Solid dose formulations for needle-free delivery

Abstract

To provide solid dose formulations for needle-free delivery, and novel methods useful for producing such solid dose formulations.SOLUTION: The present disclosure relates to solid dose formulations for needle-free delivery comprising 0.01-60% (w / w) of one or more therapeutic and / or prophylactic agents, and 40.0-99.99% (w / w) of dextran. The invention further relates to methods of producing solid dose formulation tablets and to their particular medical uses, in particular as a vaccine.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present invention relates to novel solid dose formulations for needle-free delivery of therapeutic or prophylactic agents, such as immunogens, and further to methods for making tablets containing said solid dose formulations. do. [Background technology]

[0002] A common route of administration for therapeutic or prophylactic agents is parenteral delivery of liquid formulations via needle and syringe. Parenteral delivery is typically used for therapeutic or prophylactic agents that are poorly absorbed by other routes and / or require rapid delivery.

[0003] Disadvantages associated with parenteral delivery via needles include the associated discomfort and pain for the patient and the health risks posed by used sharps. The poor solubility of most therapeutic or prophylactic drugs often leads to suboptimal formulations. Furthermore, they are typically less stable in liquid dosage forms than in solid dosage forms.

[0004] Solid formulations have been developed as alternatives to liquid formulations, but these are typically manufactured for predominantly oral administration. When solid dosage forms containing therapeutic or prophylactic agents are developed for parenteral administration, they may still be intended to be delivered with the aid of a needle. Such solid dosage forms are manufactured with the goal of achieving lean manufacturing and controlled dissolution after administration. Therefore, the mechanical strength specifications for such solid dosage forms are merely directed as in-process controls to ensure manufacturing consistency and to maintain the solid dosage form during transportation and handling before and during administration.

[0005] The applicant has previously developed needle-free devices for parenteral delivery of therapeutic or prophylactic compounds in solid dosage forms to overcome various drawbacks associated with both parenteral delivery and liquid dosage forms, as described above. Such devices are disclosed in the applicant's previous patent publications, such as EP1427464, EP1545662, EP1855755 and WO2016 / 124903.

[0006] A fundamental requirement of such needle-free technology is the production of a solid dosage form containing a therapeutic or prophylactic agent that has sufficient mechanical strength to penetrate the skin and an appropriate size and shape for patient comfort, as disclosed in EP 2129366. For example, Applicant previously developed a solid dosage composition, described in WO 2017 / 068351, that contains, inter alia, carboxymethylcellulose sodium salt (CMC), and was determined to have sufficient mechanical strength of at least 80 MPa when produced using a wet paste extrusion method followed by drying and cutting to the desired shape, to be compatible with the aforementioned needle-free delivery device.

[0007] Other manufacturing methods have been used in the art to attempt to produce solid dosage forms with sufficient mechanical strength to allow parenteral administration, such as those described in EP1173151 (Novo Nordisk) and WO2011 / 042542 (Azurebio).

[0008] Tablet compression is a common method for producing solid dosage forms suitable for oral administration, but they will usually be of a size and shape that is not suitable for patient comfort during parenteral administration. There are examples of 1 mm diameter tablets under investigation in the literature, but such formulations are typically not suitable for needle-free parenteral delivery due to insufficient mechanical strength. "Development of 1 mm and 2 mm diameter mini-tablets" f mini-tablets with 1 mm and 2 mm diameter)”, Tissen et al., Internat ional Journal of Pharmaceutics 416(2011)164-170.

[0009] Therefore, it remains highly desirable to provide new methods useful for preparing solid dosage forms for needle-free parenteral delivery. The present invention was derived from the need to provide novel solid dosage forms and related methods for their improved manufacture. [Prior art documents] [Patent documents]

[0010] [Patent Document 1] European Patent No. 1427464 [Patent Document 2] European Patent No. 1545662 [Patent Document 3] European Patent No. 1855755 [Patent Document 4] International Patent Publication No. 2016 / 124903 [Patent Document 5] European Patent No. 2129366 [Patent Document 6] International Patent Publication No. 2017 / 068351 [Patent Document 7] European Patent No. 1173151 [Patent Document 8] International Patent Publication No. 2011 / 042542 [Non-patent literature]

[0011] [Non-Patent Document 1] Tissen et al., International Journal of Pharmaceutics 416(2011)164-170 Summary of the Invention

[0012] The present invention relates to a solid formulation having a compressive strength of 80 MPa or more for needle-free delivery, the solid formulation comprising 0.01 to 60% (w / w) of a therapeutic and / or prophylactic agent; and at least 40.0% to 99.99% (w / w) of dextran.

[0013] Importantly, to be suitable for needle-free administration, the solid dosage form must possess the mechanical strength described herein to withstand the stresses imposed during subcutaneous delivery and allow successful injection of the active agent provided therein. The solid dosage form can include, inter alia, a composition comprising at least one pharmaceutical agent.

[0014] Surprisingly, compositions of the present invention having a percentage of dextran defined in the above range, which is much higher than is typically found in tablet formulations of the art, achieve the mechanical and structural integrity required for needle-free administration, i.e., a compressive strength of 80 MPa or greater.

[0015] Applicant believes that the art has previously provided little to no data regarding the production of tablets that achieve such high mechanical strength, particularly where this is specific to the technical problem addressed in this application. This is especially true when the excipients used in typical tableting / formulations are generally used in small amounts for their intended purpose.

[0016] Applicant has developed novel formulations in which dextran provides a substantial component or substance of the formulation (excluding therapeutic and / or prophylactic agents). When dextran is present in the range of 40.0-99.99% (w / w), it imparts important and useful characteristics to the resulting solid dosage form, particularly with regard to the delivery mechanism. It has been found that a relatively high proportion of dextran, as defined in the above range, imparts important strength parameters to tablet formulations, particularly microtablet formulations, required for needle-free parenteral delivery. This is particularly relevant for needle-free delivery. Therefore, the present invention is considered to be extremely useful.

[0017] In embodiments, dextran provides 40% or more of the total composition (w / w). For example, formulations typically contain dextran in the range of, for example, 40-99%, 49.5-99%, or 50-99%.

[0018] In particular, the dextran is 51 to 99% (w / w) dextran, 63 to 99% (w / w) dextran, preferably 66 to 99% (w / w) dextran, 74 to 99% (w / w) dextran or 82-99% (w / w) dextran. In some cases, the formulation may contain up to 90%, 95%, 97%, 98%, 99%, 99.90%, or 99.99% dextran at the upper end of the range, which can be combined with any lower end of the range and is disclosed as such.

[0019] The inventors further concluded that the technical problem can be solved in another novel and inventive way, in that a solid formulation comprising 0.01% (w / w) of at least one therapeutic and / or prophylactic agent can retain a compressive strength of at least about 80 MPa, suitable for needle-free delivery.

[0020] The inventors have successfully demonstrated that the compressive strength of the resulting composition / formulation can be maintained during strength testing if at least 25.0% (w / w) dextran is present along with at least one different excipient or combination of different excipients. However, this requires careful selection and combination of the excipient(s) used in the formulation, and is not an arbitrary choice. Typically, a combination of dextran with one different excipient, or a combination of dextran with additional excipients, constitutes at least 90-99% of the solid formulation to solve the same technical problem and obtain a composition with sufficient compressive strength for needle-free delivery.

[0021] Thus, the present invention extends to a solid formulation having a compressive strength of at least about 80 MPa for needle-free delivery, comprising 0.01% to 75.0% (w / w) of at least one therapeutic and / or prophylactic agent; at least 25.0% (w / w) dextran; and at least 50% (w / w) of at least one, or a combination of two or more, different excipients excluding dextran. In one embodiment, the at least one different excipient, or the combined two or more excipients (excluding dextran) are in the range of 50% to 74% (w / w). In other words, the different excipients or the total combination of different excipients excluding the dextran component constitute 50% to 74% (w / w) of the composition. In one embodiment, the excipient(s) excluding dextran constitute approximately 74%. These are preferably selected from mannitol and / or trehalose and / or CMC.

[0022] Optionally, any of the inventive formulations described herein may include at least 0.5% (w / w) of a lubricant. In some embodiments, the lubricant can be selected from magnesium stearate, polyethylene glycol (PEG), or lysine. Lubricants are typically provided at at least 0.5% to 1% (w / w), but can be up to 5%. Lubricants can improve manufacturability, for example, during the tableting or microtabletting process, and can help provide a consistent and reliable output when the formulation is ejected from the press (e.g., with minimal ejection force).

[0023] In embodiments, the formulation may include one or more excipients, the excipients being selected from binders, fillers, or combinations thereof. In embodiments, the one or more excipients are methionine, cysteine, histidine, citric acid, sodium chloride, sodium hydroxide, hydrochloric acid, potassium chloride, Tween 20, Tween 40, Tween 60, Tween 80, albumin, mannitol, trehalose, sucrose, calcium. The excipients are selected from either carboxymethylcellulose sodium salt (CMC), polylactic-co-glycolic acid (PLGA), polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), or polylactic acid (PLA). Selection can also include combinations of these and other excipients to provide additional benefits to the resulting formulation.

[0024] In particular, CMC may also be present in the formulation. When the lower end of the range of dextran percentages, approximately 40% or higher, is used, it is believed that the minimum compressive strength of the formulation (80 MPa) can be maintained by including a percentage of CMC in combination with the dextran, e.g., 50% CMC.

[0025] The formulation may contain a lower level of CMC, e.g., 10% to 50% (w / w), when a high level of dextran is used, e.g., at least 49.5% (w / w), and one or more other excipients, such as mannitol, are present. The combination of dextran and CMC is particularly beneficial when dextran is present at 50% (w / w) or more. In some cases, the addition of a specific proportion of an additional excipient, such as mannitol, also allows for the maintenance of compressive strength. In embodiments where 10% to 50% CMC is used, at least In some embodiments, the solid formulation provides a single unit dose, thus eliminating variability caused by the technique of the administering individual and ensuring that a consistent dose is achieved each time.

[0026] Additionally, compositions were prepared using different grades of dextran to test their effect on compressive strength (average molecular weight (mw) range from 1 kDa to 110 kDa). In particular, the dextran utilized can be selected from grades having an average molecular weight of 10 kDa or greater, 10 kDa to 110 kDa, or preferably about 70 kDa, since these embodiments retain a compressive strength of at least 80 MPa. Accordingly, all such grades can be used to prepare solid dosage forms to be delivered by needle-free delivery devices of the type described herein.

[0027] Particularly advantageously, such solid dosage forms can reliably retain the necessary strength when sized to the dimensions desired for optimal needle-free delivery. In embodiments, the solid dosage form is a microtablet, and the benefits of needle-free delivery technology can be fully maintained without having to increase the size of the dosage form or modify its composition beyond this disclosure. In embodiments, the solid dosage form is elongated; preferably, the length-to-width ratio is in the range of 6:1 to 2:1. Such a ratio allows for a more easily delivered solid dosage form. In embodiments, the width of the solid dosage form is 2 mm or less, preferably 0.85 mm, and / or the length of the solid dosage form is 2 to 6 mm, preferably 4 mm.

[0028] In some embodiments, the shape of the solid dosage form includes a pointed tip with an internal angle of 22.5° to 90° to further improve ease of delivery. In most embodiments, the total mass of the solid dosage form is 7 mg or less.

[0029] In a preferred embodiment, the agent is a biological agent for immunization, such as an antigen or other immunostimulatory biological component. In embodiments, the at least one agent may be selected from a vector, a protein, a subunit protein, DNA, RNA, a toxoid, or a polysaccharide-antigen conjugate and a checkpoint inhibitor.

[0030] In a preferred embodiment, the formulation may therefore comprise a vaccine. The type of vaccine may be selected from attenuated (live) vaccines, inactivated vaccines, toxoid vaccines, subunit or purified antigen vaccines, conjugate vaccines, neoantigen vaccines, RNA vaccines, DNA vaccines, heterologous "Jenner" vaccines, homologous vaccines, and recombinant vector vaccines. can.

[0031] Where the formulation comprises a vaccine, the formulation may further comprise one or more adjuvants, which may serve to stimulate the immune response and make the vaccine more effective. The addition of adjuvants to conventional attenuated vaccine formulations is intended to enhance, promote, and prolong the specific immune response to the antigen. Purified subunit or synthetic vaccines using biosynthetic recombinant or synthetic vaccines may include adjuvants to elicit the desired immune response.

[0032] Stabilizers can be used to help vaccines maintain their efficacy during storage and administration. Vaccine stability is essential, especially when the cold chain is unreliable. Instability can lead to loss of antigenicity. Some factors that affect vaccine stability are temperature and acidity or alkalinity (pH). Bacterial vaccines can become unstable due to hydrolysis and aggregation of protein and carbohydrate molecules. Stabilizers can include MgCl2 (for OPV), MgSO4 (for measles vaccine), lactose-sorbitol, and sorbitol-gelatin.

[0033] In some embodiments, one or more excipients are blended or combined with dextran by freeze drying or spray drying to first form a powder suitable for subsequent processing into a solid dosage form, such as a tablet.

[0034] In a further aspect, the invention relates to a formulation according to any of the above aspects for use as a medicament in the treatment or prevention of a condition, disease or disorder. In some embodiments, the formulations are for use in treating cancers associated with or caused by the HPV virus, such as anal cancer, oropharyngeal cancer, cervical cancer, vulvar cancer, and vaginal cancer in women, and penile cancer in men.

[0035] In some embodiments, the formulation comprises a vaccine or is used to formulate a vaccination to prevent or treat a human or animal disease, illness, or infection. In some embodiments, the disease or disorder is cancer, yellow fever, rabies, diphtheria, tetanus, Haemophilus influenzae type B (Hib), pertussis, pneumococcal disease, meningococcal disease, human papillomavirus (HPV), HTV, HSV2 / HSV1, influenza (types A, B, and C), parainfluenza, polio, RSV, rhinovirus, rotavirus, hepatitis A, acquired immune deficiency syndrome (AIDS), anthrax, gastroenteritis, enteroviral disease, measles, mumps, varicella-zoster, glandular fever, respiratory disease, rubella, human T-cell lymphoma type I (HTLV-I), hepatitis B, hepatitis C, hepatitis D, pop or a veterinary disease such as foot and mouth disease (including serotypes O, A, C, SAT-1, SAT-2, SAT-3, and Asia-1), coronavirus, bluetongue, feline leukemia virus, avian influenza, Hendra and Nipah viruses, pestivirus, canine parvovirus, and bovine viral diarrhea virus.

[0036] In some embodiments, the vaccine is a multivalent or combination vaccine. For example, the present invention can be used to treat two or more different types of disease or viral infections, such as measles, mumps, and rubella (e.g., an MMR vaccine).

[0037] In some embodiments, the vaccine is selected from an attenuated (live) vaccine, an inactivated vaccine, a toxoid vaccine, a subunit or purified antigen vaccine, a conjugate vaccine, a neo-antigen vaccine, an RNA vaccine, a DNA vaccine, and a recombinant vector vaccine. Examples of suitable vectors include adenovirus, measles virus, vaccinia virus, poxvirus, alphavirus, vesicular stomatitis virus (VSV) and lentiviral vectors.

[0038] In a preferred embodiment, when the agent is a prophylactic agent, the prophylaxis is immunization against a condition, disease or disorder. Other diseases of concern may include MERS (respiratory), Lassa, Nipah, Rift Valley fever, Chikungunya, plague, Zika, Shigella and influenza.

[0039] The vaccines of the present invention can be used to prevent or treat infections by viruses including one or more of human papillomavirus (HPV), HTV, HSV2 / HSV1, influenza virus (types A, B, and C), parainfluenza virus, poliovirus, RSV virus, rhinovirus, rotavirus, hepatitis A virus, Norwalk virus, enterovirus, astrovirus, measles virus, mumps virus, varicella-zoster virus, cytomegalovirus, Epstein-Barr virus, adenovirus, rubella virus, human T-cell lymphoma virus type I (HTLV-I), hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis D virus, poxvirus, and vaccinia virus.

[0040] Vaccines can also be used to provide an adequate immune response against a number of veterinary diseases, such as foot and mouth disease (including serotypes O, A, C, SAT-1, SAT-2, SAT-3, and Asia-1), coronavirus, bluetongue, feline leukemia virus, avian influenza, Hendra and Nipah viruses, pestiviruses, canine parvovirus, and bovine viral diarrhea virus.

[0041] In some embodiments, the vaccine is a subunit, conjugate, or multivalent or combination vaccine. The present invention further relates to a method for treating or preventing a condition, disease, or disorder, said method comprising administering to a subject in need thereof a therapeutically effective amount of a formulation as defined in any of the preceding claims. In some embodiments, the method for preventing disease comprises immunization, for example, when the composition is a vaccine and the agent is a prophylactic. Thus, usefully, the present invention enables novel, efficient, and effective means of patient compliance with vaccination. Treatment may include vaccination for any of the diseases listed herein or against any virus associated with said disease.

[0042] Furthermore, the invention described herein also relates to a novel method for producing tablets that retain the required properties when used for needle-free delivery. In particular, the invention relates to a method for producing a tablet containing a solid formulation according to any of the preceding claims by mixing the ingredients of the solid formulation in dry powder form; directly compressing the powder in a die; and drying the solid formulation at a temperature of 25°C to 40°C for at least 24 hours.

[0043] In an embodiment, the method is for producing microtablets, preferably elongated microtablets. In an embodiment, the die is configured to produce tablets having a diameter of 0.5 to 2 mm, preferably 0.75 mm to 2 mm, and most preferably 0.85 mm. Tablets with a larger diameter may be undesirable as they may increase the sensitivity felt by the recipient and reduce patient compliance associated with this type of administration.

[0044] The die itself may be elongated and / or have a diameter of between 0.5 mm and 2 mm, preferably between 0.75 mm and 1.2 mm. More preferably, the die is about 0.85 mm in diameter. In some embodiments, the drying process is carried out at approximately 25°C to 40°C for 1 to 11 days under vacuum. In some embodiments, drying is performed at approximately 10 mbar and / or at approximately 25° C. In preferred embodiments of the inventive method, mixing the ingredients may include spray drying or freeze drying the dextran together with one or more other ingredients of the formulation prior to the compression step.

[0045] The present invention further relates to a novel method for making a tablet containing a solid formulation comprising at least one therapeutic and / or prophylactic agent, dextran, and at least one excipient, the method comprising: blending the ingredients of the solid formulation in dry powder form (dextran is blended with at least one excipient by spray drying); compressing the powder in a die; and drying the solid formulation at approximately 25-40°C for at least 24 hours.

[0046] Thus, the method of the present invention provides particularly useful tablets, in the form of microtablets, that have sufficient mechanical strength for needle-free delivery. The present invention further relates to a method for treating or preventing a disease or disorder, said method comprising administering to a subject in need thereof a therapeutically effective amount of a solid formulation as described or prepared according to the present invention.

[0047] Certain aspects and embodiments of the present invention will now be illustrated by way of example and with reference to the tables / figures herein. [Brief explanation of the drawings]

[0048] [Figure 1] FIG. 1 shows the compressive stress (MPa) of 2 mm diameter tablets plotted against dextran content (%) for varying CMC content (%). [Figure 2] Figure 2 shows a contour plot of how varying the percentage % (w / w) of dextran and CMC affects the average compressive strength (MPa) of the resulting 2 mm diameter tablets. [Figure 3A] FIG. 3A shows the effect of dextran concentration as a percentage of the composition (w / w) on the average compressive strength (MPa) and ejection force (kg) of 1 mm diameter tablets obtained in combination with different excipients (trehalose). [Figure 3B] Figure 3B shows the effect of dextran concentration as a percentage of the composition (w / w) on the average compressive strength (MPa) and ejection force (kg) of 1 mm diameter tablets obtained in combination with different excipients (mannitol). [Figure 3C] Figure 3C shows the effect of dextran concentration as a percentage of the composition (w / w) on the average compressive strength (MPa) and ejection force (kg) of 1 mm diameter tablets obtained in combination with different excipients (CMC). DETAILED DESCRIPTION OF THE INVENTION

[0049] Effect of dextran and other ingredients on tablet strength It would be desirable to understand the effect on the compression strength of the final tablet when dextran is varied as a percentage of the composition in response to different excipients.

[0050] For this purpose, different blend compositions containing 29.7%, 49.5% and 99% dextran were tableted with 1% lubricant, sodium stearyl fumarate (SSF) and CMC.

[0051] Where necessary, mannitol was used as an excipient to make up the composition to 100% (w / w). A comparative composition of 99% CMC and 1% lubricant was also tested. The resulting tablets were dried in a vacuum oven at 10 mbar at 40° C. for 24 hours and then tested for compressive strength.

[0052] The data show that dextran has a favorable effect on the blend within the composition and on its own. The results show that hydroxybenzoates, in some examples in combination with CMC and / or mannitol, consistently impart desirable compressive strength (at least 80 MPa) to tablets and help improve or maintain that strength.

[0053] 99% dextran was shown to provide a strength of 148 MPa (compared to 80 MPa), significantly exceeding the strength required for the present invention, confirming that this component provides a specific strength useful for this type of needle-free solid dosage form. In contrast, CMC or mannitol alone imparted insufficient compression strength to the resulting tablets, far below the strength required for the present application.

[0054] Furthermore, from the extrapolated curve of the graphical analysis, 66% dextran alone appears sufficient to retain a technically acceptable compressive strength of 80 MPa. Graphical analysis confirms that CMC can retain acceptable compressive strength when combined with dextran (possibly in combination with mannitol), however, when CMC and dextran alone are combined at specific percentages, compressive strength can be maintained or even increased.

[0055] However, such combinations did not reach the post-drying strength achieved by using high percentages of dextran alone, strongly suggesting that CMC was not the primary strength-imparting factor in the final test tablet composition (particularly with reference to Figure 2).

[0056] The table below shows the results, along with the percentage of the working range when the desired strength (80 MPa) is selected from the curves in the graphs provided in Figures 1 or 2 (Graphs (from) and show the estimate.

[0057] [Table 1]

[0058] Dextran concentration versus compressive strength Additionally, the following formulations were prepared having the following compositions as shown in the table below.

[0059] [Table 2]

[0060] It is desirable to understand the effect on compressive strength when dextran concentration is varied as a percentage of the composition with different excipients. The blends of the above compositions were tableted using a 1 mm die.

[0061] After drying under vacuum at 25°C for 5 days, each tablet was tested for its compressive strength. The data indicate that a substantial percentage of dextran in the composition consistently imparts desirable compressive strength (at least 80 MPa) to the solid dosage form. The data also indicate that in certain embodiments, a dextran 70 content as low as 25% (w / w) is sufficient. In Figure 3, a clear trend can be seen showing that the mean ejection force (kg) decreases with increasing dextran content, regardless of the second excipient combined with dextran.

[0062] Selection of excipients in processing Ejection force is the force required to eject a compressed tablet from a tablet press. Ejection requires breaking the adhesion between the die wall and the compaction surface. As a tablet is ejected from a tablet press, heat is generated due to friction between the tablet and die wall. Absorption of this heat leads to bond formation. Lubrication is necessary to reduce the ejection force and the risk of tablet defects after ejection. For the purpose of parenterally administering a suitable needle-free solid dosage form to humans, it was necessary to find a parenterally acceptable tableting lubricant. The approved lubricant was magnesium stearate (MgS). It was deemed desirable to compare the ejection force (from the die) of Dextran 70 formulated with MgS to that of sodium stearyl fumarate (SSF), one of the most commonly used lubricants in the tableting process. Lubricants were tested at levels ranging from 0.5 to 5.0% of the total blend, which otherwise contained pure dextran. The resulting formulation blends were tableted through a 2 mm die, and the ejection force of the resulting tablets was measured.

[0063] [Table 3]

[0064] Because the ejection force of tablets containing MgS was comparable to those produced using SSF, MgS was considered a useful substitute suitable for the type and purpose of production. These results suggest that MgS is a particularly suitable lubricant for tablet production throughout the percentage range indicated.

[0065] Dextran grades Dextran is the general term for a family of glucopolysaccharides produced by polymerization of the α-d-glucopyranosyl moiety of sucrose in a reaction catalyzed by the enzyme dextransucrase. A common feature is the predominance of (1→6)-linked α-d-glucopyranosyl units.

[0066] Dextran is available in several different grades. It has been shown above that dextran with an average molecular weight of 70 kDa provides good compressive strength. Additional grades of dextran were tested in this example.

[0067] A formulation consisting of dextran and 1% magnesium stearate was tableted to a diameter of 2 mm and dried for 24 hours at 40° C. Compression strength tests were performed after drying.

[0068] [Table 4]

[0069] The results showed that all grades tested, except for dextran with an average molecular weight of 1 kDa, were able to achieve the desired compressive strength of at least about 80 MPa. Processing technology Furthermore, to check the effect of processing steps on strength, such as the method of mixing the ingredients of the formulation, two further examples were prepared as follows, except that the mixing used a spray drying process.

[0070] [Table 5]

[0071] The basic solid formulation also contained 1% (w / w) lubricant along with dextran and trehalose or lysozyme. Tablets were molded to a diameter of 0.85 mm. The resulting tablets were dried in a vacuum oven at 40°C under 10 mbar for 5 days.

[0072] The average compressive strength was tested in these examples and was considered excellent, suggesting that spray drying can have a very positive impact on the mixing of excipients with dextran during the tableting process.

[0073] Compressive strength, dry and moisture content A formulation consisting of dextran with an average molecular weight of 70 kDa and 1% magnesium stearate was prepared. The tablets were made into 2 mm diameter tablets.

[0074] The resulting tablets were subjected to various drying conditions. ·room temperature 10 mbar vacuum oven at 25°C 40°C in a vacuum oven at 10 mbar · In a sealed container with desiccant at 25℃ The compressive strength and moisture content obtained for each drying condition were evaluated at the following time points:

[0075] 1 day 5 days 11th

[0076] [Table 6]

[0077] The results show that there is a clear inverse relationship between the moisture content of the tablets and their compressive strength under all conditions tested. For the 2 mm tablets, drying for 5 and 11 days resulted in tablets with sufficient compressive strength under all drying conditions.

[0078] Furthermore, a formulation consisting of 70 kDa dextran and 1% magnesium stearate was tableted to a diameter of 1.2 mm, and the resulting tablets were dried in a vacuum oven at 40°C under 10 mbar for 24 hours and found to have a compressive strength of over 80 MPa.

[0079] [Table 7]

[0080] The results clearly show that the temperature, drying duration, and method are relevant for a given drying step in the production of this type of solid tablet: if the appropriate conditions are not selected, this can have a negative impact on the resulting compressive strength.

[0081] Tablet size Applicant also produced tablets using dies of different diameters. Tablets were compressed with either a 2 mm (control), 1.2 mm (see examples above), or 0.85 mm die. Tablets were then dried at 10 mbar for 24 hours at the specified temperature. Tablet compression strength was measured before and after drying.

[0082] [Table 8]

[0083] The compression strength for both diameters tested remained above 80 MPa. Thus, it was observed that tablets of sufficient compression strength could be obtained with diameters less than 2.0 mm, particularly in the range of 0.85 to 2.0 mm, indicating that the composition can be used to manufacture microtablets that retain their suitability for needle-free delivery injection.

[0084] In some embodiments, compositions with a high dextran content result in a low ejection force, which is beneficial for tablet manufacturing processes. High ejection forces are associated with a higher risk of tablet defects after ejection and can be used as a measure to identify and mitigate these risks. Furthermore, high ejection forces indicate that the formulation is at risk of sticking and / or picking. It is a measure of how well the formulation is lubricated. Poor lubrication leads to tablet defects such as picking, sticking, and capping, while over-lubrication reduces tablet hardness. Finally, high ejection forces can also lead to increased mechanical wear.

[0085] In an embodiment, dextran may be provided at the lower end of the range, e.g., 25-49% (w / w) dextran, and the remainder of the tablet bulk may be supplemented with various excipients, e.g., excipients selected from the group trehalose, mannitol, or CMC, and / or in the range of at least 50-74% (w / w).

[0086] In embodiments where the formulation contains less than 40% or less than 30% dextran and excipients are combined with the dextran, it is believed that this ratio maintains or enhances the mechanical strength to achieve the minimum compressive strength required for needle-free delivery of the solid composition.

[0087] In some cases, as shown in Figures 3A and 3B, formulations containing less than 40% (w / w) dextran can still exhibit sufficient mechanical strength when present at least 25% (w / w) in an appropriate ratio with a different excipient. This is particularly demonstrated when the different excipient is selected from the group consisting of trehalose and mannitol. In such examples, the second excipient constitutes the majority of the bulk composition with dextran.

[0088] In an embodiment, the formulation comprises at least 27% dextran, more particularly at least 28% (w / w) dextran and at least 70% (w / w) of the second excipient. The excipient selected can be trehalose, as shown in Figure 3A, to achieve a compressive strength of at least 80 MPa.

[0089] In an embodiment, the formulation comprises at least 25% dextran (w / w) and at least 73% (w / w) of an additional excipient, for example, when the selected excipient is mannitol, it is possible to achieve a compressive strength of at least 80 MPa, as shown in Figure 3B.

[0090] In examples, the excipient may additionally or alternatively be a stabilizer such as MgCl, MgSO, lactose-sorbitol, sorbitol-gelatin, or Tris-EDTA, a binder such as povidone, starch, gelatin, or alginic acid, or a bulking agent such as mannitol, sucrose, CMC, trehalose, PLGA, PVP, PVA, or PLA.

[0091] In some cases, as shown in Figure 3C, example formulations containing 49% or more dextran still exhibit sufficient mechanical strength when combined with additional excipients in appropriate ratios, particularly when the second excipient (in addition to dextran) is CMC.

[0092] Compressive Strength Testing with Formulated API Compositions It is essential to understand what effect, if any, at least one therapeutic and / or prophylactic agent has on compressive strength.

[0093] To assess whether this property changes with the inclusion of API, different blend compositions formulated with 0.125%, 0.250%, and 0.625% API (w / w) (vaccine) were tableted with 89% dextran (w / w) and 1% lubricant (w / w). The manufacture of these formulations involved lyophilizing 10% of the total vaccine-containing powder prior to the tableting process.

[0094] The following formulations having the following compositions were prepared as listed in the table below.

[0095] [Table 9]

[0096] The resulting tablets were 1 mm in diameter and were produced using a compression force of 100 kg. All tablets were dried at 10 mbar and 25°C for 5 days and were found to have a compression strength of over 80 MPa.

[0097] The data show that vaccines in the range of 0.125% to 0.625% (w / w) have no appreciable effect on compressive strength when the bulk dextran content is 89% (w / w), mannitol is 2.0% (w / w), PVP is 0.20% (w / w), sucrose is 1% (w / w), and MgS is 1% (w / w).

[0098] Accordingly, Applicant believes that any of the compositions of the present invention can be successfully formulated with an API, such as a vaccine-based API, and maintain compressive strength to provide a solid dosage form suitable for needle-free delivery. We came to the conclusion that this is possible.

Claims

1. A solid dosage form having a compressive strength of at least about 80 MPa for needle-free delivery, 0.01-60% (w / w) of at least one therapeutic and / or prophylactic agent; and 40.0% to 99.99% (w / w) dextran A solid dosage form comprising:

2. A solid dosage form having a compressive strength of at least about 80 MPa for needle-free delivery, 0.01-25.0% (w / w) of at least one therapeutic and / or prophylactic agent; at least 25.0% (w / w) dextran; and At least 50% (w / w) of at least one, or a combination of two or more, different excipients other than dextran A solid dosage form comprising:

3. 3. The solid dosage form according to claim 2, comprising at least 50-74% (w / w) of one or a combination of two or more excipients other than dextran.

4. 4. The solid formulation according to claim 2 or 3, wherein the excipient(s) are selected from trehalose, mannitol and CMC.

5. 10. A solid dosage form according to any preceding claim, further comprising at least 0.5% (w / w) of a lubricant.

6. 10. A solid dosage form according to any preceding claim, wherein at least one agent is an immunogen.

7. 10. A solid dosage form according to any of the preceding claims, wherein at least one drug is a biological or chemical agent for immunization.

8. 10. The solid dosage form according to any of the preceding claims, wherein at least one agent is a biological or chemical agent selected from a vector, a protein, a subunit protein, DNA, RNA, a toxoid, or a polysaccharide-antigen conjugate and a checkpoint inhibitor.

9. 10. The solid dosage form of any preceding claim, further comprising a binder, a filler, a stabilizer, or a combination thereof.

10. 10. A solid dosage form according to any preceding claim, further comprising one or more adjuvants.

11. 10. A solid formulation according to any preceding claim, wherein the solid formulation comprises dextran in the range of 40-99%, 49.5-99%, 50-99%, 51-99%, 63-99%, 66-99%, 74-99% or 82-99% (w / w).

12. 10. A solid formulation according to any of the preceding claims, wherein the dextran is selected from the grades having an average molecular weight of 10 kDa or more, or between 10 kDa and 110 kDa, preferably 70 kDa.

13. 10. A solid formulation according to any of the preceding claims, wherein the selected dextran contains 0.5% to 6% (w / w) water, preferably 1% to 5%, more preferably 1% to 4% water.

14. 10. A solid dosage form according to any preceding claim, wherein the solid dosage form is a tablet or microtablet and / or is preferably elongated.

15. 10. A solid form according to any preceding claim, wherein the solid form has a length to width ratio of from 2:1 to 6:1, preferably about 4:

1.

16. 10. A solid dosage form according to any preceding claim, wherein the solid dosage form has a width of from 0.5 mm to 2 mm, preferably from 0.75 mm to 1.2 mm, most preferably about 0.85 mm.

17. 10. A solid dosage form according to any preceding claim, wherein the solid dosage form has a length of 1.7 to 12 mm, preferably 2 to 6 mm, more preferably about 4 mm.

18. 15. The solid dosage form according to claim 14, wherein the tablet or microtablet has a cusp with an internal angle of 22.5° to 90°.

19. 10. The solid dosage form of any preceding claim, further comprising one or more of methionine, cysteine, histidine, citric acid, sodium chloride, sodium hydroxide, hydrochloric acid, potassium chloride, Tween 20, Tween 40, Tween 60, Tween 80, albumin, mannitol, trehalose, sucrose, carboxymethylcellulose sodium salt, or combinations thereof.

20. 10. A solid dosage form according to any preceding claim, wherein the lubricant is magnesium stearate.

21. 10. A solid dosage form according to any of the preceding claims, wherein the formulation comprises up to 5% (w / w) of a lubricant.

22. 10. A solid dosage form according to any of the preceding claims, wherein the formulation further comprises CMC, preferably in the range of 10-50% (w / w), more preferably the formulation comprises 36%-50% (w / w) CMC, optionally together with 9-39% (w / w) mannitol.

23. 10. A solid dosage form according to any preceding claim for use in the treatment or prevention of one or more diseases or disorders.

24. If the disease or disorder is cancer, yellow fever, rabies, diphtheria, tetanus, Haemophilus influenzae type B (Hib), whooping cough, pneumococcal disease, meningococcal disease, human papillomavirus (HPV), HIV, HSV2 / HSV1, influenza (types A, B, and C), parainfluenza, polio, RSV, rhinovirus, rotavirus, hepatitis A, acquired immune deficiency syndrome (AIDS), anthrax, gastroenteritis, enteroviral disease, measles, mumps, varicella-zoster, glandular fever, respiratory disease, rubella, human T-cell lymphoma type I (HTLV-I), hepatitis B, hepatitis C, hepatitis D, poxvirus disease, 24. The solid dosage form of claim 23, wherein the solid dosage form is selected from or associated with one or more of cholera, Japanese encephalitis, Zika, Chikungunya, bat lyssavirus, Q fever, Rift Valley fever, Hendra virus, tularemia, Nipah virus, Lassa fever, typhoid, Crimean-Congo haemorrhagic fever, Ebola, plague and Shigella, or veterinary diseases such as foot and mouth disease (including serotypes O, A, C, SAT-1, SAT-2, SAT-3 and Asia-1), coronavirus, bluetongue, feline leukemia, avian influenza, Hendra and Nipah viruses, pestivirus, canine parvovirus and bovine viral diarrhea virus.

25. 10. A solid formulation according to any of the preceding claims, wherein the solid formulation is for use as a vaccine, preferably a single-dose vaccine.

26. 26. The solid dosage form of claim 23, 24 or 25, wherein the treatment or prevention comprises the use of a needle-free delivery device.

27. Use of a solid formulation according to any of the preceding claims in a method of needle-free vaccination.

28. Yellow fever, rabies, diphtheria, tetanus, Haemophilus influenzae type B (Hib), whooping cough, pneumococcal disease, meningococcal disease, human papillomavirus (HPV), HIV, HSV2 / HSV1, influenza virus (types A, B and C), parainfluenza virus, poliovirus, RSV virus, rhinovirus, rotavirus, hepatitis A virus, lentivirus including human immunodeficiency virus (HIV), Norwalk virus, enterovirus, astrovirus, measles virus, mumps virus, varicella zoster virus, cytomegalovirus, Epstein-Barr virus, adenovirus, respiratory disease, rubella, human T-cell lymphoma virus type I (HTLV-I), hepatitis B virus, hepatitis C virus, 10. Use of a solid formulation according to any of the preceding claims in a method of needle-free vaccination against infections by Hepatitis D virus, Poxvirus and Vaccinia virus, Cholera, Japanese encephalitis virus, Zika virus, Chikungunya virus, Bat lyssavirus, Q fever, Rift Valley fever virus, Hendra virus, Tularemia, Nipah virus, Lassa fever, Typhoid fever, Crimean-Congo hemorrhagic fever virus, Ebola virus, Plague and Shigella, or against veterinary diseases such as Foot and Mouth Disease (including serotypes O, A, C, SAT-1, SAT-2, SAT-3 and Asia-1), Coronavirus, Bluetongue, Feline Leukemia Virus, Avian Influenza, Hendra and Nipah viruses, Pestivirus, Canine Parvovirus and Bovine Viral Diarrhea Virus.

29. 10. A vaccine comprising a solid formulation according to any preceding claim, wherein the type of vaccine is selected from the group consisting of attenuated (live) vaccines, inactivated vaccines, toxoid vaccines, subunit or purified antigen vaccines, conjugate vaccines, neoantigen vaccines, RNA vaccines, DNA vaccines, heterologous "Jenner" vaccines, homologous vaccines and recombinant vector vaccines.

30. 10. A method for producing a tablet containing a solid formulation or vaccine according to any of the preceding claims, comprising the steps of: Mixing the ingredients of the solid formulation in dry powder form; compressing the powder in a die; and The solid is dried at approximately 25-40°C for at least 24 hours. A manufacturing method by

31. 31. The method of claim 30, wherein the step of mixing the components of the solid formulation in dry powder form comprises spray drying or freeze drying the dextran together with one or more of the other components of the solid formulation.

32. 1. A method for making a tablet containing a solid formulation comprising at least one therapeutic and / or prophylactic agent, dextran, and at least one excipient, the method comprising: The components of the solid formulation are mixed in dry powder form (dextran is mixed with at least one excipient by spray drying); compressing the powder in a die; and The solid is dried at approximately 25-40°C for at least 24 hours. The method includes:

33. 33. The method of claim 30, 31 or 32, wherein the die is configured to produce microtablets, preferably with a diameter of 0.5 mm to 2 mm, preferably 0.75 mm to 1.2 mm, most preferably 0.85 mm.

34. A method according to any of claims 30 to 33, wherein the drying step comprises drying at approximately 25°C to 40°C for 5 to 11 days under vacuum, preferably at 10 mbar.

35. 34. The method of claim 33, wherein drying is at approximately 25°C and 10 mbar for at least 5 days.

36. A method for the treatment or prevention of a disease or disorder, said method comprising administering to a subject in need thereof a therapeutically effective amount of a solid formulation as defined in any one of claims 1 to 26.

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