blister pack E n.m. 95 seconds Very difficult to remove one piece of solid unit from blister pack F n.m. 83 seconds Very difficult to remove one piece of solid unit from blister pack

It has been shown that it is possible to produce freeze-dried solid formulations with varying amounts of mannitol and / or maltodexstream and / or sorbitol and / or PEG. Formulations comprising mannitol, maltodextrin and sorbitol had a degradation time of 3 seconds.

Example  5

This example relates to the preparation of a granular composition of granules having a matrix consisting of maltodextrin, mannitol and sorbitol, wherein the matrix comprises microencapsulated allergens (MEA) and to prepare compressed tablets from the granular composition.

material

Encapsulating agent: Poly-D, L-lactide-glycolide (DL-PLG) (60/40) having a molecular weight of 40,000 g / mol from Birmingham Polymers, USA.

Active substance: Phl p extract of MEA-particle

Mannitol: Ph.Eur. <559>, No.281048 of Unikem Corporation

Sorbitol: Ph.Eur. <435>, Nomeco company No. 340927

Maltodextrin: NF 18, CPUR01915 (18DE) type from Cerestar

Talcum: Ph. Eur. <438>, No.297911 by Unicem

Magnesium stearate: Ph.Eur. <229>, No. 280560

Test Method for Compressed Tablets

Resistance to grinding

The tablet is placed horizontally on the support for the first vertical plate. At the far end, a piston fitted to a second vertical plate placed so that the two plates overlap one another side by side is moved against the tablet, and the pressure applied to the grinding time of the tablet is measured in N units.

Crushable

Twenty tablets are dusted, weighed and placed in a cylinder fitted to the inner lip. The cylinder is rotated at 25 rpm for the selected time, the tablet is removed from the cylinder, dusted and weighed. The difference between the initial and final weights is calculated as a percentage and the crushability is indicated.

Manufacture of MEA

1. Homogenization

DL-PLG was dissolved in ethyl acetate (30w / w%) and the allergen extract was dissolved in water (13w / w%). The two solutions were mixed and homogenized to form an oil / water two phase emulsion.

2. Emulsifying Oil / Water Emulsion in Aqueous Medium

The oil / water emulsion was mixed with a 2w / w% aqueous solution of PVA saturated with ethyl acetate and buffered with pH-6.8 with sodium phosphate and hydrochloric acid and emulsified to form a water / oil / water emulsion. The water / oil / water emulsion was passed through the emulsion sieve of the emulsifying apparatus to form MEA-microcapsules.

3. Extraction of ethyl acetate / PVA

To cure the MEA-microcapsules, ethyl acetate and PVA were extracted. The temperature was maintained at 22 ° C. for the first 10 minutes of extraction, after which the temperature was lowered to 12 ° C.

4. Concentration by centrifugation

Centrifuge the suspension formed in step 3.

5. Re-suspension and spray drying

After centrifugation, the microcapsules are re-suspended in water (1800 mL / 25 g) and spray dried to form the finished microcapsules.

Preparation of Granule Composition

The MEA is suspended in distilled water, mannitol, maltodextrin and sorbitol are added and the suspension is stirred. The product is injected into a chamber filled with liquid nitrogen, where the droplets are immediately frozen. During freeze-drying, some of the droplets are frozen together and therefore the frozen particle composition is optionally milled. The crushed ice particles are filtered through a cello, lyophilized and sieved again to obtain the finished granules.

Manufacture of tablets

Tablets were produced using a "Comprex II" tablet press.

Furtherance

result

* 0.5% magnesium stearate and 4.5 talcum added as polish

** Crush Granules to Reduce Size

Tablets compressed at low pressure

Tablets compressed at high pressure

Compressed tablets with compositions different from many microcapsule-containing granule compositions were prepared. All compressed tablets disintegrated quickly, which means that the granule composition is easily dispersed. As shown in the results of the table above, the particle size distribution, granule composition, and tablets after dissolution of the MEA were almost similar in all cases. Therefore, by the use of the microcapsule-matrix system of the present invention, it is possible to prepare granule compositions, which are used to prepare compressed tablets, where the microcapsules are kept intact. As also shown in the results of grinding resistance and crushing, the matrix consisting of mannitol, maltodextrin and sorbitol is strong and in any case strong enough to withstand compression into tablets.

Claims (42)

(a) a first matrix former in the form of maltodextrin having a dextrose equivalent (DE) of 1-20, (b) a second matrix former in sorbitol form, and (c) A non-compressed, fast-dispersing solid formulation suitable for oral mucosal administration of a pharmaceutically active substance comprising an active substance. The formulation of claim 1, further comprising one or more matrix formers. The formulation according to claim 1 or 2, wherein the additional matrix forming agent is monosaccharide, disaccharide or trisaccharide. The formulation according to claim 1, wherein the further matrix former is mannitol. The formulation according to claim 1, further comprising polyethylene glycol (PEG). The method according to any one of claims 1 to 5, wherein the maltodextrin is 3 to 40% (w / w), preferably 10 to 35% (w / w) and more preferably 15 to 25% of the administration solution. Formulations present in an amount of% (w / w). 7. The sorbitol of claim 1, wherein the sorbitol is 0.01-10% (w / w), preferably 0.05-5% (w / w) and more preferably 0.1-2% of the administration solution. Formulations present in an amount of (w / w). The method according to any one of claims 4 to 6, wherein mannitol is 1-20% (w / w), preferably 2-10% (w / w) and more preferably 3-6% of the administration solution. Formulations present in an amount of (w / w). 9. The PEG according to claim 5, wherein PEG is 1-20% (w / w), preferably 2-15% (w / w) and more preferably 3-10% of the administration solution. Formulations present in an amount of (w / w). The formulation of claim 1, further comprising one or more additional excipients. The method of claim 10 wherein the excipient is selected from the group consisting of adjuvants, antacids, diluents, enhancers, mucoadhesives, flavors, taste masking agents, preservatives, antioxidants, surfactants, viscosity enhancers, colorants, pH adjusters and sweeteners. Formulation. The formulation according to any one of claims 1 to 11, wherein the active substance is an allergen. The formulation of claim 12, wherein the allergen is selected from the group consisting of tree pollen allergens, grass pollen allergens, tick allergens, insect allergens, poison allergens, animal hairs and dandruff allergens and food allergens. The formulation of claim 12 or 13, wherein the allergen is in the form of an extract, a purified allergen, a modified allergen or a recombinant allergen or a mutation of a recombinant allergen or combinations thereof. The formulation of claim 13 or 14, wherein the allergen is grass pollen. The formulation according to claim 13 or 14, wherein the allergen is a dust mite. The formulation according to claim 1, which comprises at least two different allergens. 18. The formulation according to any one of claims 1 to 17, wherein the potency is 150 to 1000000 SQ-u / formulation. The change in allergen content in the unit in the blister pack is ± 10%, preferably ± 7%, more preferably ± 5% compared to the dosage set. Formulations, The formulation according to claim 1, wherein the formulation is for sublingual administration. 21. The solid formulation of claim 1, wherein the solid dosage form is less than 90 seconds, preferably less than 60 seconds, preferably less than 30 seconds, more preferably less than 20 seconds, even more preferred in the oral cavity. Where in less than 10 seconds, even more preferably less than 5 seconds, most preferably less than about 2 seconds. 22. The formulation of claim 1, wherein the formulation is strong enough to be removed from the blister pack without release of residues in the surroundings. The formulation of claim 22, wherein less than allergen 500 SQ-U, more preferably less than allergen 250 SQ-U, most preferably less than allergen 150 SQ-U is released from each solid formulation during manual treatment. The method of claim 1, wherein the crushability measured by the amount of allergen released is less than 500 SQ-U per solid formulation, more preferably less than 250 SQ-U per solid formulation in a suitable crush test. Most preferably less than 150 SQ-U per solid dosage form. The method of claim 24, wherein the shredability a) placing a single unit of solid dosage form contained in a blister pack unit sealed in a device suitable for reproducible crushability measurement, b) moving it at an appropriate speed for an appropriate time; c) removing the sealed solid dosage unit, d) opening the sealed solid dosage unit and emptying the unit in the container / positioning the rapid dispersion dosage unit in the container, e) removing the solid dosage unit from the container while leaving a lossy residue in the container, f) conducting an allergen specific assay for the residue and measuring the allergen content in the residue, g) A formulation as determined by an assay, optionally comprising calculating a percentage of allergen content in the residue compared to the total allergen content of a solid formulation unit. The formulation of claim 1, wherein at least some of the active substance is in the form of microcapsules embedded in the matrix, the microcapsules comprising a first encapsulant and the active substance. The formulation of claim 25, wherein said first encapsulant is poly (DL-lactide-co-glycolide). The formulation of claim 1, wherein the formulation is in the form of a granular composition suitable for the manufacture of compressed tablets. A blister pack containing a plurality of solid dosage forms according to any one of claims 1 to 28. 28. A method for the prophylaxis or treatment of a disease comprising administering an effective amount of an oral mucosa of a formulation according to any one of claims 1 to 27. 28. A method for the prevention or treatment of allergies or the alleviation of allergy symptoms comprising administering an effective amount of an oral mucosa of an allergen vaccine formulation according to any one of claims 1 to 27. Use of a pharmaceutically active substance for the preparation of a fast dispersing non-pressed solid dosage form according to claim 1. Use of an allergen for the preparation of a fast dispersing non-compressed allergen vaccine solid dosage form according to claim 1. A fast dispersing, non-compressed solid formulation according to claim 1 for the prevention or treatment of oral mucosal diseases. A fast dispersing non-compressed allergen vaccine solid dosage form according to claim 1 for oral mucosal prophylaxis or treatment of allergy or oral mucosal alleviation of allergic symptoms. Use of a pharmaceutically active substance for the preparation of a rapidly dispersed or non-compressed solid formulation according to claim 1 for the prevention and treatment of oral mucosal diseases. Use of an allergen for the preparation and preparation of a rapid dispersion or non-compressed allergen vaccine solid dosage form according to claim 1 for the prevention and treatment of oral mucosa of allergy or the relief of oral mucosa of allergic symptoms. A process for the preparation of a fast dispersing non-pressed solid dosage form according to claim 1, wherein Preparing an aqueous solution of administration of the pharmaceutically active substance and maltodextrin and optionally one or more additional matrix formers and suitable excipients, Introducing the solution into a depression of the multilayered blister sheet, and Freezing and freeze-drying the loaded sheet using standard conditions of shelf temperature and chamber pressure. A method for obtaining a fast dispersing non-compressed allergen vaccine solid dosage form suitable for oral mucosal administration, the method comprising 1) to produce a rapidly dispersed, non-compressed solid allergen vaccine formulation, 2) measuring the crushability of the formulation in the assay consisting of the following steps, a) placing the solid dosage form contained in the sealed blister pack unit into a device suitable for crushability measurement, b) moving it at a suitable speed for a suitable time; c) removing the sealed solid dosage unit, d) opening the sealed solid formulation and emptying the unit in the container and / or placing the rapid dispersion formulation in the container, e) removing the solid dosage unit from the container while leaving a lossy residue in the container, f) performing an immunochemical allergen specific analysis on the residue to detect the amount of allergen content in the residue, g) calculating the percentage of allergen content in the residue compared to the total allergen content of the solid formulation unit, and h) detecting that the formulation meets the requirements for low crushability, And 3) repeating 1) and 2) until the requirements for formulation are met. A compressed tablet comprising the granule composition of claim 28. A dosage solution for preparing a fast-dispersing solid composition suitable for oral mucosal administration of a pharmaceutically active substance, wherein the dosage is (a) a first matrix former in the form of maltodextrin having a dextrose equivalent (DE) of 1-20, and (b) an aqueous solution containing microcapsules comprising a first encapsulation matrix former and an active substance. A method of preparing a formulation according to claim 28, wherein the method  Preparing a microcapsule comprising a first encapsulation matrix former and a pharmaceutically active substance, Preparing an aqueous solution of administration of microcapsules and maltodextrin and optionally one or more additional matrix formers and appropriate excipients, Spray-freezing the aqueous solution of administration to produce primary granules, and Freeze-drying the primary granules to produce secondary granules.