SOLID DOSE FORMULATIONS FOR NEEDLE-FREE DELIVERY

Abstract

The present disclosure relates to solid dose formulations for needle-free delivery comprising 0.01 to 60 (w/w) of one or more therapeutic agent and/or prophylactic agent; and 40.0% to 99.99% (w/w) of dextran. The invention further concerns methods of producing a solid dose formulation tablet and application its particular medical uses, in particular as a vaccine.

Claims

1. (canceled)

2. A solid dose formulation having a compressive strength of at least about 80 MPa for needle-free delivery comprising: 0.01%-25.0% (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, or combination of two or more, different excipients, excluding dextran.

3. (canceled)

4. The solid dose formulation according to claim 2, wherein the excipient or excipients are selected from the group consisting of trehalose, mannitol and CMC.

5. The solid dose formulation according to claim 2, further comprising at least 0.5% (w/w) of a lubricant.

6. The solid dose formulation according to claim 2, wherein the at least one therapeutic and/or prophylactic agent is an immunogen.

7. (canceled)

8. The solid dose formulation according to claim 2, wherein the at least one therapeutic and/or prophylactic agent is a biological or chemical preparation selected from the group consisting of a vector, a protein, a protein subunit, DNA, RNA, a toxoid or a polysaccharide-antigen conjugate, and a checkpoint inhibitor.

9-10. (canceled)

11. The solid dose formulation according to claim 2, wherein the solid dose formulation comprises dextran in the range of 40-99%.

12. The solid dose formulation according to claim 2, wherein the dextran is selected from a grade with a mean molecular weight between 10 kDa and 110 kDa.

13. The solid dose formulation according to claim 2, wherein the dextran selected includes 0.5% to 6% (w/w) water.

14. The solid dose formulation according to claim 2, wherein the solid dose formulation is a tablet or micro tablet, and/or is elongated.

15. The solid dose formulation according to claim 2, wherein the solid dose formulation has a length to width ratio from 2:1 to 6:1.

16. The solid dose formulation according to claim 2, wherein the solid dose formulation has a width from 0.5 mm to 2 mm and a length from 1.7 to 12 mm.

17. (canceled)

18. The solid dose formulation according to claim 14, wherein the tablet or micro tablet has a pointed tip with an internal angle of between 22.5° and 90°.

19. The solid dose formulation according to claim 2, 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, sodium carboxymethylcellulose salt, or a combination thereof.

20. The solid dose formulation according to claim 5, wherein the lubricant is magnesium stearate.

21. (canceled)

22. The solid dose formulation according to claim 2, wherein the formulation further comprises CMC, in the range of 10-50% (w/w) and 9-39% (w/w) mannitol.

23-36. (canceled)

37. A method of treatment or prevention of one or more diseases or disorders, the method comprising: providing a solid dose formulation having a compressive strength of at least about 80 MPa for needle-free delivery comprising: 0.01%-25.0% (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, or combination of two or more, different excipients, excluding dextran; and using a needle-free delivery device, administering a therapeutically-effective amount of said solid dose formulation to a patient.

38. The method of treatment or prevention of one or more diseases or disorders of claim 37 wherein the disease or disorder is selected from the group consisting of: cancer, yellow fever, rabies, diphtheria, tetanus, haemophilus influenza type B (Hib), pertussis, pneumococcal diseases, meningococcal diseases, human papilloma viruses (HPV), HTV, HSV2/HSV1, influenza (types A, B and C), para influenza, polio, RSV, rhinoviruses, rotaviruses, hepatitis A, acquired immunodeficiency syndrome (AIDS), anthrax, gastroenteritis, enterovirus diseases, measles, mumps, varicella zoster, glandular fever, respiratory diseases, rubella, human T-cell lymphoma type I (HTLV-I), hepatitis B, hepatitis C, hepatitis D, poxvirus diseases, cholera, Japanese encephalitis, zika, chikungunya, bat lyssavirus, Q fever, rift valley fever, hendra virus, tularaemia, nipah virus, lassa fever, typhoid fever, Crimean-Congo haemorrhagic fever, ebola, 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 leukaemia, avian influenza, hendra and nipah virus, pestivirus, canine parvovirus, and bovine viral diarrhoea virus.

39. The method of treatment or prevention of one or more diseases or disorders of claim 37 wherein the solid dose formulation further comprises: at least 0.5% (w/w) of a lubricant; 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, sodium carboxymethylcellulose salt, or a combination thereof; wherein the at least one therapeutic and/or prophylactic agent is a biological or chemical preparation selected from the group consisting of a vector, a protein, a protein subunit, DNA, RNA, a toxoid or a polysaccharide-antigen conjugate, and a checkpoint inhibitor, and wherein the excipient or excipients are selected from the group consisting of trehalose, mannitol and CMC.

40. The method of treatment or prevention of one or more diseases or disorders of claim 37 wherein the solid dose formulation is a tablet or micro tablet having a pointed tip with an internal angle of between 22.5° and 90°.

41. A method of vaccinating a patient against one or more diseases or disorders, the method comprising: providing a solid dose formulation having a compressive strength of at least about 80 MPa for needle-free delivery comprising: 0.01%-25.0% (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, or combination of two or more, different excipients, excluding dextran; and using a needle-free delivery device, administering a therapeutically-effective amount of said solid dose formulation to a patient.

Description

DESCRIPTION OF THE INVENTION

[0056] Certain aspects and embodiments of the invention will now be illustrated by way of examples and with reference to the tables/figures herein.

[0057] FIG. 1 shows compression stress (MPa) plotted against dextran content (%) for 2 mm diameter tablets when CMC content (%) is varied.

[0058] FIG. 2 shows a contour plot how varying the percentage % (w/w) of dextran and CMC impacts mean compressive strength (MPa) of the resulting 2 mm diameter tablet.

[0059] FIGS. 3A, 3B and 3C show the impact dextran concentration as a percentage (w/w) of the composition has on mean compressive strength (MPa) and ejection force (kg) of the resulting 1 mm diameter tablet in accordance with different excipient combinations.

IMPACT OF DEXTRAN VS OTHER COMPONENTS ON TABLET STRENGTH

[0060] It is desirable to understand the impact on compressive strength of the final tablet when the dextran as a percentage of the composition is varied in accordance with different excipients.

[0061] To this end, different blends of compositions with 29.7%, 49.5% and 99% dextran were tableted with 1% of a lubricant, Sodium Stearyl Fumarate (SSF) and CMC.

[0062] Where required, mannitol was used as the excipient to make up the composition to 100% (w/w).

[0063] A comparison composition of 99% CMC and 1% lubricant was also tested. The resulting tablets were dried at 40° C. in a vacuum oven at 10 mbar for 24 hours and then tested for compression strength.

[0064] The data shows that dextran impacts desirably on the blends within the composition, consistently conferring a desirable compressive strength (at least 80 MPa) to the tablet alone and in some examples in combination with CMC and or mannitol, helping to improve or maintain that strength).

[0065] 99% Dextran was shown to provide a strength well in excess of that which is needed for the present invention 148 MPa (as compared to 80 MPa) confirming that this component conveys specific strength useful in this type of needle-free solid dose formulation. In contrast, CMC or mannitol alone conferred an insufficient compressive strength to the resulting tablet, well below what is required for this application.

[0066] Furthermore, from the extrapolated curve of the graphical analysis, 66% of dextran alone appears sufficient to retain a technically acceptable compressive strength of 80 MPa.

[0067] The graphical analysis confirms that CMC (sometimes in combination with mannitol) can be combined with dextran to retain acceptable compressive strength. However, if CMC and dextran are combined alone, in specific percentages the compressive strength can be maintained or enhanced.

[0068] However, such combinations do not reach the strength post drying achieved by use of dextran in high percentage alone suggesting strongly (particularly as it relates to FIG. 2) that CMC is not the major strength giving factor in the final tested tablet composition.

[0069] The following table lists the results and further the extrapolated percentages for a working range when the desired strength (80 MPa) is selected from the curve in the graph, provided in FIG. 1 or FIG. 2.

TABLE-US-00001 Sodium carboxymethyl Sodium Stearyl Compressive Strength cellulose salt Dextran Fumarate after drying (CMC) Mannitol 70 (SSF) (MPa) — — 99% 1% 148 — 33% 66% 1% 80 (FIG. 1) 36% — 63% 1% 80 (FIG. 2) 10% 39% 50% 1% 80 (FIG. 2) 49.5%.sup.  — 49.5%.sup.  1% 136 50%  9% 40% 1% 80 (FIG. 1) 49.5%.sup.  19.9%.sup.  29.7%.sup.  1%  40 99% — — 1% — Insufficient robustness to test — 69.2%.sup.  29.8%.sup.  1%  44 — 99% — 1%  34

[0070] Dextran Concentration on Compressive Strength

[0071] Further, the following formulations with the following compositions which were made as listed in the table below:

TABLE-US-00002 Mean compressive Mean strength Dextran Magnesium Stearate ejection after drying 70 Mannitol CMC Trehalose (MgS) force (N) (MPa) 99% — — — 1% 0.98 132 98%  1% — — 1% 1.13 131 95%  4% — — 1% 1.13 128 90%  9% — — 1% 1.43 128 74% 25% — — 1% 2.15 131 49% 50% — — 1% 3.67 116 25% 74% — — 1% 7.89 89.2 24% 75% — — 1% — — 98% —  1% — 1% 0.75 138 95% —  4% — 1% 0.63 146 90% —  9% — 1% 0.65 140 74% — 25% — 1% 0.62 122 49% — 50% — 1% 0.61 80.7 25% — 74% — 1% 0.76 29.8 24% — 75% — 1% — — 98% — —  1% 1% 2.25 132 95% — —  4% 1% 2.79 134 90% — —  9% 1% 2.46 136 74% — — 25% 1% 4.17 128 49% — — 50% 1% 7.56 108 25% — — 74% 1% 9.71 77.9 24% — — 75% 1% — —

[0072] It is desirable to understand the impact on compressive strength when the dextran concentration as a percentage of the composition changes in accordance with different excipients. Blends of the above compositions were tableted in a 1 mm die.

[0073] After vacuum drying at 25° C. for 5 days, each tablet was tested for its compressive strength.

[0074] The data show that a substantial percentage of dextran within the composition consistently confers a desirable compressive strength (at least 80 MPa) to the solid dose. The data also show that in certain embodiments, Dextran 70 content can be as low as 25% (w/w) and confer sufficient mechanical strength. A clear trend can be seen in FIG. 3 showing a reduction in mean ejection force (kg) with increased dextran content irrespective of the second excipient combined with dextran.

[0075] Excipient Selection in Processing

[0076] Ejection force is the force required to eject the compressed tablet from the tableting machinery. Ejection involves breaking the adhesions between the die wall and compact surface. Heat is generated when the tablet is ejected from the tableting machinery through friction between the tablet and the die wall. Absorption of this heat leads to bond formation. Lubrication is necessary to reduce ejection forces and reduce the risk of tablet defects post-unloading. For the purpose of administering a suitable needle-free solid dose formulation parenterally in humans, it was necessary to find a parenterally acceptable tableting lubricant. A lubricant identified was magnesium stearate (MgS). It was desirable to compare the ejection force (from the die) of dextran 70 blended with MgS as compared to sodium stearyl fumarate (SSF)—one of the most commonly used lubricants in tableting processes. Lubricants were tested in quantities ranging from 0.5 to 5.0% of the total blend comprising otherwise pure dextran. Blends of the resulting formulations were tableted in a 2 mm die and ejection forces of the resulting tablets were measured.

TABLE-US-00003 Lubricants Amount added (%) Mean ejection force (kg) SSF 0.5 1.39 1.0 1.52 2.0 1.33 MgS 0.5 1.71 1.0 1.33 2.0 1.25 5.0 1.36

[0077] The ejection force of tablets comprising MgS was comparable to those prepared using SSF and therefore MgS was deemed to represent a useful alternative suitable for the manufacturing type and purpose. These results suggest that MgS is a particularly suitable lubricant for tableting manufacturing across the percentage range shown.

[0078] Grade of Dextran

[0079] Dextran is a generic term for a family of glucopolysaccharides made by polymerization of the α-d-glucopyranosyl moiety of sucrose in a reaction catalysed by the enzyme dextransucrase. The common feature is a preponderance of (1.fwdarw.6)-linked α-d-glucopyranosyl units.

[0080] Dextran is available in a number of different grades. It has been shown above that dextran with a mean molecular weight of 70 kDa provides good compressive strength. In this example, further grades of dextran were tested.

[0081] Formulations consisting of dextran and 1% magnesium stearate were tableted at a diameter of 2 mm, and dried at 40° C. for 24 hours. Compressive strength testing was conducted after drying.

TABLE-US-00004 Mean compressive Dextran grade strength Mean mw (kDa) (MPa) 1 73 10 117 40 110 110 104

[0082] The results show that all the grades tested were able to achieve the desired compressive strength of at least about 80 MPa, with the exception of dextran that had a mean molecular weight of 1 kDa.

[0083] Processing Techniques

[0084] Furthermore, to check the effect of processing steps on strength, such as the method of combining components of the formulation, two further examples were prepared as follows but the step of spray drying was used to combine them.

TABLE-US-00005 Mean compressive Dextran strength 70 Component Lubricant (1%) (MPa) 79.2% Trehalose Magnesium 137 (19.8%) stearate (MgS) 96.5% Lysozyme Magnesium 148 (2.5%) stearate (MgS)

[0085] The base solid dose composition comprised dextran and trehalose or lysozyme with a further 1% (w/w) of lubricant. Tablets were formed with a diameter of 0.85 mm. The resulting tablets were dried at 40° C. in a vacuum oven at 10 mbar for 5 days.

[0086] The mean compressive strength was tested and considered superior in these examples, suggesting spray drying may have a very positive impact when combining excipients with dextran during the tableting process.

[0087] Compressive Strength, Drying and Moisture Content

[0088] Formulations consisting of dextran with a mean molecular weight of 70 kDa and 1% magnesium stearate were tableted at a diameter of 2 mm.

[0089] The resulting tablets were set at various drying conditions: [0090] Room temperature [0091] 25° C. in a vacuum oven at 10 mbar [0092] 40° C. in a vacuum oven at 10 mbar [0093] 25° C. in a sealed container with desiccant

[0094] The resulting compressive strength and moisture content for each drying condition was evaluated at the following time points: [0095] 1 day [0096] 5 days [0097] 11 days

TABLE-US-00006 Drying Moisture time Compressive content Drying conditions (days) strength (MPa) (%) Room temperature 0 66 4.7 Vacuum oven 25° C. 1 65 4.5 5 84 3.8 11 84 3.0 Vacuum oven 40° C. 11 98 1.8 Desiccant 25° C. 1 72 3.8 5 86 3.0 11 94 2.3

[0098] The results show a clear inverse relationship between the moisture content of the tablet and its compressive strength at all conditions tested. For 2 mm tablets, 5 and 11 days drying resulted in tablets with sufficient compressive strength at all drying conditions.

[0099] In addition, a formulation consisting of dextran with a mean molecular weight of 70 kDa and 1% magnesium stearate was tableted at a diameter of 1.2 mm. The resulting tablets were dried at 40° C. in a vacuum oven at 10 mbar for 24 hours and found to have a compressive strength above 80 MPa.

TABLE-US-00007 Drying time Compressive Drying conditions (days) strength (MPa) Vacuum oven 40° C. 1 91

[0100] The results clearly demonstrate that temperature, period of drying and mode are relevant in a given drying process during manufacture of this type of solid dose tablets; the resulting compressive strength may be adversely affected, if suitable conditions are not selected.

[0101] Tablet Size

[0102] Tablets have also been manufactured by the applicants using different diameter dies.

[0103] Tablets were compressed in either a 2 mm (control), 1.2 mm (see above example) or 0.85 mm die. Tablets were then dried for 24 hrs at 10 mbar with the temperatures specified. Compressive strength of the tablets was conducted before and after drying.

TABLE-US-00008 Drying Drying Powder temperature time Compressive Die size (mm) mass (° C.) (days) strength (MPa) 2.0 (Control) 20 mg  25° C. 5 84 1.2 7 mg 40° C. 5 91 0.85 4 mg 25° C. 5 95

[0104] The compressive strength at both diameters tested was still above 80 MPa. It is therefore observed that tablets of sufficient compressive strength can be obtained at a range of diameters below 2.0 mm, and particularly in the range 0.85 to 2.0 mm, demonstrating the composition may be used to produce a microtablet which retains suitability for needle-free delivery injection.

[0105] In embodiments, compositions with increased dextran content confer reduced ejection force which is advantageous in the tablet manufacturing process. High ejection force is associated with a higher risk of tablet defects post-unloading and can be used as a metric to identify and mitigate these risks. Moreover, high ejection force indicates that the formulation is at risk of sticking and/or picking. It is a measure of how well lubricated the formulation is; poor lubrication results in tablet defects such as picking, sticking and capping whereas over lubrication reduces tablet hardness. Lastly, high ejection force can lead to increased mechanical wear.

[0106] In examples, dextran may be provided at the lower end of the range, such as 25-49% (w/w) dextran, the bulk of the tablet may be made up with a different excipient, for example, an excipient selected from the group of trehalose, mannitol, or CMC and/or in a range of at least 50-74% (w/w)

[0107] In examples wherein the formulation comprises dextran, at less than 40% or less than 30%, and an excipient is combined with dextran, the ratio is thought to maintain or consolidate mechanical strength to achieve the minimum compressive strength required for needle-free delivery of a solid composition.

[0108] In some cases, as demonstrated in FIGS. 3A and 3B, for example formulations that comprise dextran below 40% (w/w) may still exhibit sufficient mechanical strength when present at least 25% (w/w) with a different excipient in an appropriate ratio. This has been shown particularly when the different excipient is selected from the group of trehalose and mannitol. In such examples, the second excipient makes up the majority of the bulk composition with dextran.

[0109] In examples, the formulation comprises at least 27% dextran, more particularly, at least 28% (w/w) dextran and at least 70% (w/w) of said second excipient. The excipient selected may be trehalose as shown in FIG. 3A to achieve an compressive strength of at least 80 MPa.

[0110] In examples, the formulation comprises at least 25% dextran (w/w) and at least 73% (w/w) of a further excipient. For example, when the excipient selected is mannitol it is possible to achieve a compressive strength of at least 80 MPa, as shown in FIG. 3B,

[0111] In examples, the excipient may additionally or alternatively be a stabiliser such as MgCl.sub.2, MgSO.sub.4, lactose-sorbitol, sorbitol-gelatine or tris-EDTA, a binding agent such as povidone, starch, gelatin or alginate, or a bulking agent such as mannitol, sucrose, CMC, trehalose, PLGA, PVP, PVA or PLA.

[0112] In some cases, as demonstrated in FIG. 3C, example formulations that comprise dextran as low as 49% and still exhibit sufficient mechanical strength when combined with a further excipients in an appropriate ratio, this has been shown particularly wherein the second excipient (additional to the dextran) is CMC.

[0113] Compressive Strength Testing with Formulated API Compositions

[0114] It is imperative to understand what impact, if any, the at least one therapeutic and/or prophylactic agent has on compressive strength.

[0115] To evaluate whether this property is altered by the inclusion of API different blends of 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). Producing these formulations involved freeze drying 10% of the total powders including the vaccine before the tableting process.

[0116] The following formulations with the following compositions were made as listed in the table below.

TABLE-US-00009 Formulation details Included in freeze dried matrix (10% of total powders) Bulk powders Max Dextran Dextran Magnesium stress Mannitol PVP 70 Sucrose Tris-EDTA Vaccine 70 stearate (MPa) 2.00% 0.20% 6.644% 1.00% 0.031% 0.125% 89% 1% 137 2.00% 0.20% 6.489% 1.00% 0.061% 0.250% 89% 1% 138 2.00% 0.20% 6.032% 1.00% 0.152% 0.625% 89% 1% 134

[0117] The resulting tablets were 1 mm in diameter and manufactured using 100 kg compaction force. All tablets were dried at 25° C. at 10 mbar for 5 days and found to have a compressive strength above 80 MPa.

[0118] The data show that vaccine within the range of 0.125%-0.625% (w/w) has no discernible impact on compressive strength where bulk dextran content is 89% (w/w), mannitol content is 2.0% (w/w), PVP content is 0.20% (w/w), sucrose content is 1% (w/w) and MgS content is 1% (w/w).

[0119] The applicants therefore conclude that any of the compositions of the invention maybe successfully formulated with API, for example vaccine-based API, to yield a solid dose suitable for needle-free delivery, as the compressive strength is able to be maintained.