Solid dosage formulations for needle-free delivery

Abstract

The present invention relates to a solid dosage formulation for needle-free delivery comprising 0.01 to 60 (w / w) of one or more therapeutic and / or prophylactic agents; and 40.0% to 99.99% (w / w) of dextran. The present invention also relates to a method of preparing a tablet of the solid dosage formulation and specific medical uses thereof, in particular as a vaccine.

Description

[0001] This application is a divisional application of patent application No. 202080046949.9, filed on June 25, 2020, entitled "Solid Dosing Formulation for Needle-Free Delivery". Technical Field

[0002] This invention relates to novel solid dosage forms for needle-free delivery of therapeutic or preventative pharmaceutical agents, including immunogenic agents, and also to methods for preparing tablets comprising said solid dosage forms. Background Technology

[0003] A common route of administration for therapeutic or prophylactic medications is through parenteral delivery of liquid formulations using needles and syringes. Parenteral delivery is used for therapeutic or prophylactic medications that are poorly absorbed by other routes and / or require rapid delivery.

[0004] One of the disadvantages of parenteral delivery via needles is the associated discomfort and pain for the patient, as well as the health risks posed by the use of sharp objects.

[0005] Most therapeutic or preventative pharmaceutical agents have poor solubility, often resulting in suboptimal formulations. Furthermore, their stability in aqueous form is generally lower than in solid dosage forms.

[0006] Solid dosage forms have been developed as alternatives to liquid dosage forms; however, these are typically prepared for oral administration and are primarily intended for oral administration.

[0007] Even where solid dosage forms containing therapeutic or prophylactic agents for parenteral administration have been developed, delivery via needles is sometimes still anticipated. The aim of preparing such solid dosage forms is to achieve a streamlined preparation process and controlled dissolution after administration. Therefore, the mechanical strength specifications of such solid dosage forms are used only as process controls to ensure consistent production and to maintain the solid dosage form during transport and handling before and during administration.

[0008] The applicant has previously developed needle-free devices for the parenteral delivery of therapeutic or prophylactic compounds in solid dosage forms to overcome various drawbacks associated with both parenteral delivery and liquid formulations as described above. Such devices have been disclosed in the applicant's prior patent publications, including EP1427464, EP1545662, EP1855755, and WO2016 / 124903.

[0009] The fundamental requirement for such needle-free technology is the preparation of solid dosage forms containing therapeutic or prophylactic agents, and having sufficient mechanical strength to penetrate the skin, as well as a size and shape suitable for patient comfort, such as those disclosed in EP2129366. For example, the applicant previously developed solid dosage compositions, as described in WO2017 / 068351, which specifically contain sodium carboxymethyl cellulose (CMC), and were determined to have sufficient mechanical strength of at least 80 MPa and compatibility with the needle-free delivery devices previously mentioned in this application when prepared using a wet paste extrusion method, followed by drying and cutting into the desired geometry.

[0010] Other preparation methods have been used in the art to attempt to prepare solid dosage forms with sufficient mechanical strength for parenteral administration, such as those described in EP1173151 (Novo Nordisk) and WO2011 / 042542 (Azurebio).

[0011] Tableting is a common method for preparing solid dosage forms suitable for oral administration, the size and shape of which are often unsuitable for patient comfort during parenteral administration. Examples of 1 mm diameter tablets are under investigation in the literature, but such formulations are generally unsuitable for needle-free parenteral delivery due to insufficient mechanical strength: “Development of mini-tablets with 1 mm and 2 mm diameter”, Tissen et al., International Journal of Pharmaceutics 416 (2011) 164-170.

[0012] Therefore, there remains a strong desire to provide new methods for preparing solid dosage forms for needle-free parenteral delivery.

[0013] This invention arose from the need to provide new solid dosage forms and methods for their improved preparation. Summary of the Invention

[0014] The present invention relates to a solid dosage form for needle-free delivery having a compressive strength equal to or greater than 80 MPa, the solid dosage form comprising: 0.01 to 60% (w / w) of a therapeutic agent and / or a preventive agent; and at least 40.0% to 99.99% (w / w) of dextran.

[0015] Crucially, as described in this application, in order to be suitable for needle-free administration, solid dosage forms must possess sufficient mechanical strength to withstand the stresses applied thereto during subcutaneous delivery, thereby enabling successful injection of the active substance delivered therein. Solid dosage forms can contain compositions, particularly comprising at least one pharmaceutical agent.

[0016] Surprisingly, the compositions of the present invention have a percentage of dextran defined in the above range, which is much greater than that typically found in tablet formulations in the art, achieving the mechanical and structural integrity required for needle-free administration, i.e., a compressive strength of 80 MPa or higher.

[0017] The applicant believes that, to date, publications in the art have provided virtually no data on the preparation of tablets achieving such high mechanical strength, especially in the context of the technical problem addressed in this application. This is particularly true when excipients used in typical tableting / formulation are typically used in small amounts for their intended purpose.

[0018] The applicant has developed a novel formulation in which dextran provides the main component or substance of the formulation (other than therapeutic and / or preventative agents). When the dextran is present in the range of 40.0% to 99.99% (w / w), it imparts significant and useful properties to the resulting solid dosage form, particularly in terms of delivery mechanisms. It has been found that relatively high proportions of dextran, as defined above, impart key strength parameters required for needle-free parenteral delivery of tablet formulations, especially microtablet formulations. This is especially true in needle-free delivery, and the present invention is considered extremely useful for needle-free delivery.

[0019] In the embodiments, dextran comprises 40% or more (w / w) of the total composition. For example, the formulation typically contains dextran in the range of, for example, 40-99%, 49.5-99%, or 50-99%.

[0020] Specifically, the majority of the dextran may be provided, for example, 51-99% (w / w) of dextran, 63-99% (w / w) of dextran, preferably 66-99% (w / w) of dextran, 74-99% (w / w) of dextran, or 82-99% (w / w) of dextran. In some cases, the formulation may contain up to the upper limit of 90%, 95%, 97%, 98%, 99%, 99.90%, or 99.99% of dextran. This may be combined with any lower limit within this range and is equally disclosed.

[0021] The inventors further conclude that the aforementioned technical problem can be solved in another new and inventive way, wherein a solid dosage form containing 0.01% (w / w) of at least one therapeutic and / or preventive agent is able to maintain a compressive strength of at least about 80 MPa suitable for needle-free delivery.

[0022] 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) of dextran is present in combination with at least one different excipient or a combination of different excipients. However, this requires careful selection of the (multiple) excipients and combinations used during formulation, rather than arbitrary selection. Typically, a combination of dextran and one different excipient, or a combination of dextran and another excipient, will account for at least 90-99% of the solid dosage form to address the same technical problem and produce a composition with sufficient compressive strength in needle-free delivery.

[0023] Therefore, the present invention extends to solid dosage forms for needle-free delivery having a compressive strength of at least about 80 MPa, comprising: 0.01% - 75.0% (w / w) of at least one therapeutic and / or prophylactic agent; at least 25.0% (w / w) of dextran; and at least 50% (w / w) of at least one different excipient other than dextran, or a combination of two or more different excipients. In embodiments, the at least one different excipient other than dextran or the combination of two or more excipients is in the range of 50% - 74% (w / w). In other words, the different excipients or the total combination of different excipients that do not contain the dextran component constitute 50% - 74% (w / w) of the composition. In embodiments, one or more excipients other than dextran constitute about 74%. These are preferably selected from mannitol and / or trehalose and / or CMC.

[0024] Optionally, the formulation of any invention described in this application may contain at least 0.5% (w / w) of a lubricant. In some instances, the lubricant may be selected from magnesium stearate, polyethylene glycol (PEG), or lysine. The lubricant is typically provided at at least 0.5% to 1% (w / w), but may be up to 5%. The lubricant can improve ease of preparation, for example, in tableting or microtableting processes, to help provide a consistent and reliable output when the formulation is demolded from the press (and, for example, demolded with minimal extrusion pressure).

[0025] In an embodiment, the formulation may comprise one or more excipients, wherein the excipients are selected from adhesives, fillers, or combinations thereof.

[0026] In the examples, one or more excipients are selected from 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, sodium carboxymethyl cellulose (CMC), lactic acid-glycolic acid copolymer (PLGA), polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), or polylactic acid (PLA). Selections may include combinations of these excipients and other excipients to provide additional advantages to the resulting formulation.

[0027] In particular, CMC can also be present in the formulation. It is believed that when using the lower limit of the dextran percentage range, approximately 40% or higher, the minimum compressive strength (80 MPa) of the formulation can be maintained by including a certain percentage of CMC in combination with the dextran, such as 50% CMC.

[0028] Formulations may contain low levels of CMC, such as 10% to 50% (w / w); in cases where higher levels of dextran are used, such as at least 49.5% (w / w), one or more other excipients, such as mannitol, are present. The combination of dextran and CMC is particularly advantageous when dextran is present at 50% (w / w) or more. In some cases, adding additional excipients, such as mannitol, in specific proportions may also allow for maintenance of compressive strength. Examples include the use of at least 10%–50% CMC.

[0029] In some instances, solid dosage forms provide a single unit dose. Therefore, this formulation ensures consistent dosing every time, eliminating variability caused by the administerer's technique.

[0030] Furthermore, compositions have been prepared using different grades of dextran. The effects of these (average molecular weight (mw) ranging from 1 kDa to 110 kDa) on compressive strength were tested. Specifically, the dextran used can be selected from grades with an average molecular weight of 10 kDa or greater, between 10 kDa and 110 kDa, or preferably about 70 kDa, because these embodiments maintain a compressive strength of at least 80 MPa. Therefore, all these grades can be used to prepare solid dosage forms delivered by needle-free delivery devices of the type described in this application.

[0031] A particular advantage is that such solid dosage forms reliably maintain the required strength when the dimensions are adjusted to the ideal size 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 retained without having to increase the size of the dosage form or change its composition beyond the scope of this application. In embodiments, the solid dosage form is elongated; preferably, the aspect ratio is in the range of 6:1 to 2:1. Such a ratio allows for easier delivery of the 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.

[0032] In some embodiments, the solid dosage form has a sharp tip with an interior 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.

[0033] In a preferred embodiment, the agent is a biological agent for immunization, such as an antigen or other immunostimulatory biological component.

[0034] In the implementation scheme, the at least one agent may be selected from carriers, proteins, protein subunits, DNA, RNA, toxoids or polysaccharide-antigen conjugates and checkpoint inhibitors.

[0035] 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.

[0036] In formulations containing vaccines, the formulation may also contain one or more adjuvants, which help stimulate the immune response and make the vaccine more effective. Adding adjuvants to conventional attenuated vaccine formulations aims to enhance, accelerate, and prolong the specific immune response to antigenic agents. Purified subunits of biosynthetic recombinants or synthetic vaccines may contain adjuvants to elicit the desired immune response.

[0037] Stabilizers are used to help vaccines maintain their effectiveness from storage until administration. Vaccine stability is crucial, especially when the cold chain is unreliable. Instability can lead to loss of antigenicity. Some factors affecting vaccine stability are temperature and acidity or alkalinity (pH). Bacterial vaccines can become unstable due to the hydrolysis and aggregation of protein and carbohydrate molecules. Stabilizers can include MgCl2 (for OPV), MgSO4 (for measles vaccines), lactose-sorbitol, and sorbitol-gelatin.

[0038] 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.

[0039] In another aspect, the present invention relates to preparations according to any of the above embodiments, which are used as medicines for treating or preventing symptoms, diseases or disorders.

[0040] In some embodiments, the preparation is used to treat cancers associated with or caused by HPV-related cancers, including anal cancer, oropharyngeal cancer, cervical cancer, vulvar cancer, and vaginal cancer in women, and penile cancer in men.

[0041] In some instances, the preparation contains a vaccine or is used to establish vaccination for the prevention or treatment of human or animal diseases, conditions, or infections. In some instances, the disease or condition is selected from, associated with, or caused by: cancer, yellow fever, rabies, diphtheria, tetanus, Haemophilus influenzae type b (Hib), pertussis, pneumococcal disease, meningococcal disease, human papillomavirus (HPV), HTV, HSV2 / HSV1, influenza (A, B, and C), parainfluenza, poliomyelitis, RSV, rhinovirus, rotavirus, hepatitis A, acquired immunodeficiency syndrome (AIDS), anthrax, gastroenteritis, enterovirus disease, measles, mumps, varicella-zoster, glandular fever, respiratory diseases, rubella, and human papillomavirus type 1. T-cell lymphoma (HTLV-I), hepatitis B, hepatitis C, hepatitis D, poxvirus disease, cholera, Japanese encephalitis, Zika virus, chikungunya, bat rabies virus, Q fever, Rift Valley fever, Hendra virus, tularemia, Nipah virus, Lassa fever, typhoid fever, Crimean-Congo hemorrhagic fever, Ebola virus, plague and Shigella, or for veterinary diseases such as foot-and-mouth disease (including serotypes O, A, C, SAT-1, SAT-2, SAT-3 and Asia-1), coronavirus, bluetongue disease, feline leukemia virus, avian influenza, Hendra and Nipah viruses, distemper virus, canine parvovirus and bovine viral diarrhea virus.

[0042] In some implementations, the vaccine is a multivalent or combination vaccine. For example, the present invention can be used to treat infections caused by two or more different types of diseases or viruses, such as measles, mumps, and rubella (e.g., MMR vaccine).

[0043] In some implementations, the vaccine is selected from attenuated (live) vaccines, inactivated vaccines, toxoid vaccines, subunit or purified antigen vaccines, conjugate vaccines, neoantigen vaccines, RNA vaccines, DNA vaccines, and recombinant vector vaccines. Examples of suitable vectors include adenovirus, measles virus, vaccinia virus, poxvirus, alpha virus, vesicular stomatitis virus (VSV), and lentiviral vectors.

[0044] In a preferred embodiment, the agent is a preventative agent, and the prevention is an immune response against a symptom, disease, or disorder.

[0045] Other diseases of interest may include MERS (respiratory), Lassa fever, Nipah virus disease, Rift Valley fever, Chikungunya fever, plague, Zika virus disease, Shigella disease, and influenza.

[0046] The vaccine of the present invention can be used to prevent or treat viral infections, said viruses including one or more of human papillomavirus (HPV), HTV, HSV2 / HSV1, influenza virus (A, B, and C), parainfluenza virus, poliovirus, RSV virus, rhinovirus, rotavirus, hepatitis A virus, norovirus, 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.

[0047] The vaccine can also be used to provide an appropriate immune response against a variety 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 disease, feline leukemia virus, avian influenza, Hendra and Nipah viruses, distemper virus, canine parvovirus, and bovine viral diarrhea virus.

[0048] In some implementation schemes, the vaccine is a subunit vaccine, a conjugate vaccine, a multivalent vaccine, or a combination vaccine.

[0049] The present invention also relates to methods for treating or preventing conditions, diseases, or disorders, said methods comprising administering to a subject in need a therapeutically effective amount of an agent as defined in any of the preceding claims. In some embodiments, for example when the composition is a vaccine and the agent is a prophylactic agent, the method of preventing disease comprises immunization. Therefore, it is useful that the present invention provides a novel, efficient, and effective means by which patient-compliant vaccination can be performed. Treatment methods may include vaccination against any of the diseases listed in this application or against any of the viruses associated with said diseases.

[0050] Furthermore, the invention described in this application also relates to a novel method for preparing tablets that retains the characteristic requirements needed for needle-free delivery. In particular, the invention relates to a method for preparing tablets comprising a solid dosage form according to any of the preceding claims by the following steps: combining the components of the solid dosage form in the form of a dry powder; compressing the powder directly in a mold; and drying the solid dosage form at a temperature of 25°C to 40°C for at least 24 hours.

[0051] In the embodiments, the above method is used to prepare microtablets, preferably elongated microtablets. In the embodiments, the mold is configured to prepare tablets with a diameter of 0.5 to 2 mm, preferably 0.75 to 2 mm, and most preferably 0.85 mm. Tablets with a wider diameter may not be desirable because they may increase the sensation felt by the recipient; reducing patient compliance associated with this type of administration.

[0052] The mold itself can be elongated and / or have a diameter of 0.5 mm to 2 mm, preferably 0.75 mm to 1.2 mm. More preferably, the diameter of the mold is about 0.85 mm.

[0053] In some instances, the drying step includes drying under vacuum at about 25°C to 40°C for 1 to 11 days. In some instances, drying is performed at about 10 mbar and / or about 25°C. In a preferred embodiment of the method of the invention, combining components may include spray-drying or freeze-drying the dextran together with one or more other components of the formulation prior to the compression step.

[0054] The present invention also relates to a novel method for preparing tablets comprising a solid dosage form, said solid dosage form comprising at least one therapeutic and / or preventive agent, a dextran, and at least one excipient, said method comprising: combining the components of the solid dosage form into a dry powder form, wherein said dextran is combined with at least one excipient by spray drying; compressing the powder in a mold; and drying said solid dosage form at about 25-40°C for at least 24 hours.

[0055] Therefore, the method of the present invention provides particularly useful tablets, and in embodiments, microtablets are provided that have sufficient mechanical strength for needle-free delivery. The present invention also relates to methods for treating or preventing diseases or disorders, the methods comprising administering to a subject in need a therapeutically effective amount of a solid dosage form as described in this application or prepared according to the present invention. Attached Figure Description

[0056] Figure 1 The graph shows the relationship between the compressive stress (MPa) of a 2 mm diameter tablet and the dextran content (%) as the CMC content (%) changes.

[0057] Figure 2 A contour plot showing how changes in the percentage (w / w) of dextran and CMC affect the average compressive strength (MPa) of the resulting 2 mm diameter tablets.

[0058] Figure 3A , 3B The results from 3C and 3C show the effect of dextran concentration as a percentage (w / w) of the composition on the average compressive strength (MPa) and extrusion pressure (kg) of the resulting 1 mm diameter tablets, depending on the different excipient combinations. Detailed Implementation

[0059] Certain aspects and embodiments of the invention will now be illustrated with reference to examples and the tables / figures in this application.

[0060] Effect of dextran and other ingredients on tablet strength

[0061] When the percentage of dextran in the composition varies depending on the different excipients, it is desirable to understand its effect on the compressive strength of the final tablet.

[0062] For this purpose, blends of different compositions containing 29.7%, 49.5% and 99% dextran were compressed together with 1% of the lubricant sodium stearoyl fumarate (SSF) and CMC.

[0063] When necessary, mannitol is used as an excipient to bring the composition up to 100% (w / w).

[0064] A comparative composition with 99% CMC and 1% lubricant was also tested. The resulting tablets were dried in a vacuum oven at 40°C and 10 mbar for 24 hours, and then the compressive strength was tested.

[0065] Data shows that dextran has a desirable effect on the blends within the composition, imparting the desired compressive strength (at least 80 MPa) to the tablets, alone and in some instances in combination with CMC and / or mannitol, and helps to improve or maintain that strength.

[0066] The 99% dextran demonstrated a strength of 148 MPa, far exceeding the strength required by this invention (compared to 80 MPa), confirming that this component provides the specific strength suitable for this type of needle-free solid dosage form. In contrast, CMC or mannitol alone imparted insufficient compressive strength to the resulting tablets, far below the strength required for this application.

[0067] Furthermore, based on the extrapolation curves from the graphical analysis, 66% dextran alone appears to be sufficient to maintain a technically acceptable compressive strength of 80 MPa.

[0068] Graphical analysis confirms that CMC (sometimes in combination with mannitol) can be combined with dextran to maintain acceptable compressive strength. However, if CMC and dextran are combined alone in specific percentages, compressive strength can be maintained or improved.

[0069] However, such a combination cannot achieve the post-dry strength attainable by using only a high percentage of dextran, which strongly suggests (especially with) Figure 2 (When relevant) CMC is not the primary strength-contributing factor in the final tested tablet composition.

[0070] The following table lists when from Figure 1 or Figure 2 When selecting the desired intensity (80 MPa) in the curve provided in the chart, the working range results and additional extrapolation percentages are shown.

[0071]

[0072] Effect of dextran concentration on compressive strength

[0073] In addition, the following formulations having the following compositions as listed in the table below were prepared:

[0074]

[0075] When the percentage of dextran concentration in the composition varies depending on different excipients, it is desirable to understand its effect on compressive strength. The blends of the above compositions are tableted in a 1 mm mold.

[0076] After vacuum drying at 25°C for 5 days, the compressive strength of each tablet was tested.

[0077] Data shows that a significant percentage of dextran in the composition consistently imparts the desired compressive strength (at least 80 MPa) to the solid dosage form. Data also shows that in some embodiments, the dextran 70 content can be as low as 25% (w / w) and still impart sufficient mechanical strength. A clear trend can be seen in Figure 3, showing that regardless of the second excipient combined with the dextran, the average extrusion pressure (kg) decreases with increasing dextran content.

[0078] Selection of excipients in processing

[0079] Extrusion pressure is the force required to eject a compressed tablet from a tableting machine. Ejection involves breaking the adhesive forces between the die wall and the compact surface. Heat is generated through friction between the tablet and the die wall as the tablet is demolded from the tableting machine. Absorption of this heat leads to bond formation. Lubrication is necessary to reduce extrusion pressure and the risk of post-expansion tablet defects. For appropriate needle-free solid dosage forms to be administered parenterally, it is necessary to find a parenterally acceptable tableting lubricant. The identified lubricant is magnesium stearate (MgS). The extrusion pressure of dextran 70 blended with MgS needs to be compared with that of sodium stearate fumarate (SSF) (one of the most commonly used lubricants in the tableting process) (from the die). The tested amount of lubricant is 0.5% to 5.0% of the total blend containing pure dextran in other ways. The resulting formulation blend is tableted in a 2 mm die, and the extrusion pressure of the resulting tablets is measured.

[0080]

[0081] The extrusion pressure of tablets containing MgS is comparable to that of tablets prepared using SSF, thus MgS is considered a useful alternative suitable for both preparation type and purpose. These results indicate that MgS is a particularly suitable lubricant for tablet preparation within the indicated percentage range.

[0082] Grades of beta-glucan

[0083] Dextran is a collective term for a family of glycopolysaccharides prepared by polymerization of the α-d-d-glucopyranosyl moiety of sucrose in a reaction catalyzed by the enzyme dextransulanase. A common characteristic is the dominance of (1 → 6)-linked α-d-glucopyranosyl units.

[0084] Dextran can be obtained in various grades. As shown above, dextran with an average molecular weight of 70 kDa provides good compressive strength. In this example, other grades of dextran were tested.

[0085] The formulation consisting of dextran and 1% magnesium stearate was compressed into tablets with a diameter of 2 mm and dried at 40°C for 24 hours. Compression strength was tested after drying.

[0086]

[0087] The results showed that, except for the dextran with an average molecular weight of 1 kDa, all tested grades were able to achieve the expected compressive strength of at least about 80 MPa.

[0088] Processing technology

[0089] In addition, to examine the effect of processing steps, such as the method of combining formulation components, on strength, two more examples were prepared as follows, but combined using a spray drying step.

[0090]

[0091] The basic solid dosage composition contains dextran and trehalose or lysozyme, as well as an additional 1% (w / w) lubricant. Tablets with a diameter of 0.85 mm were formed. The resulting tablets were dried in a vacuum oven at 40°C and 10 mbar for 5 days.

[0092] The average compressive strength was tested in these examples and was considered excellent, indicating that spray drying can have a very positive effect when excipients are combined with dextran during the tableting process.

[0093] Compressive strength, drying and moisture content

[0094] The formulation, consisting of dextran with an average molecular weight of 70 kDa and 1% magnesium stearate, is compressed into tablets with a diameter of 2 mm.

[0095] The resulting tablets were placed under various drying conditions:

[0096] room temperature

[0097] In a vacuum oven at 25°C and 10 mbar

[0098] In a vacuum oven at 40°C and 10 mbar

[0099] In a sealed container with desiccant at 25°C

[0100] The compressive strength and moisture content obtained under each drying condition were evaluated at the following time points:

[0101] 1 day

[0102] 5 days

[0103] 11 days

[0104]

[0105] The results showed a clear inverse relationship between the moisture content of the tablets and their compressive strength under all test conditions. For 2 mm tablets, tablets with sufficient compressive strength were obtained after drying for 5 and 11 days under all drying conditions.

[0106] Furthermore, a formulation consisting of dextran with an average molecular weight of 70 kDa and 1% magnesium stearate was compressed into tablets with a diameter of 1.2 mm. The resulting tablets were dried in a vacuum oven at 40°C and 10 mbar for 24 hours, and their compressive strength was found to be above 80 MPa.

[0107]

[0108] The results clearly demonstrate that temperature, drying time, and mode are relevant in the preparation of this type of solid dosage tablets, given the drying process; and that the resulting compressive strength may be adversely affected if suitable conditions are not selected.

[0109] Tablet size

[0110] The applicant also prepared tablets using molds of different diameters.

[0111] Tablets were compressed in molds with diameters of 2 mm (control), 1.2 mm (see examples above), or 0.85 mm. The tablets were then dried at 10 mbar and the specified temperature for 24 hours. The compressive strength of the tablets was measured before and after drying.

[0112]

[0113] The compressive strength of the two diameters tested remained above 80 MPa. Therefore, it was observed that tablets with sufficient compressive strength can be obtained in the diameter range below 2.0 mm, particularly in the range of 0.85 to 2.0 mm, indicating that the composition can be used to prepare microtablets that maintain suitability for needle-free injection.

[0114] In the implementation, compositions with increased dextran content impart reduced extrusion pressure, which is advantageous in tablet manufacturing processes. High extrusion pressure is associated with a higher risk of tablet defects after extrusion and can be used as a measure to identify and mitigate these risks. Furthermore, high extrusion pressure indicates a risk of adhesion and / or sticking in the formulation. It is a measure of the degree of lubrication in the formulation; poor lubrication can lead to tablet defects such as adhesion, sticking, and cracking, while excessive lubrication can reduce tablet hardness. Finally, high extrusion pressure can lead to increased mechanical wear.

[0115] In examples, dextran can be provided at the lower end of the range, for example, 25-49% (w / w) of dextran, and the body of the tablet can be composed of different excipients, such as excipients selected from trehalose, mannitol or CMC and / or in the range of at least 50-74% (w / w).

[0116] In instances where the formulation contains less than 40% or less than 30% dextran and the excipient is combined with the dextran, this proportion is considered to maintain or reinforce mechanical strength to achieve the minimum compressive strength required for needle-free delivery of solid compositions.

[0117] In some cases, such as Figure 3A and 3B As shown, formulations containing, for example, less than 40% (w / w) of dextran can still exhibit sufficient mechanical strength when at least 25% (w / w) of different excipients are present in appropriate proportions. This is particularly illustrated when the different excipients are selected from trehalose and mannitol. In such examples, the second excipient constitutes the majority of the main composition containing dextran.

[0118] In this example, the formulation contains at least 27% dextran, more particularly, at least 28% (w / w) dextran and at least 70% (w / w) of the second excipient. Figure 3A As shown, the selected excipient can be trehalose to achieve a compressive strength of at least 80 MPa.

[0119] In this example, the formulation contains at least 25% (w / w) of dextran and at least 73% (w / w) of additional excipients. For example, such as... Figure 3B As shown, when the selected excipient is mannitol, a compressive strength of at least 80 MPa can be achieved.

[0120] In examples, excipients may additionally or alternatively be stabilizers, such as MgCl2, MgSO4, lactose-sorbitol, sorbitol-gelatin, or tris-EDTA; binders, such as povidone, starch, gelatin, or alginate; or fillers, such as mannitol, sucrose, CMC, trehalose, PLGA, PVP, PVA, or PLA.

[0121] In some cases, such as Figure 3C As demonstrated in the study, the example formulation contains as little as 49% dextran and still exhibits sufficient mechanical strength when combined with other excipients in appropriate proportions, particularly where the second excipient (in addition to dextran) is CMC.

[0122] Compressive strength test using the formulated API composition

[0123] It is necessary to understand the effect of the at least one therapeutic agent and / or preventive agent on compressive strength, if any.

[0124] To evaluate whether this property is altered by the inclusion of API, blends of different compositions formulated with 0.125%, 0.250%, and 0.625% (w / w) API (vaccine) were tableted together with 89% (w / w) dextran and 1% (w / w) lubricant. Preparation of these formulations involved freeze-drying 10% of the total powder, including the vaccine, prior to the tableting process.

[0125] The following formulations, having the following compositions, were prepared as shown in the table below.

[0126]

[0127] The resulting tablets had a diameter of 1 mm and were prepared using a compression force of 100 kg. All tablets were dried at 25°C and 10 mbar for 5 days, and their compressive strength was found to be greater than 80 MPa.

[0128] Data shows that vaccines in the range of 0.125% - 0.625% (w / w) had no discernible effect on compression strength, with the main dextran content being 89% (w / w), mannitol content being 2.0% (w / w), PVP content being 0.20% (w / w), sucrose content being 1% (w / w), and MgS content being 1% (w / w).

[0129] The applicant therefore concludes that any of the compositions of the present invention can be successfully formulated with an API, such as a vaccine-based API, to produce a solid dosage form suitable for needle-free delivery, as it is able to maintain compressive strength.

Claims

1. A solid dosage form for needle-free delivery having a compressive strength of at least about 80 MPa, comprising: At least one therapeutic and / or preventative agent at a concentration of 0.01% - 60% (w / w); and 40.0% - 99.99% (w / w) of dextran. The solid dosage form described herein can be used for direct tableting.

2. The solid dosage form according to claim 1 further comprises at least 0.5% (w / w) of lubricant.

3. The solid dosage form according to claim 1 or claim 2, wherein the form may contain one or more additional excipients, wherein the excipients are selected from binders, fillers, stabilizers or combinations thereof.

4. The solid dosage form according to any one of claims 1 to 3, further comprising one or more of the following substances: 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, sodium carboxymethyl cellulose, or combinations thereof.

5. The solid dosage form according to claim 3, wherein the combination of dextran and one or more excipients other than dextran accounts for 90-99% (w / w) of the solid dosage form.

6. The solid dosage form according to claim 3, wherein the stabilizer is selected from MgCl2, MgSO4, lactose sorbitol, sorbitol gelatin or tris-EDTA.

7. The solid dosage form according to claim 3, wherein the binder is selected from povidone, starch, gelatin or alginate.

8. The solid dosage form according to claim 3, wherein the filler is selected from mannitol, sucrose, CMC, trehalose, PLGA, PVP, PVA or PLA.

9. The solid dosage form according to any one of claims 1 to 8, wherein the at least one therapeutic agent and / or prophylactic agent is an immunogen.

10. A solid dosage form according to any one of claims 1 to 8, wherein the at least one pharmaceutical agent is a biological or chemical agent for immunization.

11. The solid dosage form according to any one of claims 1 to 8, wherein the at least one pharmaceutical agent is a biological or chemical agent selected from carriers, proteins, protein subunits, DNA, RNA, toxoids or polysaccharide-antigen conjugates and checkpoint inhibitors.

12. The solid dosage form according to any one of claims 1 to 11 further comprises one or more adjuvants.

13. The solid dosage form according to any one of claims 1 to 12, wherein the dextran is selected from the class with an average molecular weight of 10 kDa to 110 kDa.

14. The solid dosage form according to any one of claims 1 to 13, wherein the selected dextran comprises 0.5% to 6% (w / w) water.

15. The solid dosage form according to any one of claims 1 to 14, wherein the solid dosage form is a tablet or microtablet, and / or preferably elongated.

16. The solid dosage form of claim 15, wherein the solid dosage form has an aspect ratio of 2:1 to 6:

1.

17. The solid dosage form of claim 15, wherein the solid dosage form has a width of 0.5 mm to 2 mm.

18. The solid dosage form of claim 15, wherein the solid dosage form has a length of 1.7 mm to 12 mm.

19. The solid dosage form of claim 15, wherein the tablet or microtablet has a sharp tip with an interior angle of 22.5° to 90°.

20. A solid dosage form according to any one of claims 1 to 19, used for the treatment or prevention of one or more diseases.

21. The solid dosage form of claim 20, wherein the treatment or prevention includes the use of a needle-free delivery device.

22. The solid dosage form according to claim 20 or claim 21, wherein the disease is selected from one or more of the following diseases or is associated with one or more of the following diseases: cancer, yellow fever, rabies, diphtheria, tetanus, Haemophilus influenzae type b, pertussis, pneumococcal disease, meningococcal disease, human papillomavirus, HTV, HSV2, HSV1, influenza A, influenza B, influenza C, parainfluenza, poliomyelitis, RSV, rhinovirus, rotavirus, and influenza A. Hepatitis, Acquired Immunodeficiency Syndrome, Anthrax, Measles, Mumps, Varicella-zoster, Glandular Fever, Rubella, Type I Human T-cell Lymphoma, Hepatitis B, Hepatitis C, Hepatitis D, Cholera, Japanese Encephalitis, Zika Virus, Chikungunya, Q Fever, Rift Valley Fever, Hendra Virus, Tularemia, Nipah Virus, Lassa Fever, Typhoid Fever, Crimean-Congo Hemorrhagic Fever, Ebola Virus, Plague, Shigella, Coronavirus, Bluetongue Disease, Avian Influenza, Distemper Virus, Canine Parvovirus, and Bovine Viral Diarrhea Virus.

23. The solid dosage form of claim 20, wherein the disease is selected from veterinary diseases.

24. The solid dosage form according to claim 23, wherein the veterinary disease is foot-and-mouth disease, selected from serotypes O, A, C, SAT-1, SAT-2, SAT-3 and Asia-1.

25. The solid dosage form of claim 20, wherein the disease is selected from one or more of the following diseases or is associated with one or more of the following diseases: gastroenteritis, enterovirus disease, respiratory disease, poxvirus disease, bat rabies virus, and feline leukemia.

26. The solid dosage form according to any one of claims 1 to 19, wherein the solid dosage form is used as a vaccine.

27. The solid dosage form of claim 26, wherein the solid dosage form is used as a single-dose vaccine.

28. Use of the solid dosage form according to any one of claims 1 to 27 in the preparation of a medicament for use in a needle-free vaccination method.

29. The use according to claim 28, wherein the drug is used for a needle-free vaccination method against infections caused by: yellow fever, rabies, diphtheria, tetanus, Haemophilus influenzae type b, pertussis, pneumococcal disease, meningococcal disease, human papillomavirus, HTV, HSV2, HSV1, influenza A virus, influenza B virus, influenza C virus, parainfluenza virus, poliovirus, RSV virus, rhinovirus, rotavirus, hepatitis A virus, human immunodeficiency virus, norovirus, astrovirus, measles virus. Mumps virus, varicella-zoster virus, cytomegalovirus, Epstein-Barr virus, adenovirus, rubella, human T-cell lymphoma virus type I, hepatitis B virus, hepatitis C virus, hepatitis D virus, poxvirus, cholera, Japanese encephalitis virus, Zika virus, chikungunya virus, Q fever, Rift Valley fever virus, Hendra virus, tularemia, Nipah virus, Lassa fever, typhoid fever, Crimean-Congo hemorrhagic fever virus, Ebola virus, plague, Shigella, coronavirus, bluetongue disease, feline leukemia virus, avian influenza, distemper virus, canine parvovirus, or bovine viral diarrhea virus.

30. The use according to claim 28, wherein the drug is used for a needle-free vaccination method against veterinary diseases.

31. The use according to claim 30, wherein the veterinary disease is foot-and-mouth disease, selected from serotypes O, A, C, SAT-1, SAT-2, SAT-3 and Asia-1.

32. The use according to claim 28, wherein the drug is used for a needle-free vaccination method against infections caused by lentiviruses, enteroviruses, respiratory diseases, poxviruses, or bat rabies viruses.

33. A vaccine comprising a solid dosage form according to any one of claims 1 to 27, wherein the type of vaccine is selected from live attenuated 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.

34. A method for preparing a tablet comprising a solid dosage form according to any one of claims 1 to 27 or a vaccine according to claim 33, the method comprising: The components of the solid dosage form are combined in the form of a dry powder; The powder is compressed in a mold; as well as The solid dosage form is dried at 25-40°C for at least 24 hours.

35. The method of claim 34, wherein the step of combining the components of the solid dosage form in the form of a dry powder comprises spray-drying or freeze-drying the dextran together with one or more of the other components of the solid dosage form.

36. A method for preparing a tablet comprising a solid dosage form according to any one of claims 1 to 27 or a vaccine according to claim 33, the method comprising: The components of the solid dosage form are combined into a dry powder form, wherein the dextran is combined with the at least one excipient by spray drying; The powder is compressed in a mold; as well as The solid dosage form is dried at 25-40°C for at least 24 hours.

37. The method of claim 34, 35 or 36, wherein the mold is configured for preparing microtablets.

38. The method of claim 37, wherein the mold is configured to prepare microtablets with a diameter of 0.5 mm to 2 mm.

39. The method of claim 37, wherein the mold is configured to prepare microtablets with a diameter of 0.75 mm to 1.2 mm.

40. The method of claim 37, wherein the mold is configured to prepare microtablets with a diameter of 0.85 mm.

41. The method according to claim 34, 35 or 36, wherein the drying step comprises drying under vacuum at 25°C to 40°C for 5 to 11 days.

42. The method according to claim 34, 35 or 36, wherein the drying step comprises drying at 25°C to 40°C for 5 to 11 days at 10 mbar.

43. The method of claim 42, wherein the drying is carried out at about 25°C and 10 mbar for at least 5 days.

44. Use of a solid dosage form as defined in any one of claims 1 to 27 in the preparation of a medicament for the treatment or prevention of a disease or disorder.

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