Methods and systems for injectable formulations

Abstract

Systems and methods for an injectable formulation are provided. The injectable formulation includes a carrier and dry particles. The dry particles have a tap density greater than 0.45 mg / mL and are suspended in the carrier at greater than or equal to 40 wt. %. The injectable formulation can be injected using a glide force less than or equal to 100 N.

Description

Cross-reference to related applications

[0001] This application claims priority to U.S. Provisional Application No. 63 / 605,430, filed December 1, 2023, entitled “METHODS AND SYSTEMS FOR INJECTABLE FORMULATIONS”. The entire contents of the foregoing application are hereby incorporated by reference for all purposes. Technical Field

[0002] This specification generally relates to the physical properties of spray-dried powders contained in injectable formulations and methods for producing such powders. Background Technology

[0003] It is not uncommon for certain pharmaceutical formulations containing specific types of active pharmaceutical ingredients (APIs), such as proteins, to require delivery by injection. For such formulations, administration via subcutaneous or intramuscular injection is preferred. Subcutaneous or intramuscular injections can be performed at home, and in some instances, using an autoinjector. Home administration improves patient experience and compliance, and can also reduce healthcare costs. Formulations of active pharmaceutical ingredients (such as proteins) delivered via subcutaneous or intramuscular injection typically require high concentrations of API and / or high injection volumes to achieve the target dose. Alternatively, ocular injections may similarly require high concentrations of API. One method to increase the dose concentration in injectable pharmaceutical formulations is to prepare a suspension of API-containing microparticles in a carrier that does not dissolve the microparticles. The methods described above have been shown to achieve suspensions with API concentrations up to 500 mg / mL or higher. However, these suspensions are highly viscous, and the injection force required for subcutaneous administration with an appropriately sized needle is greater than the acceptable injection force for manual administration or the force supported by an autoinjector. Summary of the Invention

[0004] In one instance, the aforementioned problem can be at least partially addressed by an injectable formulation comprising a carrier and a spray-dried powder composed of microparticles having a tap density greater than 0.45 g / mL, suspended in the carrier at a concentration greater than or equal to 40 wt%, wherein the injectable formulation is injected using a gliding force less than or equal to 100 N at a rate of 1 mL per 1 mL pre-filled syringe with a 27-gauge, ½-inch needle. By targeting the threshold tap density of the API-containing particles, the overall properties of the particles are determined to achieve the desired suspension viscosity and distributive force. The tap density of spray-dried particles can be influenced by particle morphology, particle size and distribution, and composition. As an example, these particles can be dried from a solution by spray drying. The tap density of the dried particles can be increased by maximizing the concentration of API in the solution. However, API stability and / or solution viscosity may limit the maximum API concentration. The tap density of the dried particles can be further increased by spray drying under vacuum. Spray drying under vacuum can reduce the outlet temperature and slow down the drying rate, which may lead to an increase in tap density. This can be utilized as an orthogonal method to increase tap density. Further spray drying under vacuum or without vacuum, while adjusting the atomization conditions, can regulate the average particle size.

[0005] It should be understood that the above overview is provided to introduce, in a simplified form, some concepts further described in the detailed description. It is not intended to identify key or essential features of the claimed subject matter, the scope of which is solely defined by the claims following the detailed description. Furthermore, the claimed subject matter is not limited to embodiments that address any shortcomings pointed out above or in any part of this disclosure. Attached Figure Description

[0006] Figure 1 A block diagram of the workflow for spray drying compounds under reduced pressure is shown.

[0007] Figure 2 A graph showing the slip force of the particle suspension as a function of the particle tap density is presented.

[0008] Figure 3 A graph comparing the slip forces of suspensions of particles with different average sizes is shown.

[0009] Figure 4 A graph comparing the slip forces of suspensions containing particles with different concentrations of API is shown.

[0010] Figure 5 A line graph showing the slip force of the particle suspension as a function of the particle tap density, and SEM images of the data points corresponding to the line graph are shown.

[0011] Figure 6 A line graph showing the slip force of the particle suspension as a function of the particle tap density is presented, which includes comparable data points for particles dried by standard spray drying and particles dried by vacuum spray drying.

[0012] Figure 7 It shows the depiction of T 出口 Line graph showing the correlation between solids wt.% and tap density of spray-dried particles.

[0013] Figure 8 A flowchart is shown for a method of spray drying to obtain particles having at least the desired tap density.

[0014] Figure 9 Line graphs showing the slip force and viscosity of suspensions of dried particles as a function of the weight percentage of solids in these suspensions are presented.

[0015] Figure 10 A graph is shown showing the slip force of the particle suspension as a function of the particle tap density for particles spray-dried at atmospheric pressure.

[0016] Figure 11 A graph is shown showing the slip force of the particle suspension as a function of the particle tap density for particles spray-dried under reduced dryer pressure.

[0017] Figure 12 A graph showing the slip force of the particle suspension as a function of outlet temperature is presented.

[0018] Figure 13 A line graph showing the slip force of the particle suspension as a function of the weight percentage of solids in the spray-dried liquid feed is presented.

[0019] Figure 14 The graph shows the slip force of the suspension as a function of the particle tap density for suspensions prepared with two different wt.% particles.

[0020] Figure 15 A line graph showing tap density as a function of droplet drying rate is presented over a range of spray drying parameters. Detailed Implementation

[0021] The following description relates to systems and methods for pharmaceutical formulations administered by injection. These pharmaceutical formulations may be suspensions of particles containing an API (such as a peptide or protein) that is required to be administered by injection. Other examples of APIs include, but are not limited to, antibodies or antibody fragments, peptides, enzymes, DNA / RNA or DNA / RNA fragments, protein degraders, and small molecules. Small molecules may contain chemically synthesized pharmaceutical ingredients typically <1500 Da. To prepare suspensions in which the slip force for administration from needles and syringes is equal to or below a threshold slip force, the particles contained in the pharmaceutical formulation may have a tap density above a threshold tap density. The effect of tap density on slip force depends on the carrier and solids concentration in the suspension; for suspensions approaching the maximum volume fraction defined by the Krieger & Dougherty equation (Equation 1), tap density has a significantly greater effect.

[0022] (1) η is the viscosity of the suspension, η0 is the viscosity of the continuous phase (e.g., the carrier), φ is the volume of the dispersed phase (e.g., the solid), and φ 最大 It is the maximum volume when the viscosity diffuses to infinity.

[0023] In some instances, the threshold tap density can be 0.45 g / mL. In some instances, the threshold slip force can be 50 N. In alternative instances, the threshold slip force can be 100 N. In some instances, powders at or above the threshold tap density can be produced by drying a solution or suspension containing an API via vacuum spray drying. A block diagram of an exemplary spray drying system is shown below. Figure 1 As shown. Powders composed of dried particles containing API can have characteristic tap densities. Spray drying parameters can be selected and adjusted to increase both tap density and yield, such as... Figure 8 The method is illustrated as a flowchart. Spray drying parameters can be adjusted to maximize the tap density of the dried particles, such as... Figure 7 and Figure 15 The line graph is shown. Multivariate analysis showed that both outlet temperature and spray solution concentration had a statistically significant effect on the tap density of powder produced by spray drying. The slip force can be tested as a function of different spray drying parameters, suspension concentration, and suspension carrier, such as... Figures 9 to 14 As shown. When powder is incorporated into a high-concentration suspension, the tapped density can be related to the slip force of the solution injected through a syringe, such as... Figure 2 As shown. Compared to other particle properties, tap density can be a more reliable indicator of the resulting slip force of a suspension. When comparing powders with different d50 sizes (e.g. Figure 3 (as shown), or when comparing powders containing different concentrations of API (such as...) Figure 4As shown in the figure, minute changes are observed in the slip forces of the suspension. Furthermore, comparing the physical appearance of particles via SEM cannot predict tap density, as... Figure 5 The slip force and the corresponding SEM image line graph are shown. Vacuum spray drying (such as by...) Figure 1 The system shown enables spray drying at low outlet temperatures, which may be advantageous for obtaining dried particles with higher tap density. Figure 6 The line graph shown compares the tap density of particles obtained by conventional spray drying and by vacuum spray drying. Different types of APIs can be vacuum spray dried for inclusion in injectable formulations. As an example, Figure 11 It was demonstrated that BSA, IgG, and lysozyme protein can all be spray-dried under vacuum to simultaneously achieve acceptable product yield and powder tap density, thereby achieving a slip force of less than 50 N.

[0024] Turn now Figure 1 A schematic diagram of a spray drying system 100 is shown. In some instances, the spray drying system 100 may include a vacuum 112 as further described below, and may be a vacuum spray drying (VSD) system. The spray drying system 100 may include a drying chamber 106. The drying chamber 106 may be configured to receive a heated gas 102 and a liquid feed 104. In some instances, the drying chamber 106 may be a jacketed drying chamber, including a jacket layer 107 fluidly connected to a temperature control bath 109. By setting the temperature of the temperature control bath 109, the user can actively control the temperature of the drying chamber 106. Under vacuum conditions, the heated gas 102 can flow at a lower mass flow rate compared to conventional (e.g., atmospheric pressure) spray drying. The lower mass flow rate may result in a greater impact of ambient heat exchange on the operating temperature (e.g., outlet temperature) of the drying chamber 106. The jacket layer 107 and the temperature control bath 109 isolate the drying chamber from heat exchange with the environment and provide increased accuracy in controlling the operating temperature of the drying chamber 106.

[0025] Drying chamber 106 may be configured to receive heated gas 102 and liquid feed 104. Liquid feed 104 may be a suspension or solution comprising a liquid phase and a product suspended or dissolved in the liquid phase. Spray drying system 100 may be configured to dry particles having a tap density above a threshold tap density. As an example, the product may be an active pharmaceutical ingredient (API) in a pharmaceutical formulation. The pharmaceutical formulation may contain the API and other excipients. As an example, the API may be a pharmaceutically active protein (e.g., antibody, enzyme, phage, cytokine, hormone, etc.). As another example, the API may contain nucleic acids, such as DNA or RNA. The type of RNA may include, but is not limited to, messenger RNA (mRNA), transfer RNA (tRNA), and / or short interfering RNA (siRNA). As a further example, the API may be a self-assembled nanoparticle encapsulating a pharmaceutical compound. The self-assembled nanoparticle may be formed from lipids and / or block copolymers. In some instances, the self-assembled nanoparticle may not be an API, but may be a carrier of the API. For example, lipid nanoparticles encapsulating RNA fragments may be spray-dried. As an additional example, the product may be an amorphous solid dispersion of the API. Preferably, the aforementioned API, as well as other APIs, can be administered to a patient via subcutaneous or intramuscular injection. For subcutaneous or intramuscular administration, a suspension containing an API at or above a threshold dose may be required, resulting in a slip force through a needle and syringe / cassette suitable for subcutaneous, ocular, or intramuscular delivery that is at or below the threshold slip force. As an example, the API may be a protein, and the threshold dose may be 200 mg / mL. As an alternative example, the threshold dose may be 500 mg / mL. In some examples, the threshold dose may be greater than 500 mg / mL. As a further example, the threshold slip force may be 50 N. In an alternative example, the threshold slip force may be 100 N. A suspension of API having the aforementioned properties can be prepared from particles with a high tap density produced by a vacuum spray dryer. Furthermore, spray drying using a vacuum spray dryer enables low TT... 出口 Spray drying, in addition to promoting high tap density, is also preferred for the aforementioned APIs that may degrade at elevated temperatures.

[0026] The liquid phase of the spray solution can be water or a highly volatile organic solvent (e.g., acetone, methanol, ethanol, isopropanol, ethyl acetate, etc.) having a boiling point of 100°C or lower, or some combination thereof. As an example, the liquid phase can be 100% water. As an alternative example, the liquid phase can be between 50% and 100% water by weight, and less than or equal to 50% organic solvent by weight. As a further example, the liquid phase can contain between 5% and 100% a low-volatile organic solvent. The low-volatile organic solvent can be an organic solvent having a boiling point above 150°C at standard pressure (e.g., 1 atm), such as dimethyl sulfoxide (DMSO), dimethylformamide (DMF), N,N-dimethylacetamide (DMAc), or N-methyl-2-pyrrolidone (NMP). The remainder of the liquid phase can consist of a miscible co-solvent, which can be water or a highly volatile organic solvent.

[0027] The heating gas 102 can be, for example, air or nitrogen. Nitrogen can be used as the heating gas 102 when the product is easily oxidized or if the liquid phase is flammable. The heating gas 102 and the liquid feed 104 can be introduced into the drying chamber 106. The liquid feed 104 can enter the drying chamber 106 via an atomizer 105. The atomizer 105 can be configured to disperse the liquid feed 104 into small droplets, thereby maximizing the amount of liquid surface area exposed to the heating gas 102. The liquid feed 104 and the heating gas 102 can enter the drying chamber 106 with different geometries. In one embodiment, both the heating gas 102 and the liquid feed 104 can enter from the top of the drying chamber 106 in a co-current configuration. In an alternative embodiment, the liquid feed 104 can enter from the top of the drying chamber 106 while the heating gas 102 enters from the bottom of the drying chamber 106 in a counter-current configuration.

[0028] The operating parameters of the spray drying system 100 can be selected such that the interaction between the heating gas 102 and the atomized droplets of the liquid feed 104 causes the atomized droplets to evaporate in the liquid phase as they leave the drying chamber 106. The operating parameters may include the pressure inside the drying chamber 106, the temperature at the outlet of the drying chamber 106, and the ratio of the liquid feed 104 to the heating gas 102.

[0029] The product can exit the drying chamber 106 and enter a cyclone separator 108. The cyclone separator 108 can be configured to separate the product particles 110 from the heated gas via vortex separation. The product particles 110 can be collected from the outlet of the cyclone separator 108. A vacuum 112 can be fluidly connected to the drying chamber 106 via the cyclone separator 108. In this way, the vacuum 112 can evacuate the drying chamber 106, and thus reduce the operating pressure within the drying chamber 106. The size of the cyclone separator 108, positioned between the vacuum 112 and the drying chamber 106, can be selected based on a balance between the desired operating pressure of the VSD and the desired collection efficiency. In one example, a larger cyclone separator reduces the pressure drop between the inlet and outlet of the cyclone separator 108, and the load on the vacuum 112 can be reduced. A smaller cyclone separator can collect particles, especially smaller particles, more efficiently than a larger one. Therefore, a smaller cyclone separator can be selected if a smaller average particle size distribution is desired.

[0030] The collected product may be a dried powder containing an API. This dried powder may be contained in a non-aqueous suspension configured for subcutaneous, ocular, or intramuscular administration to a patient. To achieve the target API dose and syringe slip force, the particles constituting the suspension are dried to have a tap density above a threshold tap density. Tap density reflects both overall particle properties and particle-particle interactions, both of which affect the suspension viscosity and, consequently, the force dispensing from the syringe.

[0031] Method 800 for spray drying particles with high tap density Figure 8 The flowchart is shown in the image. Spray drying can be performed in spray drying systems (such as...). Figure 1 The spray drying is performed on the spray drying system 100 shown. The spray drying system can be used in a co-current or counter-current configuration.

[0032] At 802, method 800 includes determining the maximum concentration of API and other excipients in the liquid feed. The maximum concentration in the liquid feed may contain API and other excipients dissolved in a suitable solvent or solvent blend. This solvent or solvent blend may be selected to facilitate spray drying and / or to ensure compatibility with API and other excipients. As an example, the maximum concentration of API in the liquid feed may be determined by the solubility of the API in the solvent or solvent blend, the stability of the API in the solvent or solvent blend (e.g., protein stability), and / or the viscosity of the resulting liquid feed solution. Selecting the maximum concentration of the liquid feed increases the amount of solids in each spray droplet, thereby increasing the tap density of the resulting dried particles.

[0033] At 804, method 800 includes selecting the relative saturation (RS) and T outlet of the spray dryer. Selecting a lower temperature and a higher relative saturation can further increase the particle density. Lowering T 出口 Furthermore, increasing relative saturation can delay the formation of particulate crusts, thereby increasing particle density and contributing to an increase in tapped density. However, high relative saturation and low T... 出口 This can also reduce the drying rate and the yield of dried particles. Since high API concentrations favor high-density particles, a higher Td can be selected for liquid feeds with higher maximum API concentrations compared to liquid feeds with lower maximum API concentrations. 出口 Furthermore, a lower RS ​​can be selected to achieve a balance between low void volume and desired yield.

[0034] Briefly go to Figure 7 Figure 700 shows the measured tap density of the collected spray-dried powder as T during spray drying. 出口 The function. As shown in line graph 700, decreasing T 出口 A strong correlation exists between increased tap density and increased solids content. A second line graph 702 shows the tap density of the collected spray-dried powder as a function of the spray solids wt.% in the liquid feed. Arrow 706 indicates the direction of increase in solids wt.% along the x-axis of line graph 702. As shown in line graph 702, increasing solids wt.% is strongly correlated with increasing tap density. Based on the correlation between line graphs 700 and 702, the tap density can be determined based on solids wt.% and the selected T... 出口 The tap density of spray-dried products (e.g., API) was predicted to obtain data points in line plots 700 and 702. Based on the data plotted in line plots 700 and 702, the accuracy of the prediction is shown in line plot 704, where the measured tap density is a function of the predicted tap density. Line 708 in line plot 704 corresponds to a perfect 1:1 prediction of the tap density. This data correlates well with line 708, confirming the T discussed above. 出口 The effect of wt.% of solids on the tap density of spray-dried particles.

[0035] Briefly go to Figure 15 The scatter plot 1500 of tap density as a function of the calculated drying rate (e.g., droplet drying rate) also shows a near-linear correlation and can be used to predict tap density. The calculated drying rate can be expressed as T 出口 Both relative saturation and density are incorporated into a single parameter, which can be used to adjust the tap density of the resulting spray-dried powder. (Astro) Data points in the () shape represent data collected via vacuum spray drying, while circular data points represent data collected via conventional spray drying. The color gradient corresponds to T values ​​in the range of 15°C to 50°C. 出口The data collected below. The data points within box 1502 correspond to T values ​​within the range of 15℃ to 30℃. 出口 The data collected below, and the data points outside frame 1502 correspond to T values ​​in the range of 35°C to 50°C. 出口 The data collected below. As shown in scatter plot 1500, the tap density and droplet drying rate exhibit a near-linear relationship. In this way, the calculated droplet drying rate can be proportional to the tap density of the resulting spray-dried powder. Furthermore, the calculated droplet rate can be used to predict and / or forecast the tap density of the resulting spray-dried powder.

[0036] Now back Figure 8 T 出口 It can be below room temperature. In some instances, T 出口 It can be lower than the boiling point of the solvent or most solvent blends (e.g., >50% by volume). In some instances, T 出口 It can be below 40℃. In a further example, T 出口 Temperature can be below 30°C. RS can be higher than the conventional target RS used for spray drying from an aqueous liquid feed. As an example, RS can be in the range of 5% - 20%. As an alternative example, RS can be in the range of 5% - 50%. In further examples, RS can be greater than 10%. In some examples, RS and T... 出口 They can be selected together. For example, T 出口 Temperature can be below 40℃, and RS can be >10%.

[0037] At 806, method 800 includes selecting P. 干燥器 In which T 出口 In instances where the P-value is sufficiently low and / or the RS is sufficiently high to reduce the spray drying yield below an acceptable level, the P-value may be reduced. 干燥器 In order to provide compensation. As an example, P 干燥器 It can be less than the atmospheric pressure of the spray dryer. As a further example, P 干燥器 It can be less than 0.6 bar or less than 0.8 bar. In some instances, when T 出口 At temperatures below 35°C, P 干燥器 It can be less than 0.6 bar or less than 0.8 bar. As a further example, when T 出口 When the temperature is below 50℃ and the RS is greater than 5%, P 干燥器 It can be less than 0.6 bar or less than 0.8 bar.

[0038] At 808, method 800 includes the selected T 出口 P 干燥器The liquid feed is spray-dried under RS ​​conditions. Methods 800 to 810 are then performed, including determining whether the spray-dried powder reaches or exceeds a target tap density, or whether the suspension of the spray-dried powder is distributed with a slip force at or below a threshold and a yield at or above a threshold. The target tap density can be measured using conventional laboratory equipment such as graduated cylinders and balances, as per the United States Pharmacopeia (USP). <616> As an example, the threshold tap density can be 0.45 mg / mL. As a further example, the tap density can be in the range of 0.5 g / mL to 0.8 g / mL. In an alternative example, the tap density can be in the range of 0.65 g / mL to 0.75 g / mL. Among other things, the threshold yield can depend on the scale of spray drying (e.g., the total volume of the liquid feed). As an example, the threshold yield can be 45%. In some instances, 808 may additionally include determining whether the particle size distribution of the spray-dried particles is within the threshold particle size distribution range. Determining the desired particle size (e.g., D... V, 90 The threshold range is referred to below. Figure 3 Further discussion.

[0039] If the desired tap density and target yield determined at 810 do not reach or exceed the desired values, then method 800 proceeds to 812, and the T of the liquid feed is adjusted. 出口 ,RS,P 干燥器 And / or maximum spray solution concentration. For example, if the dried particles are above the threshold tap density but below the threshold yield, then it is possible to maintain T 出口 While keeping RS constant, reduce P 干燥器 As an alternative example, if the dried particle yield is above the threshold but below the threshold tap density, then it is possible to maintain P 干燥器 While keeping T constant, reduce T 出口 And increase RS. In a further example, adjustment may include decreasing T. 出口 Increase RS, while also decreasing P 干燥器 Then method 800 returns to step 808, and in the adjusted T... 出口 RS and P 干燥器 The next step is to perform spray drying with liquid feed.

[0040] If at 810 it is determined that the dried powder (e.g., spray-dried granules) reaches or exceeds the threshold yield and threshold particle density, then method 800 proceeds to 814 and includes preparing an injectable formulation from the dried granules. The prepared injectable formulation can be delivered via an auto-injector, a pre-filled syringe, or a standard needle and syringe. Preparing the injectable formulation may include suspending the dried granules in a suitable solvent (e.g., a carrier). In instances where the API is soluble in water (e.g., a protein), a non-aqueous carrier may be preferred. The non-aqueous carrier may be selected from carriers approved by the FDA based on the viscosity, density, and compatibility of the carrier with the API, protein, and injection device material. As an example, the carrier may be a mixture of tricaprylic acid glyceride / tricaprylic acid glyceride, triacetin, ethyl oleate, or propylene glycol dicaprylic acid ester / dicaprylic acid ester, a combination of the aforementioned carriers, or other proprietary compositions.

[0041] The API concentration in the injectable formulation may be high enough to deliver the desired dose of API in a single rapid injection. For example, the desired dose may be delivered in a suspension ranging from 1 mL to 2 mL. Further, the API concentration in the injectable formulation may be greater than 200 mg / mL or greater than 500 mg / mL. The injectable formulation may contain greater than or equal to 40 wt.% spray-dried powder. In some instances, the injectable formulation may contain greater than or equal to 50 wt.% spray-dried powder. In further instances, the injectable formulation may contain greater than or equal to 60 wt.% spray-dried powder. The threshold dispensing force (e.g., slip force) used to dispense the injectable formulation may be less than or equal to 50 N or less than or equal to 100 N, at a rate greater than or equal to 0.1 mL / s (e.g., 1 mL in 10 seconds) or greater than or equal to 1 mL in 8 seconds, through a 27.5-gauge needle. In some instances, the wt.% spray-dried powder may be included with increasing threshold dispensing force. For example, an injectable formulation having a threshold slip force of 50 N or less may contain 40 wt.% or more of spray-dried powder. Alternatively, an injectable formulation having a threshold slip force of 100 N or less may contain 50 wt.% or more, or 60 wt.% or more of spray-dried powder. Furthermore, the injectable formulation may be stable at temperatures of 25°C or less for up to two years. In some instances, the injectable formulation may be stable for up to two years at temperatures ranging from 2°C to 8°C. Method 800 ends.

[0042] Now go to Figure 9The following line graphs are shown: Line graph 900 shows the slip force as a function of wt.% of the spray-dried particles in the suspension; and line graph 950 shows the viscosity as a function of wt.% of the spray-dried particles in the suspension. The suspension used for the slip force measurement in line graph 900 is the same as the suspension used for the viscosity measurement in line graph 950. The spray-dried particles contain BSA as a model protein and also contain an equal weight of sucrose. For the slip force measurement, the suspension was injected at a rate of 0.125 mL / sec through a special thin-walled (STW) needle of 27.5 inches in length.

[0043] First line plot 900 includes dataset 902, and second line plot 950 includes dataset 904. Datasets 902 and 904 (marked in red) each correspond to suspensions prepared using tricaprylic acid glyceride / tridecanoic acid glyceride carriers. First line plot 900 includes dataset 906, and second line plot 950 includes dataset 908 (marked in blue). Datasets 906 and 908 each correspond to suspensions prepared using triacetyl glyceride as a carrier. First line plot 900 includes dataset 910, and second line plot 950 includes dataset 912 (marked in green). Datasets 910 and 912 each correspond to suspensions prepared using propylene glycol dicaprylic acid ester / didecanoic acid ester.

[0044] Comparing line graph 900 with line graph 950, the increases in suspension wt.% in datasets 902, 906, and 910 each follow similar trends to those in datasets 904, 908, and 912. Therefore, suspension viscosity can determine extrusion pressure. As an example, at 2000 s... -1 The 250 cP measured at a shear rate can be the maximum viscosity corresponding to a threshold slip force of 50 N (indicated by line 914 on line graph 900). Further, line graph 950 shows that the increase in viscosity relative to the solid load can vary for different carriers. In an alternative example, the threshold slip force can be 100 N. In such an example, at 2000 s... -1 The viscosity of the suspension measured at the specified rate can be less than or equal to 500 cP.

[0045] Now go to Figure 2The graph shows the slip force as a function of tapped density. Multiple data points 202 correspond to the tapped density of the dried powder and the slip force for injecting a 40 wt.% suspension of spray-dried powder containing BSA and sucrose, administered via a 27.5-inch STW needle from a 1 mL pre-filled syringe at an injection rate of 0.125 mL / min. Multiple data points 202 show a negative correlation between slip force and tapped density up to the minimum slip force indicated by line 204. As shown in graph 200, the slip force can be reduced by approximately 60% by increasing the tapped density of the dried particles contained in the injectable formulation. A second line 206 corresponds to an example of the upper limit threshold slip force for subcutaneous or intramuscular administration. Suspensions with higher tapped densities can contain fewer particles than suspensions with lower tapped densities. The reduction in the total number of particles reduces the viscosity of the suspension and thus reduces the slip force required for injection. By increasing the tap density, the slip force of a suspension incorporating dried particles can be adjusted to below a threshold slip force. In this way, the properties of the dried particles can be controlled, and injectable suspensions can be produced without adjusting other suspension properties (such as particle concentration) or using suspension additives (such as viscosity reducers), which could increase the overall cost of the suspension or destabilize the API. Furthermore, viscosity reducers can decrease the stability of the suspension (e.g., increase the degradation rate), and reducing or eliminating the need for viscosity reducers can therefore increase the stability of the suspension.

[0046] Now go to Figure 10 It shows a first line graph 1000, which shows the relationship between atmospheric pressure and T. 出口 The slip force required to inject a suspension of 40 wt.% particles into a 27.5-inch STW needle at an injection rate of 0.125 mL / s, as a function of the particle tap density, for spray-dried particles at >40°C. Data set 1004 corresponds to spray-dried particles containing BSA suspended in a tricaprylyl / tricaprylyl carrier. Line graph 1000 also shows data for lysozyme suspended in tricaprylyl / tricaprylyl, indicated by label 1008. The tendency of slip force to decrease with increasing tap density is independent of the type of active ingredient (or model active ingredient) contained in the particles.

[0047] Figure 10The second line plot 1002 shows the slip force as a function of tap density for spray-dried particles dried in substantially the same manner as the particles in the first line plot 1000, and prepared as a suspension and dispensed in substantially the same manner as in the first line plot 1000. The second line plot 1002 includes dataset 1006 corresponding to spray-dried particles containing BSA. Spray-dried particles containing IgG 1010 and spray-dried particles containing lysozyme 1012 are also shown. Each is suspended in propylene glycol dicaprylyl / dicaprylyl. Comparing dataset 1004 with dataset 1006, the relationship between slip force and tap density is similar regardless of the carrier used. However, the magnitude of the decrease in slip force with increasing tap density can vary depending on the carrier and suspension concentration. For example, in the data shown in line plot 1000 where the carrier is tricaprylyl / dicaprylyl, the magnitude of the change in slip force as a function of tap density is observed to be greater than in the data shown in line plot 1002 where the carrier is propylene glycol dicaprylyl / dicaprylyl.

[0048] Now go to Figure 11 It shows a first line graph 1100 and a second line graph 1102. Both the first line graph 1100 and the second line graph 1102 show the effect of passing through a pressure below atmospheric pressure and T. 出口 Particles prepared by spray drying at <40°C were used, with slip force as a function of tap density. Slip force was measured from a suspension of 40 wt.% particles using a 27.5-inch STW needle at an injection rate of 0.125 mL / s. Linear plot 1100 includes data point 1104 corresponding to spray-dried particles containing BSA and data point 1108 corresponding to spray-dried particles containing lysozyme, each suspended in a tricaprylyl / tridecanoic acid ester carrier. Linear plot 1102 includes data point 1106 corresponding to spray-dried particles containing BSA and data point 1110 corresponding to spray-dried particles containing IgG, each suspended in a propylene glycol dicaprylyl / didecanoic acid ester carrier.

[0049] Comparing datasets 1104 and 1106, similar results were observed regarding the magnitude of changes in the dependence of slip force on tap density when the carrier of the suspension was changed. Furthermore, Figure 10 Comparing dataset 1004 with dataset 1104 shows that when P 干燥器 and T 出口 When both decrease, the particle tap density shifts overall towards a higher tap density. This can also be observed in... Figure 10 A similar comparison is made between the data in line graph 1100 and the data in line graph 1102. Furthermore, this can be achieved by reducing P... 干燥器 and T 出口To increase the maximum tap density achieved by spray-dried particles. For example, Figure 10 The maximum tap density of the dataset shown is 0.70 g / mL, while Figure 11 The maximum tap density of the dataset shown is 0.73 g / mL.

[0050] As described above regarding method 800, the concentration of API in the liquid feed can be maximized to increase particle and powder density. However, the maximum concentration of API may be limited by solubility, stability, or solution viscosity, and additional adjustments to spray drying parameters (such as T) may be required. 出口 RS and P 干燥器 To optimize particle and powder tap density.

[0051] Now go to Figure 12 The diagram shown is graph 1200, which illustrates the slip force as T. 出口 The slip force is a function of the force applied to the injection of a suspension of spray-dried particles contained in 40 wt.% of tricaprylic acid / tricaprylic acid, distributed as described above. Figure 10 and Figure 11 The spray-dried particles may contain either BSA (solid circle) or lysozyme (hollow circle) as a model API. Both BSA and lysozyme are prepared from a liquid feed consisting of <9 wt.% solid material containing the model API.

[0052] Line 1202 will be selected for spray drying at atmospheric pressure using T 出口 (>40℃) and selection for use in P 干燥器 T spray drying at below atmospheric pressure 出口 (<40℃) Distinguish them. The first dataset 1204, located to the right of line 1202, corresponds to a suspension of particles obtained by spray drying at 50℃ and atmospheric pressure. If it is desirable to reduce the slip force measured relative to the first dataset 1204, but increasing the solids concentration is not feasible, then as described above regarding method 800, reduce T. 出口 This can slow down the drying rate, resulting in denser particles. Lowering T 出口 Subsequently, it may be necessary to lower P. 干燥器 To maintain the desired yield. The second dataset 1206, located to the left of line 1202, corresponds to the data obtained through T. 出口 <40℃ and P 干燥器 A suspension of particles obtained by spray drying at below atmospheric pressure. This is achieved by lowering T... 出口 The resulting particle suspension exhibits reduced slip forces. This reduction in slip forces may be due to the decrease in T... 出口 The increase in density is achieved by slowing down the spray drying rate.

[0053] Now go to Figure 13 This illustrates the effect of solid load in the spray solution on the slip force. Figure 13 The diagram includes a first line graph 1300 and a second line graph 1302, both showing the slip force of a suspension containing spray-dried particles as a function of the solid weight percentage in the liquid feed used to prepare these spray-dried particles. Arrow 1301 indicates the direction of increasing solid weight percentage along the x-axis of the first line graph 1300, and arrow 1303 indicates the direction of increasing solid weight percentage along the x-axis of the second line graph 1302. The slip force in the first line graph 1300 and the slip force in the second line graph 1302 were each measured by injection using a 27.5-inch STW needle at an injection rate of 0.125 mL / sec.

[0054] Dataset 1304 of line graph 1300 corresponds to particles suspended in tricaprylic / tricaprylic glycerol. Dataset 1304 shows that the slip force decreases with increasing wt.% of sprayed solids. This decrease in slip force is likely due to the corresponding increase in tap density as the amount of solids in the spray solution increases, as referenced above. Figure 7 As stated above.

[0055] The second line plot 1302 includes a second dataset 1306 and a third dataset 1308. The second dataset 1306 and the third dataset 1308 can each correspond to a suspension of particles suspended in propylene glycol dioctyl ester / didecanoate. The second dataset 1306 further corresponds to the slip force of a 40 wt.% suspension of spray-dried particles, and the third dataset 1308 corresponds to the slip force of a 50 wt.% suspension of spray-dried particles. Regardless of the suspension wt.%, the trend of slip force as a function of solids wt.% is the same as in the first line plot 1300. Furthermore, comparing the second dataset 1306 with the third dataset 1308, the decrease in slip force as a function of solids load percentage is greater as the weight of particles in the injected suspension increases.

[0056] Now go to Figure 14 The figure 1400 shows a line graph 1400 showing the slip force of the two suspensions as a function of tap density. The first suspension is a 40 wt.% suspension of spray-dried particles, and the second suspension is a 50 wt.% suspension of spray-dried particles. Both the first and second suspensions were prepared using a propylene glycol diester carrier and were dispensed via a 27.5-inch STW needle at a rate of approximately 0.1 mL / s. Line 1406 represents the 50 N threshold.

[0057] The first dataset 1402 corresponds to the measured slip force of the first suspension, and the second dataset 1404 corresponds to the second suspension. As shown in line graph 1400, by using particles with a high (e.g., >0.45 g / mL) tap density to prepare the second suspension, the weight percentage of particles in the suspension can be increased, while the slip force does not exceed the 50 N threshold.

[0058] The correlation between the tap density of a dried powder and the slip force of a syringe suspension containing that powder can be stronger than that of other physical properties of the dried powder. For example, as Figure 3 As shown in line graph 300, for a subset of the suspension in line graph 200, slip forces are compared based on particle size rather than tap density. The first column 302 corresponds to a D with a diameter between approximately 4 µm and approximately 7 µm. v,50 (e.g., average particle size) dried particles. The second column 304 corresponds to D particles with a diameter between approximately 10 µm and approximately 13 µm. v,50 The heights of the first column 302 and the second column 304 correspond to the slip force indicated by the y-axis of line graph 300. Although the particle corresponding to column 304 is approximately twice the size of the particle corresponding to column 302, the slip force increases by only a relatively small amount.

[0059] The slip force of the suspension may not be closely dependent on the particle size, but rather the particle size can be selected based on the diameter of the needle delivering the suspension. For example, an upper limit D might be desired. v,90 It is one-quarter of the needle's inner diameter. As an example, the inner diameter of a 27g needle could be 0.2mm, and the upper limit D... v,90 It can be less than or equal to 50 µm. As a further example, the upper limit of the particle size can be D. v,90 The lower limit of particle size is 100 µm. The lower limit of particle size can depend on the collection yield of the drying system. As an example, the lower limit of particle size could be D... v,10 , which is 1 µm.

[0060] Furthermore, the tap density of the dried powder may have a stronger effect on the slip force than the total concentration of API in the dried powder. For example, as Figure 4As shown, line graph 400 compares the slip forces of suspensions of the same dried particles at different protein concentrations. The first column 402 corresponds to a formulation containing approximately 0.45 to 0.53 mass fractions of protein relative to the total solids (e.g., protein plus other excipients) in the liquid feed. The second column 404 corresponds to a formulation containing approximately 0.68 to approximately 0.77 mass fractions of protein. The third column 406 corresponds to a formulation containing approximately 0.84 to approximately 0.92 mass fractions of protein. The height of the column along the y-axis of line graph 400 corresponds to the slip force of an injection containing the formulation. Although the percentage of protein corresponding to column 406 is almost twice that of the first column 402, the height variations of the first column 402, second column 404, and third column 406 do not exceed 10%.

[0061] Furthermore, tap density is likely easier to quantify and more closely related to slip forces than the observed physical properties of dry particles, such as those visible in scanning electron microscopy (SEM) images. For example, Figure 5 Line graph 500 is shown, which is similar to Figure 2 Line graph 200 plots data points corresponding to the slip force as a function of the tap density of the dry particles contained in the suspension. First SEM image 502 corresponds to the first set of data points 504. Second SEM image 506 corresponds to the second set of data points 508. Third SEM image 510 corresponds to the third set of data points 512. Fourth SEM image 514 corresponds to the fourth set of data points 516. Although the first, third, and fourth SEM images each correspond to significantly different slip forces, the surface morphology of the particles shown in the first, third, and fourth SEM images is very similar, as shown in line graph 500. Second SEM image 506 shows an ensemble of particles with a relatively smooth morphology compared to the particles in the first, third, and fourth SEM images. The particles in image 506 can be described as essentially free of wrinkles, dents, and pores. However, data point 508 corresponding to the second SEM image 506 has a higher slip force than data points corresponding to the third and fourth SEM images (which show a rougher, more wrinkled morphology), and a lower slip force than data points corresponding to the first image (which also shows a wrinkled morphology). In this way, the tap slip force of the resulting suspension shows no strong correlation with the surface morphology of the particles.

[0062] Furthermore, image analysis can be used to quantify the percentage composition of particles constituting a powder sample, relative to the volume percentage of hollow particles, the volume percentage of internal voids, and the volume percentage of solid particles (e.g., solid particles without internal voids). For example, image analysis can be performed using X-ray computed tomography to create a 3-D representation of the powder sample. Hollow particles can refer to bubble-like particles with a solid exterior and a central void. Internal voids can refer to the volume of air trapped within these bubbles. Table 1 below compares the volume percentage of each of the phases listed above for two different spray-dried powder samples, in addition to the measured tap density.

[0063]

[0064] Table 1. Particle properties and tap density of spray-dried granular samples Table 1 illustrates that geometric parameters alone may not be sufficient to explain the differences in tap density. It is shown that Sample 1 contains more internal voids and hollow particles than Sample 2, as a percentage of the total particle volume, and therefore this analysis might predict that the tap density for Sample 1 is likely higher than that for Sample 2. However, at the time of measurement, the tap density of Sample 1 was significantly lower than that of Sample 2. Furthermore, as... Figure 2 As shown, the tap density of the powder correlates well with its ability to produce high-concentration suspensions. This demonstrates that tap density can incorporate additional properties of the powder into a single measurable parameter that is predictive of injectable suspensions. Such additional properties may include, but are not limited to, polydispersity, particle size distribution shape, and attractive or repulsive interactions between individual particles. These factors can also be modulated as part of the spray drying process.

[0065] In other words, Table 1 also compares the tap density of powders from Sample 1 and Sample 2. Surprisingly, given that particle density analysis indicates that the particles in Sample 1 are less dense than those in Sample 2, the tap density of Sample 1 is higher than that of Sample 2. This demonstrates that the tap density of a powder is not equal to or proportional to the density of the particles constituting the powder. The results shown in Table 1 unexpectedly demonstrate that the density of an individual particle may not be proportional to the tap density. As discussed above (e.g., refer to...) Figure 2 The tap density of a powder is proportional to the slip force of a suspension prepared from that powder. Therefore, when formulating injectable suspensions, the tap density of a powder can be used as a material parameter without requiring image analysis to determine the percentage of particle solids and voids. Tap density may include additional properties such as, but not limited to, polydispersity, particle size distribution shape, and attractive or repulsive interactions between individual particles. As discussed herein, factors affecting tap density can be modulated by adjusting the spray drying process. For example, by adjusting the relative saturation in the liquid feed, T... 出口 P干燥器 And one or more of the excipient concentrations.

[0066] As an example, the tap density of the dried powder collected from the spray drying system can be increased by increasing the concentration of the solute in the liquid feed (e.g., liquid feed 104) supplied to the spray dryer. As a further example, the tap density of the dried powder collected from the spray drying system can be increased by drying at a lower outlet temperature, such as by using a vacuum spray dryer (e.g.,... Figure 1 This is achieved using a vacuum spray dryer 100. Spray drying under vacuum has the added benefit of exposing APIs to lower temperatures than conventional spray drying, making spray drying applicable to APIs that are generally considered thermally unstable to spray drying.

[0067] Now go to Figure 6 Line graph 600 shows the slip force as a function of tap density, similar to... Figure 2 Specifically, observe the first data point 602, which corresponds to the first spray solution dried using a conventional spray dryer. The second data point 604 corresponds to the first solution dried using a vacuum spray dryer. By drying under vacuum, the tap density of the powder obtained from the same starting solution is increased. Now turn to the third data point 606, which corresponds to the second solution dried using a conventional spray dryer. The first solution is a low wt% solution, while the second solution is a high wt% solution. By increasing the wt% of the solution, the tap density of the dried particles obtained from this solution is also increased. However, the solubility and stability of the API may limit the wt% of the solution. For example, a high wt% may be the maximum concentration of the API. The fourth data point 608 corresponds to the second solution dried using a vacuum spray dryer. By using vacuum spray drying, a dried powder with a higher tap density can be produced than that achievable simply by increasing the wt% of the spray-dried solution. Furthermore, when the tap density of conventional spray drying is low, the increase in tap density from vacuum spray drying is greater compared to conventional spray drying. In this way, vacuum spray drying may be particularly suitable for situations where the API has low solubility, or where the concentration of the spray solution is limited due to API stability, or where the maximum tap density is low due to solution viscosity when spray drying is performed by conventional spray drying.

[0068] As mentioned above, the measured tap density of the resulting dried particles can be adjusted by increasing the protein loading in the liquid feed during spray drying. Table 2 below shows the results of spray drying a test solution containing bovine serum albumin (BSA) and sucrose in aqueous solution. The weight ratio of BSA to sucrose was 1:1. The liquid feed may also contain hydrophilic surfactants, such as polysorbate 80.

[0069]

[0070] Table 2: Spray drying test of proteins Tests #1 to #6 in Table 2 were all conducted at P below atmospheric pressure. 干燥器 Spray drying was performed at both low and high solids weight percentages, both yielding acceptable yields and tap densities for injectable formulations. Differences in dryer pressure between Tests #1 and #5 may also have a relatively small impact on yield and tap density. Comparing Test #3 with Test #4, decreasing the outlet temperature from approximately 21°C to approximately 16°C did indeed result in a decrease in yield, although the tap density remained relatively constant. However, even with the yield decrease in Test #4, it was greater than 50%. Comparing Test #4 and Test #5, increasing the atomization pressure to reduce droplet size also improved the percentage yield without affecting the desired tap density. Furthermore, comparing Test #5 with Test #6, increasing the L / G ratio also negatively impacted the yield.

[0071] As a further example, additional tests were conducted on spray drying of a 1:1 BSA:sucrose solution containing buffer and polysorbate at low solids wt.%, and the results are shown in Table 3 below. Such tests may be a relevant model for proteins that may not be suitable for high-concentration spray drying of liquid feeds. Higher concentrations may not be achievable due to protein solubility and / or stability, or due to the viscosity of the liquid feed.

[0072]

[0073] Table 3: Spray drying of low-concentration proteins The results of tests #1 to #6 shown in Table 3 confirm that even with a low wt.% solids content of protein in the liquid feed, spray drying under reduced pressure can produce powders with acceptable tap densities (e.g., >0.45 g / mL) for injectable formulations. Comparing test #1 with test #2 in Table 3, the pressure was reduced by approximately 78 mbar, while the product yield and tap density remained essentially unchanged. Furthermore, comparing test #2 with test #3 in Table 3, the decrease in outlet temperature resulted in an increase in the product tap density. High-tap-density powders can also be produced from low-concentration liquid feeds by adjusting the temperature to a lower level without reducing the yield below acceptable levels. Additionally, comparing test #3 with test #4 in Table 3, the increase in atomization pressure resulted in smaller droplets. In this case, smaller droplets may lead to a lower tap density, although this tap density is still acceptable for inclusion in injectable formulations. Finally, comparing Test #4 and Test #5 in Table 2, it was found that increasing the L / G ratio by increasing the liquid feed rate can help improve throughput without significantly affecting yield or tap density.

[0074] As a further example, lysozyme can be used as a model protein for proteins to be included in injectable formulations. The tests described in Table 4 below were performed by vacuum spray drying of a liquid feed containing lysozyme and sucrose in a weight ratio of 75:25. This liquid feed may also contain a hydrophilic surfactant, such as polysorbate 80.

[0075]

[0076] Table 4: Spray drying of lysozyme under vacuum.

[0077] A comparison of tests #1 and #2, and tests #4 and #5 in Table 4 shows that decreasing the outlet temperature also increases the tap density of the lysozyme product, similar to the BSA product. This effect occurs regardless of whether the solids wt.% is high (test #5) or low (test #2). However, when the wt.% is higher, the increase in tap density with decreasing outlet temperature is greater than that with lower solids wt.%. Similarly, as shown by comparing tests #2 and #3 in Table 4, increasing the solids wt.% in the liquid feed also increases the tap density of the dried product.

[0078] The technical advantage of the methods and systems disclosed herein is the production of spray-dried powders with high tap density. Spray-dried particles with increased tap density are used to prepare injectable formulations that can be delivered via needles and syringes, sometimes with autoinjectors, using a slip force of less than or equal to 100 N or less than or equal to 50 N. Increasing the density of the spray-dried powder contained in the injectable formulation produces a formulation that can be injected using the desired slip force without having to reduce the particle concentration in the suspension, or without having to adjust the suspension or injection device in other ways that may not be cost-effective.

[0079] This disclosure also provides support for an injectable suspension comprising: a carrier, and a spray-dried powder having a tap density greater than 0.45 g / mL, the spray-dried powder being suspended in the carrier at a concentration greater than or equal to 40 wt.%, and wherein the injectable suspension can be injected through a 27-gauge, ½-inch, 1 mL needle at an injection rate of approximately 1 mL / 10 seconds using a glide force less than or equal to 100 N. In a first example of the system, the glide force is less than or equal to 50 N. In a second example of the system (optionally including the first example), the carrier is one or more of tricaprylic / tridecanoic acid ester, triacetin, propylene glycol dicaprylyl / didecanoate, or ethyl oleate. In a third example of the system (optionally including one or both of the first and second examples), the spray-dried powder comprises a peptide or protein, and wherein the spray-dried powder contains an active pharmaceutical ingredient at a concentration greater than 50 wt%. In the fourth example of the system (optionally including one or more of the first to third examples), the average diameter of the spray-dried powder is between 1 and 50 µm, and the Dv90 is less than 100 µm. In the fifth example of the system (optionally including one or more of the first to fourth examples), the viscosity of the injectable suspension at a shear rate of 2000 s⁻¹ is less than or equal to 500 cP. In the sixth example of the system (optionally including one or more of the first to fifth examples), the spray-dried powder is dried using a dryer pressure of less than 0.8 bar.

[0080] This disclosure also provides support for a method for producing spray-dried powder with high tap density, the method comprising: selecting a maximum spray solution concentration of a liquid feed defined by protein stability and solution viscosity; selecting a relative saturation and outlet temperature for spray drying; selecting a dryer pressure for spray drying the liquid feed; spray drying the liquid feed at the selected relative saturation, outlet temperature, and dryer pressure to obtain spray-dried particles; and determining the tap density of the spray-dried powder, and adjusting one or more of the maximum spray solution concentration, relative saturation, outlet temperature, or dryer pressure in response to the tap density of the spray-dried powder being below a threshold tap density, or the distribution slip force of the suspension of the spray-dried powder being above a threshold slip force. In a first example of the method, the method further comprises: preparing an injectable formulation from the spray-dried powder, wherein the injectable formulation can be delivered through a 27 g, ½” long needle with a distribution force less than or equal to 100 N. In a second example of the method (optionally including the first example), the threshold tap density is greater than 0.45. g / mL. In a third example of the method (optionally including one or both of the first and second examples), the method further includes: determining the yield of the spray-dried powder, and adjusting one or more of the relative saturation, outlet temperature, or dryer pressure in response to the spray-dried powder yield being below a threshold yield. In a fourth example of the method (optionally including one or more of the first to third examples), the outlet temperature is less than 40°C or less than 30°C. In a fifth example of the method (optionally including one or more of the first to fourth examples), the relative saturation is in the range of 5% to 20%. In a sixth example of the method (optionally including one or more of the first to fifth examples), the dryer... The pressure is less than 0.8 bar. In the seventh example of the method (optionally including one or more of the first to sixth examples), the outlet temperature is less than 50°C, the relative saturation is greater than 5%, and the dryer pressure is less than 0.8 bar. In the eighth example of the method (optionally including one or more of the first to seventh examples), the outlet temperature is less than 40°C, and the relative saturation is greater than 10%. In the ninth example of the method (optionally including one or more of the first to eighth examples), the outlet temperature is less than 35°C, and the dryer pressure is less than 0.8 bar. In the tenth example of the method (optionally including one or more of the first to ninth examples), the relative saturation is in the range of 5% to 50%.

[0081] This disclosure also provides support for injectable suspensions comprising: a carrier, and a spray-dried powder with a tap density greater than 0.45 g / mL suspended in the carrier, wherein the viscosity of the injectable suspension at a shear rate of 2000 s⁻¹ is less than or equal to 500 cP. In a first example of the system, the viscosity of the injectable suspension is less than or equal to 250 cP. This disclosure also provides support for injectable suspensions comprising: a carrier, and a spray-dried powder, wherein the spray-dried powder is dried at a dryer pressure of less than 0.8 bar.

[0082] The appended claims specifically point to certain combinations and sub-combinations that are considered novel and non-obvious. These claims may refer to a "one" element or a "first" element or its equivalent. Such claims should be understood to include the incorporation of one or more such elements, neither requiring nor excluding two or more such elements. Other combinations and sub-combinations of the disclosed features, functions, elements, and / or properties may be claimed by amendments to the claims of the invention or by the presentation of new claims in this application or related applications. Such claims, whether broader, narrower, equivalent, or different in scope from the original claims, are also considered to be included within the subject matter of this disclosure.

Claims

1. An injectable suspension comprising: carrier; and A spray-dried powder having a tap density greater than 0.45 g / mL, the spray-dried powder being suspended in the carrier at a concentration greater than or equal to 40 wt.%, and wherein the injectable suspension is injected through a 1 mL needle of a 27 gauge and ½ inch in length at an injection rate of approximately 1 mL / 10 seconds using a sliding force less than or equal to 100 N.

2. The injectable suspension according to claim 1, wherein the slip force is less than or equal to 50 N.

3. The injectable suspension according to claim 1, wherein the carrier is one or more of tricaprylic acid glyceride / tridecanoic acid glyceride, triacetin, propylene glycol dicaprylic acid ester / didecanoic acid ester or ethyl oleate.

4. The injectable suspension of claim 1, wherein the spray-dried powder comprises a peptide or a protein, and wherein the spray-dried powder comprises an active pharmaceutical ingredient at a concentration greater than 50 wt%.

5. The injectable suspension according to claim 1, wherein the average diameter of the spray-dried powder is between 1 and 50 µm, and the Dv90 is less than 100 µm.

6. The injectable suspension according to claim 1, wherein the injectable suspension is incubated for 2000 s. -1 The viscosity at the shear rate is less than or equal to 500 cP.

7. The injectable suspension of claim 1, wherein the spray-dried powder is dried using a dryer pressure of less than 0.8 bar.

8. A method for producing spray-dried powder with high tap density, the method comprising: Select the maximum spray solution concentration for liquid feed, defined by protein stability and solution viscosity; Select the relative saturation and outlet temperature for spray drying; Select the dryer pressure for spray drying the liquid feed; The liquid feed is spray-dried at a selected relative saturation, outlet temperature, and dryer pressure to obtain spray-dried particles; and The tap density of the spray-dried powder is determined, and in response to the tap density of the spray-dried powder being lower than a threshold tap density, or the suspension of the spray-dried powder being distributed with a slip force higher than a threshold, one or more of the maximum spray solution concentration, relative saturation, outlet temperature, or dryer pressure are adjusted.

9. The method of claim 8, further comprising: Injectable formulations are prepared using the spray-dried powder, wherein the injectable formulation is delivered by a 27g, ½” long needle with a dispensing force of less than or equal to 100N.

10. The method of claim 8, wherein the threshold tap density is greater than 0.45 g / mL.

11. The method of claim 8, further comprising: The yield of the spray-dried powder is determined, and in response to the yield of the spray-dried powder being lower than a threshold yield, one or more of the relative saturation, outlet temperature, or dryer pressure is adjusted.

12. The method according to claim 8, wherein the outlet temperature is less than 40°C or less than 30°C.

13. The method of claim 8, wherein the relative saturation is in the range of 5% to 20%, or in the range of 5% to 50%.

14. The method of claim 8, wherein the outlet temperature is less than 50°C, the relative saturation is greater than 5%, and the dryer pressure is less than 0.8 bar, or wherein the outlet temperature is less than 35°C and the dryer pressure is less than 0.8 bar.

15. The method of claim 8, wherein the outlet temperature is less than 40°C and the relative saturation is greater than 10%.

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