EA043077B1 - Nasal pharmaceutical compositions with porous filler - Google Patents

Description

Technical field

The invention describes nasal pharmaceutical compositions containing a porous filler and an active substance, in which the active substance is loaded on the surface of the porous filler located inside the pores of the porous filler, and the composition is adapted for nasal administration. Also described herein are methods for the manufacture and use of nasal pharmaceutical compositions.

State of the art

Intranasal delivery of active ingredients is limited due to the physiological characteristics of the nasal cavity, the physicochemical properties of the active ingredients and pharmaceutical factors such as limited application volumes. The dose in terms of dissolution, which takes into account the solubility of the active substance in relation to its dose, is particularly low in compositions with active substances that are poorly soluble or unstable active in physiological solutions. In addition, the inclusion of additional additives such as a suspending agent, co-solvents, charge modifying agents, inhibitors of destructive enzymes, antioxidants, stabilizers, membrane penetration enhancers, emulsifying agents, wetting agents, adhesive agents, viscosity increasing agents, and/ or taste masking agents further bulk up such compositions. Such high volumes are problematic, especially in the context of nasal delivery compositions. Thus, there is a need in the art for new nasal pharmaceutical compositions that effectively deliver a therapeutically effective amount of the active ingredient.

The essence of the invention

Surprisingly, the Applicant has discovered new nasal pharmaceutical compositions that solve the problems associated with traditional nasal pharmaceutical formulations discussed below.

Nasal pharmaceutical compositions containing a porous filler and an active substance are proposed, characterized in that the active substance is loaded onto the surface of the porous filler located inside the pores of the porous filler, and characterized in that the composition is adapted for nasal administration.

In some embodiments, the porous filler comprises a material selected from the group consisting of inorganic porous materials, organic-inorganic hybrids, organic polymers, and complexing agents. In particular embodiments, the porous filler is an inorganic porous material selected from the group consisting of microporous silica, mesoporous silica, macroporous silica, polyorganosiloxanes, pharmaceutical clays, silica nanotubes, silica gel, magnesium aluminosilicate, anhydrous calcium phosphate, and calcium carbonate. In specific embodiments, the implementation of the porous filler is a colloidal silicon dioxide. In specific embodiments, the porous filler is an organo-inorganic hybrid, which is an organometallic framework. In specific embodiments, the porous filler is an organic polymer formed from a carbon-carbon synthesis reaction in which the organic-inorganic hybrid contains non-metallic elements. In particular embodiments, the porous filler is a complexing agent that is an ion exchange resin selected from the group consisting of porous silica based on β-cyclodextrin, porous silica based on α-cyclodextrin, porous silica based on hydroxypropyl-v-cyclodextrin, and also porous materials based on other ion-exchange resins.

In some embodiments, the porous filler contains pores with a maximum diameter in any dimension up to 2 nm.

In some embodiments, the porous filler loaded with the active substance is coated with a polymer. In some embodiments, the polymer is selected from the group consisting of a linear polymer, a cellulose-containing polymer, a copolymer, a cross-linked polymer, a collagen-containing polymer, and combinations of any two or more of these. In particular embodiments, the linear polymer is selected from the group consisting of polyvinylpyrrolidone, hyaluronic acid, chitosan, xanthan, alginate, polyvinyl acetate, sodium starch glycolate, and combinations of any two or more of these. In specific embodiments, the cellulose-containing polymer is sodium carboxymethylcellulose. In particular embodiments, the copolymer is selected from the group consisting of polyvinylpyrrolidone/polyvinyl acetate, polyvinylpyrrolidone/polyvinyl alcohol, polyvinyl alcohol/PEG, polyvinyl caprolactam/polyvinyl acetate/polyethylene glycol, and combinations of any two or more of these. In particular embodiments, the crosslinked polymer is selected from the group consisting of crosslinked polyvinylpyrrolidone, crosslinked sodium carboxymethylcellulose, and combinations of any two or more of these. In specific embodiments, the collagen-containing polymer is gelatin. In some embodiments, the pores in the porous filler loaded with the active substance are covered with

- 1 043077 coated.

In some embodiments, the composition contains an active ingredient selected from the group consisting of aripiprazole, quetiapine, paliperidone, duloxetine, dopamine, testosterone, glatiramer acetate, interferon beta-1a, interferon beta-1b, fingolimod, natalizumab, dimethyl fumarate, pregnenolone, memantine, rivastigmine, donepezil, desvenlafaxine, progesterone, eszopiclone, atomoxetine, guanfacine, methylphenidate, lisdexamfetamine, recombinant tissue plasminogen activator (rt-PA), methotrexate, raltitrexide, 5-fluorouracil, telomerase inhibitor, monoclonal antibodies, midazolam, lakos amide, levetiracetam, lamotrigine, valproic acid, oxycodone, pregabalin, buprenorphine, hydrocodone, fentanyl, safinamide, ropinirole, pramipexole, levodopa, selegiline, cabergoline, istradephylline, and combinations of two or more of them. In some embodiments, the composition is a vaccine and the active ingredient contains an immunogen. In some embodiments, the active ingredient is in amorphous form.

In some embodiments, the composition contains a therapeutically effective amount of the active ingredient. In some embodiments, the composition contains from about 1 to about 50% wt./wt. active ingredient based on the weight of the composition.

In some embodiments, the composition is in the form of a gel. In some embodiments, the loaded porous filler is dispersed in the gel. In some embodiments, the gel contains a carrier that is an oil or mixture of oils. In specific embodiments, the carrier comprises castor oil.

Some embodiments include nasal pharmaceutical compositions comprising: (a) a porous excipient and an active agent, characterized in that the active agent is loaded onto a surface of the porous excipient located within the pores of the porous excipient; (b) a lipophilic or partially lipophilic carrier; and (c) a viscosity adjusting agent.

Some embodiments include nasal pharmaceutical compositions comprising: (a) a porous excipient and an active agent, characterized in that the active agent is loaded onto a surface of the porous excipient located within the pores of the porous excipient; (b) a coating located on the porous filler, and the coating contains the active substance, which is the same or different from the active substance loaded on the porous filler; (c) a lipophilic or partially lipophilic carrier; and (d) a viscosity adjusting agent. In some embodiments, the lipophilic or partially lipophilic carrier contains the active ingredient.

Some embodiments include nasal pharmaceutical compositions comprising: (a) mesoporous silica and an active agent, characterized in that the active agent is loaded onto the surface of the mesoporous silica located within the pores of the mesoporous silica; (b) at least one lipophilic or partially lipophilic carrier; and (c) at least a viscosity adjusting agent.

Some implementation options include nasal pharmaceutical compositions containing: (a) from about 0.5 to about 50% wt./wt. filler based on mesoporous silica based on the weight of the composition; (b) from about 0.5 to about 40% wt./wt. active substance based on the weight of the composition, characterized in that the active substance is loaded onto the surface of mesoporous silica located inside the pores of mesoporous silica; (c) from about 50% to about 90% wt./wt. castor oil based on the weight of the composition; and (d) from about 2% to about 6% wt./wt. mixtures of oleoyl macrogoglycerides based on the weight of the composition.

Some implementation options include nasal pharmaceutical compositions containing: (a) about 8% wt./wt. filler based on mesoporous silica based on the weight of the composition; (b) about 5% wt./wt. active substance based on the weight of the composition, characterized in that the active substance is loaded onto the surface of mesoporous silica located inside the pores of mesoporous silica; (c) about 80% wt./wt. castor oil based on the weight of the composition; and (d) about 10% wt./wt. colloidal silicon dioxide based on the weight of the composition.

Some implementation options include nasal pharmaceutical compositions containing: (a) about 8% wt./wt. filler based on mesoporous silica based on the weight of the composition; (b) about 5% wt./wt. active substance based on the weight of the composition, characterized in that the active substance is loaded onto the surface of mesoporous silica located inside the pores of mesoporous silica; (c) about 80% wt./wt. castor oil based on the weight of the composition; and (d) about 4% wt./wt. mixtures of oleoyl macroglycerides based on the weight of the composition.

In some of the pharmaceutical compositions described herein, the active ingredient is testosterone. In some pharmaceutical compositions, the active ingredient is progesterone.

Some embodiments include methods for intranasal delivery of an active

- 2 043077 substances, including nasal administration to a subject in need of it, the composition described in this document.

Methods for vaccinating a subject against a disease state are also provided, including nasal administration of the composition to a subject in need thereof, characterized in that the active substance contains an immunogen, for example, wherein: (a) said condition is influenza, and the active substance is a live attenuated influenza virus , inactivated virus or viral antigens; (b) said condition is hepatitis B and the active ingredient is hepatitis B virus (HBV), hepatitis B surface antigens (HBsAg) and/or hepatitis B core antigens (HBcAg); or (c) said condition is meningitis and the active ingredient is a meningococcal polysaccharide vaccine (MPSV4, a polysaccharide from the surface of meningococcal bacteria), a meningococcal conjugate vaccine (MCV4, a polysaccharide chemically bound to a protein) and/or meningococcal serogroup B vaccine (MenB , which contains four proteins taken from Neisseria meningitidis group B bacteria). In specific embodiments, the live attenuated influenza virus is selected from the group consisting of A/California/7/2009 (H1N1), A/California/7/2009 (H1N1)-like strain, A/Switzerland/9715293/2013 (H3N2), A/Switzerland/9715293/2013 (Н3N2)-like strain, B/Phuket/3073/2013, B/Phuket/3073/2013-like strain (line B/Yamagata), B/Brisbane/60/2008, B/Brisbane/60 /2008-like strain (B/Victoria vaccine virus) and combinations of two or more of them. In specific embodiments, the antigens are selected from the group consisting of antigens from influenza virus A/Panama/2007/99 (H3N2), B/Guandong/2000 and/or A/Duck/Singapore/97 (H5N3).

Also provided are compositions for use in vaccination against a disease state, characterized in that the active substance contains an immunogen, for example, wherein: (a) said condition is influenza and the active substance is a live attenuated influenza virus, an inactivated virus, or viral antigens; (b) said condition is hepatitis B and the active ingredient is hepatitis B virus (HBV), hepatitis B surface antigens (HBsAg) and/or hepatitis B core antigens (HBcAg); or (c) said condition is meningitis and the active ingredient is a meningococcal polysaccharide vaccine (MPSV4, a polysaccharide from the surface of meningococcal bacteria), a meningococcal conjugate vaccine (MCV4, a polysaccharide chemically bound to a protein) and/or meningococcal serogroup B vaccine (MenB , which contains four proteins taken from Neisseria meningitidis group B bacteria).

Also provided are compositions for use in the manufacture of a vaccine against a disease state, characterized in that the active substance contains an immunogen, for example, wherein: (a) said condition is influenza, and the active substance is a live attenuated influenza virus, an inactivated virus, or viral antigens; (b) said condition is hepatitis B and the active ingredient is hepatitis B virus (HBV), hepatitis B surface antigens (HBsAg) and/or hepatitis B core antigens (HBcAg); or (c) said condition is meningitis and the active ingredient is a meningococcal polysaccharide vaccine (MPSV4, a polysaccharide from the surface of meningococcal bacteria), a meningococcal conjugate vaccine (MCV4, a polysaccharide chemically bound to a protein) and/or meningococcal serogroup B vaccine (MenB , which contains four proteins taken from Neisseria meningitidis group B bacteria).

Also provided are methods of treating a disease state comprising nasal administration of a composition described herein to a subject in need thereof, characterized in that: (a) said condition is hypogonadism, female sexual dysfunction, arousal disorder, anorgasmia, or a disorder, associated with a weakened sexual desire in women, and the active substance is testosterone; (b) said condition is brain damage and the active ingredient is progesterone; (c) said condition is schizophrenia and the active ingredient is aripiprazole, quetiapine or paliperidone; (d) said condition is anxiety and the active substance is duloxetine or dopamine; (e) said condition is multiple sclerosis and the active ingredient is testosterone, glatiramer acetate, interferon beta-1a, interferon beta-1b, fingolimod, natalizumab, or dimethyl fumarate; (f) said condition is Alzheimer's disease and the active ingredient is pregnenolone, memantine, rivastigmine or donepezil; (g) said condition is depression and the active substance is desvenlafaxine, duloxetine or dopamine; (h) said condition is insomnia and the active substance is progesterone or eszopiclone; (i) said condition is attention deficit hyperactivity disorder and the active substance is atomoxetine, guanfacine, methylphenidate, lisdexamfetamine or dopamine; (j) said condition is a traumatic brain injury and the active substance is progesterone or recombinant tissue plasminogen activator (rt-PA); (k) said condition is a brain tumor, and

- 3 043077 the active substance is methotrexate, raltitrexide, 5-fluorouracil, telomerase inhibitor or monoclonal antibodies; (l) said condition is epilepsy and the active substance is midazolam, lacosamide, levetiracetam, lamotrigine or valproic acid; (m) said condition is pain and the active substance is oxycodone, pregabalin, buprenorphine, hydrocodone or fentanyl; or (n) said condition is Parkinson's disease and the active ingredient is safinamide, ropinirole, pramipexole, dopamine, levodopa, selegiline, cabergoline, or istradefylline.

Also provided are compositions for use in the treatment of a disease state, characterized in that: (a) said condition is hypogonadism, female sexual dysfunction, arousal disorder, anorgasmia, or a disorder associated with reduced sexual desire in women, and the active substance is testosterone; (b) said condition is brain damage and the active ingredient is progesterone; (c) said condition is schizophrenia and the active ingredient is aripiprazole, quetiapine or paliperidone; (d) said condition is anxiety and the active substance is duloxetine or dopamine; (e) said condition is multiple sclerosis and the active ingredient is testosterone, glatiramer acetate, interferon beta-1a, interferon beta-1b, fingolimod, natalizumab, or dimethyl fumarate; (f) said condition is Alzheimer's disease and the active ingredient is pregnenolone, memantine, rivastigmine or donepezil; (g) said condition is depression and the active substance is desvenlafaxine, duloxetine or dopamine; (h) said condition is insomnia and the active substance is progesterone or eszopiclone; (i) said condition is attention deficit hyperactivity disorder and the active substance is atomoxetine, guanfacine, methylphenidate, lisdexamfetamine or dopamine; (j) said condition is traumatic brain injury and the active ingredient is progesterone or recombinant tissue plasminogen activator (rt-PA); (k) said condition is a brain tumor and the active substance is methotrexate, raltitrexide, 5fluorouracil, a telomerase inhibitor, or monoclonal antibodies; (l) said condition is epilepsy and the active substance is midazolam, lacosamide, levetiracetam, lamotrigine or valproic acid; (m) said condition is pain and the active substance is oxycodone, pregabalin, buprenorphine, hydrocodone or fentanyl; or (n) said condition is Parkinson's disease and the active ingredient is safinamide, ropinirole, pramipexole, dopamine, levodopa, selegiline, cabergoline, or istradefylline.

Also provided are compositions for use in the manufacture of a medicament for the treatment of a disease state, characterized in that: (a) said condition is hypogonadism, female sexual dysfunction, arousal disorder, anorgasmia, or a disorder associated with decreased sexual desire in females, and the active substance is testosterone; (b) said condition is brain damage and the active ingredient is progesterone; (c) said condition is schizophrenia and the active ingredient is aripiprazole, quetiapine or paliperidone; (d) said condition is anxiety and the active substance is duloxetine or dopamine; (e) said condition is multiple sclerosis and the active ingredient is testosterone, glatiramer acetate, interferon beta-1a, interferon beta-1b, fingolimod, natalizumab, or dimethyl fumarate; (f) said condition is Alzheimer's disease and the active ingredient is pregnenolone, memantine, rivastigmine or donepezil; (g) said condition is depression and the active substance is desvenlafaxine, duloxetine or dopamine; (h) said condition is insomnia and the active substance is progesterone or eszopiclone; (i) said condition is attention deficit hyperactivity disorder and the active substance is atomoxetine, guanfacine, methylphenidate, lisdexamfetamine or dopamine; (j) said condition is traumatic brain injury and the active ingredient is progesterone or recombinant tissue plasminogen activator (rt-PA); (k) said condition is a brain tumor and the active substance is methotrexate, raltitrexide, 5-fluorouracil, telomerase inhibitor or monoclonal antibodies; (l) said condition is epilepsy and the active substance is midazolam, lacosamide, levetiracetam, lamotrigine or valproic acid; (m) said condition is pain and the active substance is oxycodone, pregabalin, buprenorphine, hydrocodone or fentanyl; or (n) said condition is Parkinson's disease and the active ingredient is safinamide, ropinirole, pramipexole, dopamine, levodopa, selegiline, cabergoline, or istradefylline.

Some embodiments include methods for treating nasal congestion, including

- 4 043077 for administration of a composition to a subject in need thereof, in which the active substance comprises one or more substances, including a nasal antihistamine and a decongestant. In some embodiments, nasal congestion is due to one or more of nasal dryness/crustations, colds, hay fever, upper respiratory allergies, and age. In some embodiments, the active ingredient comprises one or more of a corticosteroid, naphazoline, oxymetazoline, epinephrine, phenylephrine, nasal saline spray, brompheniramine, chlorpheniramine, clemastine, diphenhydramine, desloratadine, fexofenadine, loratadine, cromolyn, ectoine, and botanical and/or anthroposophic substances.

Some embodiments include a composition for use in the treatment of nasal congestion. Some embodiments include a composition for use in the manufacture of a medicament for the treatment of nasal congestion. In some embodiments, nasal congestion is due to one or more of nasal dryness/crustations, colds, hay fever, upper respiratory allergies, and age. In some embodiments, the active ingredient comprises one or more of a corticosteroid, naphazoline, oxymetazoline, epinephrine, phenylephrine, nasal saline spray, brompheniramine, chlorpheniramine, clemastine, diphenhydramine, desloratadine, fexofenadine, loratadine, cromolyn, ectoine, and botanical and/or anthroposophic substances.

Brief description of graphic materials

In FIG. 1 depicts scanning electron microscope photographs of various spray-dried formulations described herein with progesterone and SYLOID® 72FP particles.

In FIG. 2 depicts scanning electron microscope photographs of various spray-dried formulations described herein with progesterone and SYLOID® 244FP particles.

In FIG. 3 depicts SEM photographs of spray dried compositions described herein with SYLOID® 72FP particles and 244FP particles.

In FIG. 4 shows SEM photographs spray dried with progesterone.

In FIG. 5 depicts differential scanning calorimetry measurements of spray-dried progesterone, spray-dried SYLOID® 72FP, and spray-dried SYLOID® 244FP.

In FIG. 6 depicts differential scanning calorimetry measurements of spray-dried progesterone and SYLOID® 244FP formulations.

In FIG. 7 depicts differential scanning calorimetry measurements of spray-dried formulations with progesterone and SYLOID® 72FP.

In FIG. 8 depicts differential scanning calorimetry thermograms of the compositions described herein with progesterone loaded on OSM-7 ordered mesoporous silica.

In FIG. 9 depicts differential scanning calorimetry thermograms of the compositions described herein with 20% and 40% progesterone loaded on OSM-7 ordered mesoporous silica.

In FIG. 10 depicts the pore size distribution of OSM-7 particles with and without progesterone taken up by OSM-7.

In FIG. 11 depicts differential scanning calorimetry thermograms of the formulations described herein with testosterone loaded on OSM-7 ordered mesoporous silica.

In FIG. 12 depicts differential scanning calorimetry thermograms of the compositions described herein at 20% and 40; the content of testosterone loaded on ordered mesoporous silica OSM-7.

In FIG. 13 shows the pore size distribution of OSM-7 particles with and without testosterone absorbed by OSM-7.

In FIG. 14 shows SEM photographs spray dried with testosterone.

In FIG. 15 (FIGS. 15A-C) are scanning electron microscope photographs of spray dried compositions described herein with testosterone and polylactide.

In FIG. 16 are scanning electron microscope photographs of the spray dried compositions described herein with testosterone and chitosan.

In FIG. 17 (FIGS. 17A-B) are scanning electron microscope photographs of spray-dried formulations described herein with testosterone and gelatin.

In FIG. 18 are scanning electron microscope photographs of spray dried compositions described herein with testosterone, gelatin and an emulsifying agent.

In FIG. 19 (FIGS. 19A-E) are scanning electron microscope photographs of gelatin particles sprayed in ethanol/water mixtures with various ethanol-water ratios.

In FIG. 20 (FIGS. 20A-B) are scanning electron microscope photographs of spray-dried mesoporous silica particles.

In FIG. 21 (FIGS. 21A-E) are scanning electron microscope photographs of spray-dried mesoporous silica particles, some of which are loaded with testosterone as described herein.

In FIG. 22 shows scanning electron microscope photographs of the compositions described herein with testosterone and SYLOID® 244FP.

In FIG. 23 are scanning electron microscope photographs of the compositions described herein with testosterone and AEROSIL® 200.

In FIG. 24 shows the various compositions described herein with testosterone and mesoporous silica particles and depicts the textures associated with the various compositions.

In FIG. 25 shows the various compositions described herein with testosterone and mesoporous silica particles and depicts the textures associated with the various compositions.

In FIG. 26 (FIGS. 26A-B) are scanning electron microscope photographs of mesoporous silica particles that have been spray dried using a dual flow nozzle.

In FIG. 27 (FIGS. 27A-B) are scanning electron microscope photographs of mesoporous silica particles that have been spray dried using a three-stream nozzle.

In FIG. 28 are photographs depicting a rod test conducted to evaluate the fluidity of various formulations.

In FIG. 29 depicts the solubility data associated with various testosterone-based compositions described herein, in which the amount of castor oil in the composition is kept constant.

In FIG. 30 depicts solubility data associated with various testosterone-based compositions described herein, in which the amount of castor oil in the composition varies.

In FIG. 31 shows differential scanning calorimetry measurements using two different batches of testosterone.

In FIG. 32 shows differential scanning calorimetry measurements using two different batches of ethanol-dried testosterone.

In FIG. 33 shows differential scanning calorimetry measurements using various polylactic acid formulations.

In FIG. 34 shows differential scanning calorimetry measurements using various gelatin formulations.

In FIG. 35 depicts differential scanning calorimetry measurements using compositions having SYLOID® 244FP particles.

In FIG. 36 shows differential scanning calorimetry measurements using gelatin coated compositions.

In FIG. 37 depicts differential scanning calorimetry measurements using compositions having AEROSIL® 200 particles.

In FIG. 38 depicts differential scanning calorimetry measurements using compositions having SYLOID® XDP6035 particles.

Detailed description of the invention

Definitions.

Unless otherwise indicated, the technical and scientific terms used in this document have the generally accepted meanings understood by specialists in the field to which this invention pertains. Reference is made herein to various methodologies known to those skilled in the art. In implementing this invention, any suitable materials and/or methods known to those skilled in the art may be used. However, specific materials and methods are described. Unless otherwise specified, materials, reagents, etc., for which

- 6 043077 are referenced in the following description and examples, can be obtained from commercial sources. Publications and other materials setting forth such known methodologies to which reference is made are incorporated herein by reference in their entirety, as if they were set forth in their entirety.

As used herein, the singular forms refer to both the singular and the plural, unless the singular is explicitly stated.

The term about means that the number in question is not limited to the exact number set forth herein, but is intended to refer to numbers essentially around said number without deviating from the scope of this invention. As used herein, the term about will be understood by those skilled in the art and will vary to some extent depending on the context in which it is used. If terms are used that are not understood by those skilled in the art, given the context in which the term about is used, it will mean up to plus or minus 10% of the specific meaning.

As used herein, the term subject refers to any mammal, including humans. For example, the subject may be suffering from or at risk of developing a medical condition that can be treated or prevented by the active substance, or may be taking the active substance for health purposes.

As used herein, the phrases "therapeutically effective amount" and "therapeutic level" refer to the dose or plasma concentration of an active ingredient in a subject, respectively, that provides the specific pharmacological effect for which the active ingredient is administered to a subject in need of such treatment. It should be especially noted that a therapeutically effective amount or therapeutic level of an active substance will not always be effective in treating the disease states/diseases described herein, even if such a dose is considered by those skilled in the art to be a therapeutically effective amount. For reasons of convenience only, illustrative dosages, delivery amounts, therapeutically effective amounts, and therapeutic levels of the active ingredient in adult human subjects are provided below. Those skilled in the art can adjust such amounts in accordance with standard techniques as needed to treat a particular subject and/or disease state/disease.

Theoretical loading of the active substance means the wt.% of the active substance in the composition or porous filler, if the active substance is included in the composition or porous filler with 100% efficiency. Thus, the theoretical loading of active ingredient per porous excipient can be calculated using the following equation: theoretical loading = 100 x (mass of added active ingredient (g)) / (mass of active ingredient (g) + porous filler (g)).

The actual loading of the active substance means the actual amount of the active substance included in the composition or porous filler. Thus, the actual loading of the active substance on the porous filler can be calculated using the following equation: 100 x (mass of active substance (g) in 1 gram of loaded porous filler) / (1 g of loaded porous filler).

The loading efficiency can be calculated according to the following equation: loading efficiency = 100 x (total active ingredient with yield (g)) / (actual amount of added active ingredient at the time of loading).

active ingredients.

The active substance may include any one or more therapeutic agents that can be administered intranasally to achieve a therapeutic effect. In some embodiments, the active ingredient contains a hormone such as testosterone, progesterone, pregnenolone, or a prodrug or derivative of any of these. In some embodiments, the active substance contains a neurotransmitter such as dopamine, levodopa, or serotonin. In some embodiments, the active ingredient contains an opioid analgesic such as fentanyl or hydromorphone. In some embodiments, the active ingredient contains a benzodiazepine such as midazolam. In some embodiments, the active ingredient contains a protein, such as insulin or a growth hormone (eg, human growth hormone). In some embodiments, the active ingredient contains a cholinesterase inhibitor such as donepezil, rivastigmine, or galantamine. In some embodiments, the active ingredient comprises a nasal antihistamine and/or a decongestant such as a corticosteroid, naphazoline, oxymetazoline, adrenaline, phenylephrine, nasal saline spray, brompheniramine, chlorpheniramine, clemastine, diphenhydramine, desloratadine, fexofenadine, loratadine, cromolyn, ectoine, or vegetable and anthroposophic substances. In some embodiments, the active ingredient is selected from the group consisting of aripiprazole, quetiapine, paliperidone, duloxetine, dopamine, testosterone, glatiramer acetate, interferon beta-1a, interferon beta-1b, fingolimod, natalizumab, dimethyl fumarate, pregnenolone, memantine , rivastigmine, donepezil, desvenlafaxine, progesterone, eszopiclone, atomoxetine, guanfacine, methylphenidate, lisdexamfetamine, recombinant tissue plasminogen activator (rt-PA), methotrexate, raltitrexide, 5-fluorouracil, telomerase inhibitor, monoclonal antibodies, midazolam, lacosamide, levetiracetam, lamotrigine , valproic acid, oxycodone, pregabalin, buprenorphine, hydrocodone, fentanyl, safinamide, ropinirole, pramipexole, levodopa, selegiline, cabergoline, istradephylline, and combinations of two or more of them.

In some embodiments, the composition is suitable as a vaccine and the active ingredient comprises an immunogen, such as an influenza vaccine, a hepatitis B vaccine, or a meningitis vaccine. In embodiments where the composition is useful as an influenza vaccine, the active agent loaded onto the porous carrier may be immunogenic against influenza. Examples of active ingredients loaded onto a porous carrier where the composition is suitable as an influenza vaccine include a live attenuated influenza virus (such as, but not limited to, A/California/7/2009(H1N1) or A/California/ 7/2009 (H1N1)-like strain; A/Switzerland/9715293/2013 (H3N2) or A/Switzerland/9715293/2013 (H3N2)-like strain; B/Phuket/3073/2013 or B/Phuket/3073/2013- similar strain (B/Yamagata type) B/Brisbane/60/2008 or B/Brisbane/60/2008-like strain (B/Victoria vaccine virus lineage) In some embodiments in which the composition is useful as an influenza vaccine , the active substance loaded on the porous filler contains an inactivated virus or viral antigens (such as, but not limited to, antigens from influenza A/Panama/ 2007/99 (H3N2), B/Guandong/2000 and/or bird strain, such as A/Duck/Singapore/ 97 (H5N3)).

In embodiments in which the composition is suitable as a hepatitis B vaccine, the active ingredient loaded onto the porous carrier may comprise, for example, hepatitis B virus (HBV), hepatitis B surface antigens (HBsAg), and/or hepatitis virus core antigens. B (HBcAg).

In embodiments where the composition is suitable as a meningitis vaccine, the active ingredient loaded onto the porous carrier may comprise, for example, a meningococcal polysaccharide vaccine (MPSV4, a polysaccharide from the surface of meningococcal bacteria), a meningococcal conjugate vaccine (MCV4, a polysaccharide, chemically linked with protein) and/or serogroup B meningococcal vaccine (MenB, which contains four proteins taken from Neisseria meningitidis group B bacteria).

In some embodiments, the composition is useful in the treatment of nasal congestion, for example, which may be due to nasal dryness/crustations, colds, hay fever, upper respiratory allergies, or age. In specific embodiments useful in the treatment of nasal congestion, the active ingredient comprises a nasal antihistamine and/or decongestant such as a corticosteroid, naphazoline, oxymetazoline, epinephrine, phenylephrine, nasal saline spray, brompheniramine, chlorpheniramine, clemastine, diphenhydramine, desloratadine, fexofenadine , loratadine, cromolyn, ectoine or herbal and anthroposophic substances.

In some embodiments, the composition contains the active ingredient in amorphous form. In some embodiments, the composition contains the active ingredient in crystalline form. In some embodiments, the composition contains the active substance, both in amorphous form and in crystalline form. For example, an amorphous active agent may be loaded onto a porous excipient within the pores of the excipient, and a crystalline active agent may be incorporated into a coating and/or present in a composition carrier, eg, dissolved, suspended or dispersed in the composition carrier.

In some embodiments, the composition contains an active ingredient that is less than about 0.1%, less than about 0.5%, less than about 1%, or less than about 5% in crystalline form, such as less than 0.1% , less than 0.5%, less than 1% or less than 5% in crystalline form. In some embodiments, the composition is substantially free of the crystalline form of the active ingredient.

In some embodiments, the active ingredient may be used in a form that is not typically used, such as a polymorph or salt, which may not be satisfactorily stable in typical formulations. Without being limited by theory, it is believed that the loading of the active substance on the porous filler described in this document can stabilize the active substance, both against chemical reactions and against physical modifications (such as intrapolymorphic transformation). In some embodiments, a porous excipient is selected and/or prepared for this purpose, for example, with a certain quality of silica that stabilizes the active ingredient under investigation.

Nasal compositions.

This document provides nasal compositions containing a porous filler and an active substance. Methods for the manufacture and use of nasal compositions containing a porous filler and an active substance are also proposed.

By nasal compositions is meant compositions suitable for or adapted to

- 8 043077 for nasal delivery, including intranasal delivery. The specific form of the nasal composition is not limited. In some embodiments, the nasal composition is in the form of a solution, suspension, dispersion, emulsion, or gel. In some embodiments, the composition is in the form of an oily liquid. In some embodiments, the composition is non-aqueous or non-anhydrous. (As used herein, the term anhydrous means that the composition is formulated without water, although trace amounts may be present). In some embodiments, the composition contains an anhydrous semi-liquid phase. In some embodiments, the composition is a hydrophilic gel or emulgel (ie, an emulsion included in a gel base). In some embodiments, the composition is a hydrophobic gel, such as an oleogel or organogel. In some embodiments, the composition contains a three-dimensional viscoelastic gel with low molecular weight organoregulators and/or polymeric thickeners. In some embodiments, the composition may be smeared.

The nasal compositions described herein comprise (a) an active agent and (b) a porous excipient, characterized in that the active agent is loaded onto the surface of the porous excipient located within the pores of the porous excipient. In some embodiments, the compositions further comprise a carrier. In some embodiments, the compositions further comprise a viscosity adjusting agent. In some embodiments, the porous excipient is provided with a coating that may or may not contain an active agent (which may be the same as or different from the active agent loaded onto the porous excipient). In some embodiments, the composition contains a surfactant. In some embodiments, the composition comprises a porous excipient included in a gel network, such as a hydrophobic gel.

In some embodiments, at least a portion of the active agent-laden porous excipient is in particulate form. In some embodiments, about 10% of the particles have a maximum diameter in any dimension of less than about 0.2 microns, or less than about 0.1 microns. In some embodiments, about 90% of the particles have a maximum diameter less than about 15.5 microns, less than about 7.5 microns, or less than about 4.2 microns. In some embodiments, about 50% of the particles have a maximum diameter of less than about 5.2 microns, less than about 2 microns, or less than about 0.9 microns.

In some embodiments, the active ingredient is present in the nasal composition in an amount of from about 0.1 to about 70% w/w, including from about 0.5 to about 40% w/w, from about 5 to about 40% wt./wt., from about 10 to about 30% wt./wt. and from about 15 to about 25% wt./wt. based on the total weight of the composition and in amounts between any of these values, including about 0.1% wt./wt., about 0.5% wt./wt., about 1% wt./wt., about 5% w/w, about 10% w/w, about 15% w/w, about 20% w/w, about 25% w/w, about 30% w/w , about 35% w/w, about 40% w/w, about 45% w/w, about 50% w/w, about 55% w/w, about 60% w/w ./wt. or about 70% w/w, based on the total weight of the composition.

In some embodiments, the composition contains at least about 1 μg of the active ingredient per 150 mg of the composition. In some embodiments, the composition contains from about 1 μg to about 100 mg of active ingredient per 150 mg of composition, or from about 1 mg to about 50 mg of active ingredient per 150 mg of composition, or from about 5 mg to about 20 mg of active ingredient per 150 mg of composition. mg of composition, or from about 50 µg to about 250 µg of active ingredient per 150 mg of composition. In some embodiments, the composition contains about 1 µg, about 10 µg, about 20 µg, about 50 µg, about 100 µg, about 250 µg, about 500 µg, about 1 mg, about 2 mg, about 5 mg, about 5.5 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg or about 50 mg of active ingredient per 150 mg of composition. In some embodiments, the composition contains 1 μg, 10 μg, 20 μg, 50 μg, 100 μg, 250 μg, 500 μg, 1 mg, 2 mg, 5 mg, 5.5 mg, 7 mg, 8 mg, 9 mg, 10 mg, 15 mg, 20 mg, 25 mg or 50 mg of active ingredient per 150 mg of composition.

The composition may be adapted for nasal administration of any suitable amount of the composition, subject to the limitations of the volume of nasal administration. In some embodiments, the composition is adapted to be administered from about 0.1 ml to about 1 ml per nostril, for example, from about 0.1 to about 0.3 ml, from about 0.15 to about 0.25 ml, or from about 0.175 up to about 0.225 ml per nostril. Some embodiments are adapted to administer 0.1 to 1 ml per nostril, such as 0.1 to 0.3 ml, 0.15 to 0.25 ml, or 0.175 to 0.225 ml per nostril. In some embodiments, the composition is adapted to be administered at about 0.1 ml, about 0.15 ml, about 0.2 ml, about 0.25 ml, or about 0.3 ml per nostril.

Some implementation options are adapted to the introduction of 0.1, 0.15, 0.2, 0.25 or 0.3 ml per nostril. In some embodiments, the composition is adapted to be administered at about 0.2 ml or less per nostril. In some embodiments, the composition is adapted to be administered at 0.2 ml or less per nostril.

In some embodiments, the composition is adapted to be administered once daily per nostril, in one or both nostrils. In some embodiments, the composition is adapted to be administered twice daily per nostril, in one or both nostrils. In some embodiments, the composition is administered three, four, five, or six times daily per nostril, in one or both nostrils.

In some embodiments, the composition is stable (e.g., substantially free of degradation-related impurities) for at least about 1 month, at least about 2 months, at least about 3 months, or at least about 6 months, for example, after storage, for example, at 25°C and 60% relative humidity, at 30°C and 65% relative humidity, or under room temperature and humidity conditions. In some embodiments, the composition is stable for at least 1 month, at least 2 months, at least 3 months, or at least 6 months, for example, after storage, for example, at 25°C and 60% relative humidity, at 30°C and 65% relative humidity or room temperature and humidity conditions.

Porous fillers.

As noted above, the nasal compositions described herein contain (a) an active ingredient and (b) a porous filler. The porous excipient may be any porous material onto which the active agent may be loaded. In some embodiments, the active agent is loaded onto the surfaces of the porous filler, including surfaces located within the pores of the filler. In some embodiments, the porous excipient acts as a matrix for the active agent. In some embodiments, the composition further comprises an active agent that is not loaded onto a porous carrier; for example, the composition may contain an active ingredient in addition to the active ingredient that is loaded onto the porous carrier.

The porous filler may contain any material suitable for use in a nasal pharmaceutical composition, and on which the active substance can be loaded in accordance with the disclosure of this document. The following are non-limiting examples of suitable materials.

In some embodiments, the porous agent comprises an inorganic porous material such as colloidal silica, microporous silica, mesoporous silica, macroporous silica, polyorganosiloxanes, pharmaceutical clays, silica nanotubes, silica gel, magnesium aluminosilicate (e.g. , but not limited to VEEGUM® by Vanderbilt Minerals, LLC), activated carbon, anhydrous calcium phosphate, calcium carbonate, alumina, and combinations of any two or more of these. Examples of inorganic porous materials include porous silica, commercially available under the trademark SYLOID® from WR Grace & Co. (for example, but not limited to SYLOID® 244FP, 72FP, XDP6035 (also known as SILSOL™ 6035), XDP3050, XDP3150, AL-1FP and combinations of any two or more of these), porous silica available under the brand name AEROPERL ® from Evonik Industries, Corp. (for example, but not limited to, AEROPERL® 300, which has a surface area of about 260 to 320 m ² /g (for example, about 300 m ² /g), a pore volume of about 1.5 to 1.9 ml/g and an average particle size of about 20 to 60 µm), PARTECK® SLC silica from EMD Millipore, NEUSILIN® (a synthetic amorphous form of magnesium aluminometasilicate) from Fuji Chemical Industry, Zeolite Socony Mobil-5, Mobil Composition #41 from Matter, SBA- 15, FDU-11, OMS-7, OMSLemon-7 and IITM-56. In some embodiments, the porous agent comprises silica-based powders, which may be hydrophobic or hydrophilic, for example, depending on the groups chemically bonded to their surfaces.

As a reference, exemplary descriptions of various SYLOID® inorganic porous materials are provided below.

Index AL1FP 72FP 244FP XDP3050 XDP3150 XDP6035 S1O2 (dry basis) (%) 99.6 99.6 99.6 99.6 99.6 99.8 Average particle size (µm) 7.5 6.0 3.5 50 150 37 Oil Adsorption (lbs/100 lbs) 80 220 300 300 300 Bulk density (g/l) 566 112 70 275 275 420 Average pore volume (cm ³ /g) 0.4 1.2 1.6 1.7 1.7 0.98

In some embodiments, the porous filler comprises an organo-inorganic hybrid, such as metal-organic frameworks (MOFs). Exemplary hybrid materials can be formed by self-assembly of polydentate bridging ligands and metal bonding dots.

In some embodiments, the porous filler comprises organic polymers such as microporous organic polymers, polystyrene, cellulose, and/or poly(methyl methacrylate). In some embodiments, microporous organic polymers are formed from carbon-carbon synthesis reactions and contain non-metallic elements such as carbon, hydrogen,

- 10 043077 oxygen, nitrogen and/or boron. In some embodiments, organic polymers are produced by emulsion polymerization and hyperlinking, followed by chemical etching of sacrificial SiO2 cores. In some embodiments, organic polymer networks are formed from small organic building blocks.

In some embodiments, the porous filler comprises porous materials based on complexing agents such as an ion exchange resin (such as, but not limited to, cross-linked polystyrene) or an adsorbent (such as, but not limited to, porous silica based on β-cyclodextrin, porous silica based on α-cyclodextrin, porous silica based on hydroxypropyl-p-cyclodextrin and porous materials based on other adsorbent resins).

In some embodiments, the porous filler comprises a material with highly variable pore sizes and random shapes, such as a polylactide and/or polylactic acid containing agent. In some embodiments, the polylactide comprises polylactides available under the RESOMER® brand available from Sigma-Aldrich (such as, but not limited to, RESOMER® 202H (which has a molecular weight of about 10,000 to about 18,000 Da, a viscosity of about 0.16 to about 0.24 dl/g; _Tg from about 44 to about 48°C; and free carboxylic acid end groups) and RESOMER® 202S (which has a molecular weight of about 10,000 to about 18,000 Da, a viscosity of about 0.16 up to about 0.24 dl/g; T _g from about 38 to about 42° C. and end groups ending in ester)) and combinations of two or more of them. In some embodiments, the porous agent contains polysaccharides such as chitosan (such as, but not limited to, chitosan with 95% deacylation and a viscosity of about 200 mPa). An exemplary chitosan in this regard is CHITOSCIENCE® Chitosan 95/200 from Hepre Medical Chitosan GmbH. In some embodiments, the porous agent comprises peptides and/or proteins such as gelatin (such as, but not limited to, F15, F20, F25 Bloom grade gelatin, or combinations of two or more of these).

In some embodiments, the implementation of the porous filler contains porous particles. Without being limited by theory, it is believed that even small and large particles can be effective in fixing them in the gel network using chemical and/or physical bonds, such as hydrogen bonding and van der Waals forces. In any embodiments in which the porous filler contains porous particles, the particles may have a maximum diameter in any dimension from about 0.5 to about 350 microns, for example, from about 50 to about 300 microns, from about 100 to about 250 microns, from about 150 to about 200 microns, or about 3 to about 35 microns. In some embodiments, the maximum diameter is 0.5 to 350 microns, such as 50 to 300 microns, 100 to 250 microns, 150 to 200 microns, or 3 to 35 microns. In some embodiments, the particles have a maximum diameter of about 0.5 µm, about 0.8 µm, about 1 µm, about 2 µm, about 3 µm, about 5 µm, about 10 µm, about 35 µm, about 60 µm, or about 150 µm. In some embodiments, the particles have a maximum diameter of 0.5, 0.8, 1, 2, 3, 5, 10, 35, 60, or 150 microns.

In some embodiments, the particles have a diameter of about 0.5 to about 350 microns, such as about 50 to about 300 microns, about 100 to about 250 microns, about 150 to about 200 microns, or about 3 to about 35 microns. . In some embodiments, the median diameter is 0.5 to 350 microns, such as 50 to 300 microns, 100 to 250 microns, 150 to 200 microns, or 3 to 35 microns. In some embodiments, the median particle diameter in the composition is about 0.5 µm, about 0.8 µm, about 1 µm, about 2 µm, about 3 µm, about 5 µm, about 10 µm, about 35 µm, about 60 µm, or about 150 µm. In some embodiments, the median particle diameter in the composition is 0.5, 0.8, 1, 2, 3, 5, 10, 35, 6o, or 150 microns.

In the case of any type of porous filler, the porous filler may contain pores with a maximum diameter in any dimension of 2 nm or less (eg, the porous filler contains microporous materials). In some embodiments, the porous filler contains pores with a maximum diameter of about 2 to about 50 nm, such as 20 to 50 nm (eg, the porous filler contains mesoporous materials). In some embodiments, the implementation of the porous filler contains pores with a maximum diameter of 50 or more (for example, the porous filler is macroporous materials). In some embodiments, the porous filler contains pores with a maximum diameter of about 2 to about 20 nm, such as 2 to 20 nm. In some embodiments, at least about 90% of the pores have a diameter of about 5 to about 6 nm, about 5 to about 7.5 nm, about 5.5 to about 7 nm, about 6 to about 7.5 nm or from about 6 to about 8 nm. In some embodiments, at least about 90% of the pores are 5 to 6 nm, 5 to 7.5 nm, 5.5 to 7 nm, 6 to 7.5 nm, or 6 to 8 nm in diameter. In some embodiments, the pores have an average volume of about 0.5 to about 2 ml/g, such as about 1 ml/g, about 1.6 ml/g, or about 1.75 ml/g. In some embodiments, the pores have an average volume of 0.5 to 2 ml/g, such as 1, 1.6, or 1.75 ml/g. In some embodiments, the pores have an average volume of greater than about 0.9 ml/g, or greater than 0.9 ml/g. In some embodiments, the pores have a surface area of about 300

- 11 043077 m ² /g or more, or from about 320 to about 1000 m ² /g. In some embodiments, the pores have a surface area of 300 m ² /g or more, or from 320 to 1000 m ² /g. In some embodiments, the pores have a surface area of 1000 m ² /g or more.

The porous filler may have pores with any type of pore structure. For example, the cross section of the pore may have a regular geometric shape, such as a round, elliptical, rectangular or square shape, or an irregular shape. In some embodiments, the porous filler contains regularly shaped pores and irregularly shaped pores. In some embodiments, the porous filler additionally or alternatively comprises pores with a connected pore structure, pores with an unconnected pore structure, or both. In some embodiments, the porous filler additionally or alternatively comprises ordered pore arrays, random pore arrays, or both.

The composition may contain any suitable amount of porous excipient, for example any amount effective to provide a therapeutically effective dose of the active substance, while still being suitable for nasal administration. In some embodiments, the composition contains from about 0.01 to about 0.5 g of porous filler, for example, from about 0.01 to about 0.4 g of porous filler, from about 0.1 to about 0.25 g, or about 0.05 g, about 0.1 g, about 0.15 g, about 0.2 g, about 0.25 g or about 0.3 g of porous filler, the weight corresponding to the amount of porous filler before it is loaded with the active substance. In some embodiments, the composition contains from 0.01 to 0.5 g of porous filler, for example, from 0.01 to 0.4 g of porous filler, from 0.1 to 0.25 g, or 0.05 g, 0. 1, 0.15, 0.2, 0.25 or 0.3 g of porous filler. In some embodiments, the composition contains from about 0.5 to about 30% w/w, from about 1 to about 20% w/w, from about 5 to about 15% w/w, or from about 8 to about 10% w/w of the porous filler, based on the weight of the preloaded porous filler and the total weight of the composition. In some embodiments, the composition contains 0.5 to 30% w/w, 1 to 20% w/w, 5 to 15% w/w, or 8 to 10% w/w. wt. porous filler based on the weight of the pre-loaded porous filler and the total weight of the composition.

In some embodiments, the active substance is loaded onto the porous filler in an amount of from about 1 to about 70% wt./wt., including from about 5 to about 40% wt./wt., from about 10 to about 30% wt. /wt., and from about 15 to about 25% wt./wt. based on the total weight of the loaded porous filler and in amounts between any of these values, including 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, or 70% w/w .

In some embodiments, the weight ratio of porous excipient to active agent is from about 1:1 to about 10:1, for example, from about 1:1 to about 5:1. In some embodiments, the weight ratio of porous excipient to active ingredient is 1:1 to 10:1, such as 1:1 to 5:1. In some embodiments, the weight ratio of porous excipient to active ingredient is about 1:1, about 2:1, about 3:1, about 4:1, or about 5:1. In some embodiments, the weight ratio of porous excipient to active ingredient is 1:1, 2:1, 3:1, 4:1, or 5:1.

In some embodiments, the porous excipient may be selected and/or designed to modify the release properties of the active agent from the composition, for example, the porous excipient may be selected and/or obtained to exhibit the release modification properties of the active agent. For example, the porous excipient may be selected and/or designed to provide a sustained release of the active ingredient and/or to control the release of the active ingredient, for example to ensure the release of the active ingredient at a predetermined rate and/or to maintain a constant therapeutic level of the active ingredient for a certain period of time. period of time or providing any other type of controlled release. In some embodiments, the porous excipient allows the release of the active agent to be controlled (perhaps even biphasic release), for example, by changing the pore size and shape of the excipient and/or by functionalizing the internal or external interfaces, or both. In Martinez-Carmona et al., Nanomaterials, 5: 1906-1937 (2015), which is incorporated herein by reference, and in Vallet-Regi et al., Biomedical Applications of Mesoporous Ceramics: Drug Delivery, Smart Materials and Bone Tissue Engineering (2013) provides examples of how to modify the release characteristics of a composition.

Exemplary aspects of release modification are discussed in Martinez-Carmona et al., Nanomaterials, 5: 1906-1937 (2015), which is incorporated herein by reference, and in ValletRegi et al. Biomedical Applications of Mesoporous Ceramics: Drug Delivery, Smart Materials and Bone Tissue Engineering (2013), which is incorporated herein by reference.

In some embodiments, the surface of the porous filler, including the inner surface of the pore, may be functionalized to bind the active agent and/or control the release of the active agent over time or in response to a stimulus. For example, in exemplary embodiments, a hormone (eg, testosterone) bound to a porous vehicle may be a ligand for site-specific delivery of agents to

androgen receptor (AR) positive regions such as AR positive tumors or other organs such as the prostate, brain or testes. In some embodiments, the porous excipient may be functionalized to promote cellular uptake by the endocytosis pathway. In some embodiments, the active agent is released from the porous vehicle following cellular uptake of the porous vehicle. In some embodiments, the porous filler is functionalized with one or more organic moieties. In some embodiments, the porous filler is functionalized with amino groups, quaternary alkylamines, alkyl chains, alkoxysilanes, fluorenylmethoxycarbonyl-modified organosilanes, hydrophobic groups, mercaptopropyl groups, aminopropyl groups, hydroxypropyl groups, phenyl groups, or combinations of two or more of these. Illustrative functionalization groups are set forth in Vallet-Regi et al., Biomedical Applications of Mesoporous Ceramics: Drug Delivery, Smart Materials and Bone Tissue Engineering (2013), which is incorporated herein by reference.

The porous filler may perform one or more functions in the context of the compositions described herein. For example, the porous excipient may act as a carrier for the active agent, may protect the active agent, and/or may delay and/or control the release of the active agent. Additionally or alternatively, the porous excipient may affect the chemical, physical, physico-chemical and/or pharmacokinetic properties of the composition, as discussed in more detail below.

In some embodiments, the porous filler acts as a protective agent, i. it protects the active substance from oxidation and/or degradation and/or reaction with other components of the composition and/or the environment. This may be particularly advantageous for active substances subject to oxidation and/or degradation, such as dopamine.

In some embodiments, the porous excipient affects the chemical, physical, physicochemical, and/or pharmacokinetic properties of the composition, e.g., by acting as a gelling agent, structuring agent, solubilizing agent (e.g., solubility enhancer), release modifying agent , and/or the binding site of the active substance.

Without being limited by theory, it is believed that in some embodiments, the active substance is loaded onto the porous vehicle in a stable amorphous state, such that a supersaturated aqueous solution can be provided to the site of application, which can lead to increased transepithelial or transmucosal transport. In addition, without being limited by theory, it is believed that the number of hydroxyl groups on the porous filler available for the formation of inter - and intramolecular hydrogen bonding in the compositions, as stated, enhances dissolution.

In some embodiments, the porous excipient contains porous particles (such as, but not limited to, ordered mesoporous silica or SYLOID® particles such as AL-1FP, 244FP, XDP3050, 72FP, XDP6035, or XDP3150) that can be loaded with an active agent. Some embodiments include spray-dried particles with active ingredient loaded onto porous filler particles. In some embodiments, the loaded particles are in the form of a dry powder. In some embodiments, the particles are in granular form.

In addition to or as an alternative to selecting and/or preparing a porous excipient and/or any coating to provide the desired release profile for the active ingredient, the composition as a whole can be designed to provide the desired release profile, e.g., the desired sustained and/or controlled release profile. For example, the release of active ingredient from a composition can be modified by changing one or more of the amount of porous excipient loaded with active ingredient in the composition, the amount of active ingredient present in any coating, the amount of active ingredient present in the carrier of the composition, and/or by incorporating one or more release-modifying agents into the composition.

In some embodiments, the compositions have one or more of the following advantages over compositions without the active ingredient loaded on a porous filler: a reduction in the amount of settable fillers; increased bioavailability; low or no toxicity potential; rapid onset of action; suitability for relatively high loadings of the active substance; the possibility of deposition for prolonged release; greater control over the release of the active substance (possibly even a two-phase release), for example, by changing the pore size and shape of the filler and by functionalizing the internal or external interfaces, or both; no slurry related problems such as Ostwald ripening or homogeneity (ie segregation) problems; the ability to have therapeutic efficacy with variable particle sizes of the porous filler; lipophilic or hydrophilic active substances or even both can be included in the composition; the composition is suitable for patients with allergies, for example, because in whom

- 13 043077 positions may be missing fillers that cause an allergic response; simple and economical production process; protection of active substances sensitive to oxygen or humidity; stabilization of the amorphous form of the active substance; lack of recrystallization of active substances; the ability to provide rapid release of the active substance; the ability to purposefully affect the systemic circulation and/or the brain and/or spinal cord as a result of the functionalization of the filler; the composition can be smeared (and thus eliminate the problem of the promotion of the active substance in a particular area of the nasal cavity and the position of the head, spray angle and jet geometry); in addition, the maximum surface of the nasal mucosa can be covered.

Coating.

In some embodiments, the implementation of the porous filler contains a coating. In some embodiments, the coating is porous, while in other embodiments, the coating is non-porous. In some embodiments, the coating surrounds the porous excipient onto which the active agent is loaded (eg, provides a coating around the loaded porous excipient). In some embodiments, the coating is in the form of a film. In some embodiments, the coating functions to cover the loaded pores. In some embodiments, the coating functions to cover the pores but does not completely surround the porous filler (eg, the pores are covered but the coating does not completely surround the porous filler).

In some embodiments, the coating provides a sustained release of the active ingredient. In some embodiments, the coating provides a sustained release of the active ingredient. In some embodiments, the coating functions to enhance the bioavailability of the active ingredient. In some embodiments, the coating functions to protect the active agent loaded onto the porous excipient. In some embodiments, the coating contains an active agent (eg, the same active agent as found in the pores, or a different active agent).

The coating may contain any material suitable for use in a nasal pharmaceutical composition. In some embodiments, the coating contains one or more polymers, which may be selected to provide the desired characteristics of the coating (eg, sustained release, controlled release, protection, etc.). In some embodiments, the coating contains polymers that are oil soluble or partially oil soluble, while in other embodiments, the coating contains polymers that are slightly oil soluble or oil insoluble.

In any embodiment of the coating, the coating may comprise linear polymers such as polyvinylpyrrolidone, hyaluronic acid, xanthan, alginate, polyvinyl acetate, sodium starch glycolate, and combinations or copolymers of any two or more of these. In any embodiments of the coating, the coating may contain branched polymers such as branched polyethylene glycol or gum arabic. Additionally or alternatively, the coating may contain cellulose-containing polymers such as sodium carboxymethylcellulose. Additionally or alternatively, the coating may contain copolymers such as polyvinylpyrrolidone/polyvinyl acetate, polyvinylpyrrolidone/polyvinyl alcohol, polyvinyl alcohol/PEG, polyvinyl caprolactam/polyvinyl acetate/polyethylene glycol, and combinations of any two or more of these. Additionally or alternatively, the coating may comprise cross-linked polyvinylpyrrolidone and/or cross-linked sodium carboxymethyl cellulose. Additionally or alternatively, the coating may contain a polylactide, such as polylactic acid. Any suitable polylactide may be used, such as polylactide which contains RESOMER® 202H, RESOMER® 202S, Lupon DEPOR®, PLENAXIS®, and combinations of any two or more of these. Additionally or alternatively, the coating may contain polysaccharides such as chitosan (such as, but not limited to, chitosan 95/200). Additionally or alternatively, the coating may contain peptides and/or proteins. Additionally or alternatively, the coating may contain gelatin (such as, but not limited to, F15, F20 or F25). It should be understood that the coating may contain combinations of any two or more of the foregoing and/or chemical modifications of any of the foregoing.

In some embodiments, the coating further comprises an active agent (eg, the active agent is loaded into or onto the coating), which may be the same as or different from the active agent loaded onto the porous filler. Thus, in some embodiments, the active agent is present in the pores of the porous filler and is also present in the coating. In some embodiments, the coating does not contain an active ingredient.

In embodiments in which the pores are coated, the coating may contain materials, such as nanoparticles, covalently associated with the pore openings. Exemplary nanoparticles include cadmium sulfide (CdS) nanocrystals, Fe ₃ O ₄ nanoparticles, and cyclodextrins. Without being limited by theory, it is believed that the coating of the loaded pores can inhibit or control the release of the active substance from the pores.

Thus, in some embodiments, the composition comprises a loaded porous excipient that contains the active agent loaded onto porous excipient particles (such as, but not limited to, ordered mesoporous silica or SYLOID® particles such as 244FP, XDP3050, 72FP, XDP6035 or XDP3150), wherein the particles are coated with the material described herein (such as, but not limited to, gelatin). In some embodiments, the particles coated with the active ingredient loaded onto the porous filler particles are spray dried, for example, to form a dry powder.

Additional components.

As noted above, the nasal compositions described herein may contain, in addition to the active substance and the porous excipient, a carrier and a viscosity-adjusting agent (eg, gelation).

The carrier may be any carrier suitable as a carrier for a nasal pharmaceutical composition. In some embodiments, the carrier for the porous filler is a hydrophilic carrier. In some embodiments, the carrier is a lipophilic or partially lipophilic carrier, such as a carrier containing one or more substances, including fats, oils, waxes, phospholipids, steroids (e.g., cholesterol), sphingolipids, ceramides, sphingosines, prostaglandins, and/or vitamins soluble in fats or oils. In some embodiments, the carrier comprises an oil or mixture of oils such as vegetable oil, castor oil, hydrogenated castor oil, soybean oil, sesame oil, or peanut oil; fatty acid esters such as ethyl and oleyl oleate, isopropyl myristate; medium chain triglycerides; esters of fatty acids and glycerol; polyethylene glycol; phospholipids; white soft paraffin; or combinations of any two or more of them.

The carrier may be present in any suitable amount, such as an amount effective to provide the desired properties for nasal administration, the desired physical properties, the desired release properties, the desired pharmacokinetics, and so on. In some embodiments, the composition comprises a carrier in an amount of from about 15 to about 98% by weight, from about 30 to about 98% by weight, from about 50 to about 95% by weight, from about 75 to about 95% by weight, about 80% or about 90% by weight based on the total weight of the composition. In some embodiments, the composition contains a carrier in an amount of 15 to 98% by weight, 30 to 98% by weight, 50 to 95% by weight, 75 to 95% by weight, 80 or 90% by weight based on the total weight of the composition.

In some embodiments, the carrier contains the active ingredient, for example, the contained active ingredient is dissolved, suspended or dispersed in the carrier. The active substance(s) in the carrier may be the same(s) or different from the active substance(s) loaded(s) onto the porous carrier.

The viscosity adjusting agent, if present, can be any viscosity adjusting agent suitable for use as a viscosity adjusting agent in a nasal pharmaceutical composition. In some embodiments, the viscosity adjusting agent comprises mesoporous silica (which may or may not be loaded with active ingredient). In some embodiments, the viscosity adjusting agent comprises cellulose, cellulose containing substances, polysaccharides, carbomers, polyvinyl alcohol, povidone, colloidal silicon dioxide, cetyl alcohols, stearic acid, beeswax, petroleum jelly, triglycerides, lanolin, or combinations of any two or more of them. In some embodiments, the viscosity adjusting agent comprises colloidal silica (such as, but not limited to, AEROSIL® 200 (Evonik) and/or CAB-O-SIL® M5 (Cabot)). In some embodiments, the viscosity adjusting agent comprises a synthetic silica such as SYLODENT® (precipitated silica with a compacted bulk density of about 110 kg/m ³ , a specific surface area of about 190 m ² /g and an average particle size of about 18 microns) or silicas SYLOBLANC® (porous silica gel with a pore volume of about 1.6 ml/g and an average particle size of about 3 μm) from WR Grace & Co. In some embodiments, the viscosity adjusting agent comprises a hydrophilic fumed silica such as AEROSIL® 200 and/or a lipophilic silica such as AEROSIL® R972 (which is a fumed silica followed by dimethyldichlorosilane treatment and which has a surface area of about 90 up to about 130 m ² /g). Without being limited by theory, it is believed that hydrophilic colloidal silica can be used to obtain a thixotropic gel composition with high thermal stability compared to a comparable gel prepared with other agents that regulate the viscosity.

The viscosity adjusting agent, if present, may be present in an amount effective to adjust the viscosity of the composition to the desired level. In some embodiments, the composition contains from about 0.5 to about 20% by weight, from about 0.5 to about 10% by weight, from about

- 15 043077

0.5 to about 7% by weight, about 1 to about 4% by weight, about 4% by weight, or about 2% by weight of the viscosity adjusting agent, based on the total weight of the composition. In some embodiments, the composition contains 0.5 to 20% by weight, 0.5 to 10% by weight, 0.5 to 7% by weight, 1 to 4% by weight, 4% by weight, or 2 % by weight of the agent that regulates the viscosity, based on the total weight of the composition.

In some embodiments, the composition has a viscosity, measured with a rotational viscometer, from about 2000 to about 10000 mPa-s, for example, about 2000 mPa-s, about 3000 mPa-s, about 4000 mPa-s, about 5000 mPa-s, about 6000 mPa-s, about 7000 mPa-s, about 8000 mPa-s, about 9000 mPa-s or about 10000 mPa-s. In some embodiments, the composition has a viscosity, measured with a rotational viscometer, from 2000 to 10000 mPa-s, such as 2000, 3000, 4000, 5000, 6000, 7000, 8000, 9000 or 10000 mPa-s.

In some embodiments, the porous filler functions as the sole viscosity control agent in the composition. Thus, in some embodiments, the composition does not include a viscosity control agent other than a porous filler. For example, a porous filler having silanol groups (such as, but not limited to, mesoporous silica such as SYLOID®) can function as a viscosity control agent. In some embodiments, the porous filler has isolated, nucleated and/or vicinal silanol groups. Even if the porous filler contains silanol groups, another viscosity agent may or may not be added to the composition.

The composition may or may not contain other components suitable for use in the nasal pharmaceutical composition. For example, in some embodiments, the composition may independently contain one or more substances, including: a solubilizing agent; co-solvent; charge modifying agent; pH controlling agent; an osmotic pressure regulating agent; destructive enzyme inhibitor; antioxidant; stabilizer; a membrane penetration enhancing agent; emulsifying agent; wetting agent; suspending agent; surface-active substance; adhesive agent; and/or a taste masking agent. In some embodiments, the composition does not independently contain one or more of the following, including (i.e., one or more of the following is not present in the composition): a solubilizing agent; co-solvent, charge modifying agent; pH controlling agent; an osmotic pressure regulating agent; destructive enzyme inhibitor; antioxidant; stabilizer; a membrane penetration enhancing agent; emulsifying agent; wetting agent; suspending agent; surface-active substance; adhesive agent; and a taste masking agent. These components, if present, may be present in an amount effective to exhibit their intended functions and/or impart the desired properties of the composition. In some embodiments, the porous filler is the only filler in the composition.

The surfactant, if present, may be any surfactant suitable for use as a surfactant in a nasal pharmaceutical composition. In some embodiments, the surfactant is selected from anionic, cationic, amphoteric, and nonionic surfactants, including, but not limited to, lecithin, fatty acid esters of polyvalent alcohols, fatty acid esters of sorbitans, fatty acid esters polyoxyethylene sorbitans, polyoxyethylene fatty acid esters, sucrose fatty acid esters, polyglycerol fatty acid esters, oleoyl polyoxyglycerides (such as, but not limited to, PEG-6 esters and apricot kernel oils), oleoyl macroglycerides, and/or humectants such as sorbitol , glycerin, polyethylene glycol, a fatty acid ester of macrogol and glycerol, and combinations of any two or more of these. In some embodiments, the surfactant comprises an oleoyl macroglyceride (such as LABRAFIL® M 1944 CS (Gattefosse, Saint-Priest, France)) or a mixture of oleoyl macroglycerides.

The surfactant, if present, may be present in an amount effective to impart surfactant properties. In some embodiments, the composition contains about 1 to about 20% by weight, about 1 to about 10% by weight, about 1 to about 5% by weight, about 4% by weight, or about 2% by weight of surfactant. substances based on the total weight of the composition. In some embodiments, the composition contains 1 to 20% by weight, 1 to 10% by weight, 1 to 5% by weight, 4% by weight, or 2% by weight of a surfactant, based on the total weight of the composition.

In some illustrative embodiments, the composition contains (a) from about 0.5 to about 50% wt./wt. filler based on mesoporous silica based on the weight of the composition; (b) from about 0.5 to about 40% wt./wt. active substance based on the weight of the composition, and the active substance is loaded onto the surface of the mesoporous silica located inside the pores of the mesoporous silica; (c) from about 50 to about 90% wt./wt. castor oil per

- 16 043077 the mass of the composition; and (d) from about 0.5 to about 20% wt./wt. colloidal silicon dioxide based on the weight of the composition.

In some illustrative embodiments, the composition contains (a) from about 0.5 to about 50% wt./wt. filler based on mesoporous silica based on the weight of the composition; (b) from about 0.5 to about 40% wt./wt. active substance based on the weight of the composition, and the active substance is loaded onto the surface of the mesoporous silica located inside the pores of the mesoporous silica; (c) from about 50 to about 90% wt./wt. castor oil based on the weight of the composition; and (d) from about 2 to about 6% wt./wt. oleoyl macroglycerides based on the weight of the composition.

In some illustrative embodiments, the composition contains (a) from about 6 to about 11% wt./wt. filler based on mesoporous silica based on the weight of the composition; (b) from about 0.1 to about 30% wt./wt. active substance based on the weight of the composition, and the active substance is loaded onto the surface of the mesoporous silica located inside the pores of the mesoporous silica; and (c) from about 70 to about 80% wt./wt. castor oil based on the weight of the composition. In some illustrative embodiments, the composition contains from about 0.5 to about 20% of the agent that regulates the viscosity, based on the weight of the composition.

In some illustrative embodiments, the composition contains (a) about 8% wt./wt. filler based on mesoporous silica based on the weight of the composition; (b) about 2% wt./wt. active substance of the agent based on the weight of the composition, characterized in that the active substance is loaded onto the surface of mesoporous silica located inside the pores of mesoporous silica; (c) about 80% wt./wt. castor oil based on the weight of the composition; and (d) about 10% wt./wt. colloidal silicon dioxide based on the weight of the composition.

In some illustrative embodiments, the composition contains (a) a nasal gel containing from about 1 to about 50% wt./wt. mesoporous silica, unloaded and/or loaded with the active substance, based on the weight of the composition; and (b) additional fillers up to 100% wt./wt. based on the weight of the composition.

Manufacturing methods.

This document also provides methods for the manufacture of nasal pharmaceutical compositions containing a porous excipient and an active substance, in which the active substance is loaded onto the surface of the porous excipient located inside the pores of the porous excipient.

In some embodiments, the active ingredient is loaded onto the porous media by one or more methods selected from fluid bed impregnation, flash evaporation and sublimation, spray drying, vacuum drying, hot melt extrusion, spray crystallization, co-grinding, wet impregnation/solvent precipitation , electrospray technologies, hybridization technology, emulsion polymerization, sol-gel encapsulation, chemical bonding, coacervation and sol-gel methods.

In some embodiments, the active ingredient is loaded onto the porous vehicle via oil adsorption. In particular embodiments, the porous excipient is mixed with an active agent dissolved in an oil, for example, any one or more of vegetable oil, animal oil, and mineral oil. Illustrative oils include vegetable oil, castor oil, hydrogenated castor oil, soybean oil, sesame oil, peanut oil, linalool, TRANSCUTOL® HP (purified EP/NF diethylene glycol monoethyl ether from Gattefosse), CAPRYOL™ PGMC (propylene glycol monocaprylate (type I ) NF from Gattefosse) and combinations of any two or more of them. In some embodiments, the oil (with the dissolved active ingredient) and the porous excipient are mixed at a volume ratio of less than about 3:1 oil:excipient, e.g., about 2.5:1 oil:excipient, about 2:1 oil:excipient, about 1 ,5:1 oil:filler or about 1:1 oil:filler. In some embodiments, the oil (with dissolved active ingredient) and the porous excipient are mixed at a volume ratio of less than 3:1 oil:excipient, e.g., 2.5:1 oil:excipient, 2:1 oil:excipient, 1.5:1 oil:filler or 1:1 oil:filler. In some embodiments, the oil and porous filler are mixed at a ratio of about 10:1 oil:filler, such as about 8:1 or about 5:1 oil:filler. In some embodiments, the oil and porous filler are mixed at a ratio of 10:1 oil:filler, such as 8:1 or 5:1 oil:filler.

In some embodiments, the active ingredient is loaded onto the porous vehicle with a solvent, such as one or more of methylene chloride, dichloromethane, acetone, water, and ethanol. In specific embodiments, the porous excipient is mixed with the active ingredient dissolved in a solvent such as ethanol:water. In some embodiments, the active ingredient is dissolved in an ethanol:water mixture containing about 30:70 v/v, about 40:60 v/v, about 45:55 v/v, about 50:50 v/v. /rev., approx. 55:45 rev./rev., approx. 60:40

- 17 043077 rev/rev or about 70:30 v/v ethanol:water mixtures. Without being limited by theory, it is believed that the ratios of ethanol:water can be further changed based on the active substance used and its solubility in ethanol.

In some embodiments, a release modifying agent is used to facilitate loading of the active agent onto the porous vehicle. In some embodiments, a release-modifying agent or a solution containing a release-modifying agent is added to the active ingredient mixture (eg, an oil or solvent containing the active ingredient), and then the active ingredient is loaded onto the porous carrier. The release-modifying agent, when used, can be any release-modifying agent suitable for use in loading the active agent onto the porous carrier. In some embodiments, the release-modifying agent comprises polyvinylpyrrolidone (such as, but not limited to, PVP K25® from Ashland, Inc., which has a molecular weight of about 24,000 Da), cellulose ethers, hyaluronic acid, polyvinyl acetate (PVAc) , polyvinyl alcohol (PVA), sodium starch glycolate, polylactide, polysaccharides, solubilizers (such as, but not limited to, polyethylene glycol (PEG) or tween), or combinations of two or more of these.

In some embodiments, the solution containing the release-modifying agent contains the release-modifying agent mixed in an oil (such as, but not limited to, one or more of vegetable oil, castor oil, hydrogenated castor oil, soybean oil, sesame oil, peanut butter, linalool, TRANSCUTOL® HP (purified diethylene glycol monoethyl ether EP/NF from Gattefosse), CAPRYOL™ PGMC (propylene glycol monocaprylate (type I) NF from Gattefosse)) or solvent (such as, but not limited to, one or more substances, including methylene chloride, dichloromethane, acetone, water and ethanol). In some embodiments, the solution contains about 0.01%, about 0.05%, about 0.1%, about 0.5%, about 1%, about 2%, about 2.5%, about 3%, about 5 %, about 10%, about 20% or about 30% w/w, release modifying agent, e.g. 0.01, 0.05, 0.1, 0.5, 1, 2, 2.5, 3, 5, 10, 20 or 30% w/w release modifying agent. In some embodiments, the release-modifying agent solution is added to the active ingredient mixture in an amount of about 0.01%, about 0.05%, about 0.1%, about 0.5%, about 1%, about 2%. , about 2.5%, about 3%, about 5% or about 10%, for example 0.01, 0.05, 0.1, 5, 1, 2, 2.5, 3, 5 or 10%.

In some embodiments, the active ingredient is loaded onto a porous excipient with high loading efficiency. In some embodiments, at least about 60% of the active agent used in the method is loaded onto the porous media. In some embodiments, the active agent is loaded onto the porous vehicle with a loading efficiency of at least about 60%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least at least about 90%, at least about 95%, or about 100%, including about 60%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% . In some embodiments, the active ingredient is loaded onto a porous carrier with a loading efficiency of at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100%, including 60%, 70%, 75%, 80%, 85%, 90%, 95% or 100%. In some embodiments, the active agent is loaded onto the porous carrier with an efficiency of at least about 95% or at least 95%.

In some embodiments, the active ingredient is loaded onto the surface of the porous filler located within the pores of the porous filler. In some embodiments, the active substance is loaded onto the surface of the porous filler located inside the pores of the porous filler, but not loaded onto the outer surface of the porous filler.

Some embodiments include full or partial exchange of a gelling agent (eg, but not limited to colloidal silica) for a porous filler adsorbate (such as, but not limited to, porous silica adsorbate). In some embodiments, the active ingredient is loaded onto the porous excipient by interacting with active ingredients otherwise loaded onto the excipient, such as via capillary forces and/or van der Waals interactions (e.g., via interactions with active ingredient molecules already loaded on a porous filler). In some embodiments, the active substance is loaded onto the porous filler by interaction with silanol groups on the surface of the porous filler. Without being limited by theory, it is believed that in some embodiments (e.g., embodiments with a polar active agent), the active agent that interacts with silanol groups will be displaced and released from the porous filler as a result of contact with highly polar substances, such as biological fluids.

In some embodiments, the active ingredient is adsorbed onto a porous carrier. In some embodiments, the active substance is covalently linked to the porous excipient via functional groups on the porous excipient. Without being limited by theory, it is believed that a covalently bound active substance can be released in response to a stimulus such as a change in pH, temperature, the presence of enzymes, etc.

In some embodiments, the porous filler is synthesized from a precursor such as tetraethylorthosilicate or (3-mercaptopropyl)trimethoxysilane.

In some embodiments, compositions may be prepared without developing a thermodynamically critical slurry.

In some embodiments, the compositions are prepared using sterile materials. In some embodiments, the compositions are prepared under sterile conditions.

In some embodiments, the active ingredient and the porous excipient are independently dissolved in an oil and/or solvent (such as ethanol, water, methylene chloride, dichloromethane, acetone, or combinations of two or more) and mixed together. In some embodiments, the active agent and porous excipient are mixed in stages, such as by pumping the active agent into the agitated porous excipient. In some embodiments, the resulting mixture is dried under vacuum (for example, but not limited to, at a temperature of from about 50 to about 80°C). In other embodiments, the resulting solution is spray dried to form a porous filler loaded with the active ingredient. In some embodiments, the mixture is homogenized prior to spray drying. In some embodiments, the spray-dried particles are spray-dried a second time after mixing them with the second solution of the dissolved active ingredient.

In some embodiments, the active ingredient is dissolved in a solvent and then the porous excipient is mixed with the solvent. In some embodiments, the active agent and porous excipient are mixed in stages, such as by pumping the active agent into the agitated porous excipient. In some embodiments, the resulting mixture is dried under vacuum (for example, but not limited to, at a temperature of from about 50 to about 80°C). In other embodiments, the resulting mixture is spray dried. In some embodiments, the resulting mixture is spray dried after the active agent has been fully incorporated into the porous vehicle (eg, after the maximum amount of active agent has been loaded onto the porous vehicle).

In some embodiments, the loaded porous filler is mixed with additional components such as a carrier, a surfactant (such as, but not limited to, an emulsifying agent), an unloaded active, and a viscosity reducing agent prior to spray drying. For example, in some embodiments, the loaded porous filler is mixed with an emulsifying agent. The emulsifying agent, if present, may be any emulsifying agent suitable for use as an emulsifying agent in a nasal pharmaceutical composition. In some embodiments, the emulsifying agent comprises sodium oleate, TWEEN® 20, Natriumoleat, LUTROL® F68, or combinations of any two or more of these. The emulsifying agent, if present, may be present in an amount effective to emulsify the components of the composition. In some embodiments, the compositions contain from about 0.01 to about 2% w/w, from about 0.02 to about 1% w/w, from about 0.03 to about 0.04% w/w. wt., or about 0.08% wt./wt., emulsifying agent based on the total weight of the mixture. In some embodiments, the compositions contain from 0.01 to 2% w/w, from 0.02 to 1% w/w, from 0.03 to 0.04% w/w. or 0.08% wt./wt. emulsifying agent based on the total weight of the mixture.

In some embodiments, the methods result in a yield greater than 25%, e.g., about 25% to about 100%, about 50% to about 99%, about 60% to about 98%, about 70% to about 95%, about 50% , about 60%, about 70%, about 80%, about 90%, about 95%, about 98% or about 99%. In some embodiments, the methods result in a yield of 25 to 100%, 50 to 99%, 60 to 98%, 70 to 95, 50, 60, 70, 80, 90, 95, 98, or 99%.

In some embodiments, the coating is added to the loaded porous filler. In some embodiments, the material used to form the coating is dissolved in a solvent, and then the loaded porous filler is added to the solution. In some embodiments, the active ingredient and the coating material are independently dissolved in an oil and/or solvent (such as ethanol, water, methylene chloride, dichloromethane, acetone, or combinations of two or more of them), mixed together, and then the loaded porous filler is added to the resulting solution. The solution, both loaded with porous filler and coating material, can then be spray dried. In some embodiments, the coating material and the loaded porous filler are spray dried together without mixing them together first.

In some embodiments, the porous filler loaded with the active agent is coated as described above by spray drying or by co-treatment with a coating agent (e.g., polymers insoluble in oil or other substances described above) . In some embodiments, the loaded porous filler and coating agent are spray dried in a single phase system. In some embodiments, the loaded porous filler and coating material is spray dried in an emulsion. In some embodiments, the coated porous excipient loaded with the active agent is mixed with additional components such as a carrier, a surfactant, an unloaded active agent, and a viscosity increasing agent.

As discussed above, in some embodiments, loaded pores are coated, for example, in order to inhibit or control the release of the active substance from the pores. The pores can be coated by any suitable method, for example by covalently bonding nanocrystals (such as, but not limited to, cadmium sulfide nanocrystals) to the pore openings. Exemplary pore coating techniques are discussed in Lai et al, J. Am. soc. Chem. 125(15): 44514459 (2003), and Sun, Mesoporous silica nanoparticles for applications in drug delivery and catalysis, Graduate Theses and Dissertations, Paper 12812 (2012), both of which are incorporated herein by reference.

Application methods.

This document also provides methods for intranasal delivery of an active substance to a subject in need thereof. In some embodiments, the composition described herein, containing a therapeutically effective amount of the active substance, is administered nasally to a subject in need thereof, for example, by applying a certain amount of the composition to the nasal cavity or introducing a certain amount of the composition into the nasal cavity. The composition may be administered from any device suitable for administering nasal compositions, such as a multi-dose device or a single-dose device.

In some embodiments, the compositions achieve therapeutic levels of the active substance in the blood and/or brain within up to 2 hours after administration, up to 3 hours after administration, up to 4 hours after administration, up to 5 hours after administration, or up to 6 hours after administration. In some embodiments, the compositions reach therapeutic levels in the blood and/or brain within 6 hours or more.

The disease states that can be treated with the compositions described herein depend on the active substance(s) contained in the composition. Intranasal delivery may be particularly useful in the treatment of central nervous system disorders (such as, but not limited to, spina bifida), brain disorders, and/or spinal cord disorders. In some embodiments, the compositions described herein are useful in methods of treating neurological or psychiatric disorders. In some embodiments, the compositions described herein are useful in methods of treating: diseases caused by defective genes such as Huntington's disease or muscular dystrophy; degenerative diseases such as Parkinson's disease or Alzheimer's disease; diseases associated with blood vessels such as stroke; spinal cord and/or brain injury; convulsive disorders such as epilepsy; cancer such as brain tumors; and infections such as meningitis.

In specific embodiments, the compositions described herein containing testosterone are useful in methods of treating hypogonadism (such as primary hypogonadism or secondary hypogonadism), female sexual dysfunction, arousal disorder, anorgasmia, or a disorder associated with decreased sexual desire in women, multiple sclerosis (MS). In specific embodiments, the compositions described herein containing progesterone are useful in methods for treating insomnia and brain damage. In specific embodiments, the compositions described herein containing aripiprazole, quetiapine, or paliperidone are useful in methods of treating schizophrenia. In specific embodiments, the compositions described herein containing duloxetine or dopamine are useful in methods of treating depression and/or anxiety. In specific embodiments, the compositions described herein containing testosterone, glatiramer acetate, interferon beta-1a, interferon beta-1b, fingolimod, natalizumab, or dimethyl fumarate are useful in methods of treating multiple sclerosis. In specific embodiments, the compositions described herein containing pregnenolone, memantine, rivastigmine, or donepezil are useful in methods for improving memory or treating Alzheimer's disease. In specific embodiments, the compositions described herein containing desvenlafaxine, duloxetine, or dopamine are useful in methods of treating depression. In specific embodiments, the compositions described herein containing eszopiclone are useful in methods for treating insomnia. In specific embodiments, the compositions described herein containing atomoxetine, guanfacine, methylphenidate, lisdexamfetamine, or dopamine are useful in methods for treating attention deficit hyperactivity disorder. In specific embodiments, the compositions described herein containing progesterone or recombinant tissue plasminogen activator (rt-PA) are useful in methods of treating traumatic brain injury. In specific embodiments, the compositions described in this document

- 20 043077 documents containing methotrexate, raltitrexide, 5-fluorouracil, telomerase inhibitor or monoclonal antibodies are useful in methods of treating a brain tumor. In specific embodiments, the compositions described herein containing midazolam, lacosamide, levetiracetam, lamotrigine, or valproic acid are useful in methods of treating epilepsy. In specific embodiments, the compositions described herein, including oxycodone, pregabalin, buprenorphine, hydrocodone, or fentanyl, are useful in methods of treating pain. In specific embodiments, the compositions described herein containing safinamide, ropinirole, pramipexole, dopamine, levodopa, selegiline, cabergoline, or istradifillin are useful in methods of treating Parkinson's disease.

In some embodiments, the compositions described herein can be used to vaccinate a subject. For example, the compositions described herein can be used to vaccinate a subject against influenza, hepatitis B, or meningitis.

The following examples are included as illustrative compositions described in this document. These examples are in no way intended to limit the scope of the present invention. Other aspects of the present invention will be apparent to those skilled in the art to which the invention pertains.

Examples

Example 1 Testosterone Loaded Beads: Loading by Spray Drying.

Spray-dried testosterone-loaded beads were prepared using the following protocol.

The first stage of spray drying.

ml of ethanol (abs.) was added to 1.0 g of SYLOID® 244FP mesoporous particles and the resulting dispersion was homogenized with a magnetic stirrer operating at 500 rpm. Separately, 10 ml of ethanol (abs.) was added to 0.428 g of testosterone, and the testosterone was dissolved in a vibrating shaker operating at 900 rpm. After the testosterone was dissolved, the testosterone solution was added to the particle dispersion and the mixture was stirred for 20 hours at 500 rpm.

The mixture was then spray dried using a Mini Spray Dryer B-290 (Buchi) with a 0.7 mm nozzle tip operating in closed loop mode with nitrogen as dispersion gas (inert loop B-295). The device was started in suction mode. During spray drying, the dispersion was agitated at 500 rpm. Spray drying parameters are given in table. 1A.

Table 1A

Spray drying parameters for the first spray drying step in the testosterone loading experiment.

Parameter Setting Flow rate Inlet temperature Tin (°C) 81 - Download speed (%) 10 ~ 3.3 ml/min Aspirator flow (%) 100 35 ^m3 /h Spray gas flow (rotameter) (mm) 45 536 l/h Nozzle cleaner 1 -

The spray-dried particles were collected in a high efficiency cyclone and then dried in a vacuum drying oven at 40° C. and 10 mbar for six days.

Second stage spray drying.

0.250 g of testosterone was dissolved in 4 ml of ethanol using a vibrating shaker at 900 rpm. 1,000 g of F15 gelatin was dissolved in 55 ml of water using a thermal shaker operating at 200 rpm and 37° C. for two hours. The testosterone solution was added to the gelatin solution solution, and the mixture was stirred at 500 rpm. Then, 0.500 g of pre-spray dried particles (i.e. testosterone/244FP particles) was added to the solution and dispersed at 500 rpm. In some cases, the dispersion was further homogenized using ultrasound.

The dispersion was spray dried using a Mini Spray Dryer B-290 (Buchi) with a standard 0.7 mm diameter dual flow nozzle operating in closed loop mode with nitrogen as dispersion gas (B-295 inert loop). The device was started in suction mode. During spray drying, the dispersion was agitated at 500 rpm. Spray drying parameters are given in table. 1B.

Table 1B

Spray Drying Parameters for the Second Spray Drying Stage in Testosterone Loading Experiment

Parameter Setting Flow rate Inlet temperature Tin (°C) 135 - Download speed (%) 10 ~ 3.3 ml/min Aspirator flow rate (%) 100 35 ^m3 /h Spray gas flow (rotameter) (mm) 45 536 l/h Nozzle cleaner 1 -

The final testosterone loaded particles were dried in a vacuum oven at

- 21 043077

40°C and 10 mbar. The particles have a theoretical loading of 22.9% testosterone.

Example 2 Testosterone Loaded Particles: Free flowing powder.

A free flowing testosterone-loaded powder was prepared using the following protocol.

0.2143 g of testosterone was added to 1.5 g of linalool oil and then mixed using a vortex mixer for 10 minutes. Then, 0.5 g of SYLOID® particles (both 244FP and XDP3050 were used in independent experiments) was added to 0.75 g of the dissolved testosterone mixture, which was then stirred with a magnetic stirrer at 700 rpm for 10-15 minutes. The SYLOID®/testosterone mixture was then mixed with a spatula to re-introduce portions of the mixture adhering to the wall of the mixing container and then mixed again with a magnetic stirrer for 10-15 minutes. The particles have a theoretical loading of about 7.5% testosterone.

Example 3 Particles loaded with testosterone: free-flowing powder, loaded by oil adsorption method.

Samples loaded with testosterone were obtained using the following protocol.

0.2143 g of testosterone was added to 1.5 g of linalool oil and then mixed using a vortex mixer for 10 minutes. Then 0.5 g of SYLOID® particles (both 244FP and 72FP were used in independent experiments) was added to 1.5 g of the dissolved testosterone mixture, which was then stirred with a magnetic stirrer at 700 rpm for 10-15 minutes. The SYLOID®/testosterone mixture was then mixed with a spatula to re-introduce portions of the mixture adhering to the wall of the mixing container and then mixed again with a magnetic stirrer for 10-15 minutes. The particles have a theoretical loading of about 9.4% testosterone.

Example 4 Progesterone Loaded Beads: Loading by Spray Drying.

Spray-dried beads loaded with progesterone were prepared using the following protocol.

ml of ethanol (abs.) was added to 1.0 g of SYLOID® 244FP mesoporous particles and the resulting dispersion was homogenized with a magnetic stirrer operating at 500 rpm. Separately, 40 ml of ethanol (abs.) was added to 0.666 g of progesterone, and the progesterone was dissolved in a vibrating shaker operating at 900 rpm. After the progesterone was dissolved, the progesterone solution was added to the particle dispersion and the mixture was stirred for 20 hours at 500 rpm.

The mixture was spray dried using a Mini Spray Dryer B-290 (Buchi) with a standard 0.7 mm nozzle tip dual flow nozzle operating in closed loop mode with nitrogen as dispersion gas (B-295 inert loop). The device was started in suction mode. During spray drying, the dispersion was agitated at 500 rpm. Spray drying parameters are given in table. 2.

table 2

Spray Drying Parameters for Progesterone Loading Experiment

Parameter Setting Flow rate Inlet temperature Tin (°C) 81 - Download speed (%) 10 ~ 3.3 ml/min Aspirator flow rate (%) 100 35 ^m3 /h Spray gas flow (rotameter) (mm) 45 536 l/h Nozzle cleaner 1 -

The spray-dried particles were collected in a high efficiency cyclone and then dried in a vacuum drying oven at 40° C. and 10 mbar for six days. The particles have a theoretical loading of about 40% progesterone.

Example 5 Progesterone loading.

Spray-dried progesterone particles were prepared using the protocol set forth in Example 4, but with varying amounts of components in order to obtain particles with theoretical loadings of 30%, 40%, 50% and 60% progesterone. The yield was determined based on the weight of the composition after spray drying in the vial compared to the combined weight of the particles of progesterone and SYLOID® before spray drying. The residual moisture was calculated as the change in mass after vacuum drying of the spray dried particles.

Compositions based on progesterone was obtained using SYLOID® 72FP, as presented in table. 3A.

- 22 043077

Table FOR

Spray-dried compositions with progesterone + SYLOID® 72FP

The consignment The amount of progesterone Theoretical Progesterone Load (%) Exit (%) Residual moisture (%) MetP 111 0.428 g thirty 76.8 4.0 MetP 112 0.666 g 40 73.6 3.1 MetP_113 1 g 50 75.6 2.6 MetP_114 1.5 g 60 74.4 1.8

Scanning electron microscope photographs of the progesterone + SYLOID® 72FP formulations shown in FIG. 1. In the subfigures on the left side of FIG. 1, the bar represents a distance of 10 µm, and in the subfigures on the right side of FIG. 1 bar represents a distance of 1 µm.

Spray dried particles were also prepared using a similar protocol but with SYLOID® 244FP instead of SYLOID® 72FP. These compositions are set out in table. 3B.

Table 3B

Spray-dried compositions with progesterone + SYLOID® 244FP

The consignment The amount of progesterone Theoretical Progesterone Load (%) Exit (%) Residual moisture (%) MetP_106 0.428 g thirty 58.5 3.1 MetP 107 0.666 g 40 67.9 2.6 MetP 108 1 g 50 68.0 2.4 MetP_109 1.5 g 60 72.1 1.8

Scanning electron microscope photographs of the progesterone + SYLOID® 244FP formulations as shown in FIG. 2. Scanning electron microscope photographs were taken at two separate focal lengths; in the subfigures on the left side of FIG. 2, the bar represents a distance of 10 µm, and in the subfigures on the right side of FIG. 2 band represents a distance of 1 μm.

As a reference, formulations with SYLOID® 72FP or SYLOID® 244FP but without progesterone were prepared by spray drying. These compositions are shown in Fig. 3C.

Table 3C

Spray dried reference formulations with SYLOID® 72FP or SYLOID® 244FP

The consignment Material Material quantity Volume Tin (°C) Exit (%) MetP_46 SYLOID® 244FP 0.5 g 50 ml 110 60.1 MetP_110 SYLOID® 72FP 1 g 100 ml 81 91.2

To study the morphology and particle size, scanning electron microscope photographs were taken of the reference compositions shown in FIG. 3. Scanning electron microscope photographs were taken at two separate focal lengths; in the subfigures on the left side of FIG. 3, the bar represents a distance of 10 µm, and in the subfigures on the right side of FIG. 3 band represents a distance of 1 μm.

As a separate standard, progesterone dissolved in ethanol, i.e. not loaded onto SYLOID® particles was prepared by dissolving 0.214 g of progesterone in 50 ml of ethanol. The progesterone control formulation was spray dried using a Mini Spray Dryer B-290 (Buchi) with a dual flow nozzle in a closed loop system. The settings were constant with aspirator flow rate of 100%, atomizing gas flow at 45 mm, pump speed of 10%, nozzle cleaner at 1 and Tin of 81°C. The yield was determined to be 17.3% by comparing the weight of the empty glass vial with the glass vial containing the spray dried particles. Scanning electron microscope photographs of the progesterone reference were taken to study the morphology and size of the particles, as shown in FIG. 4. Scanning electron microscope photographs were taken at two separate focal lengths; in the subfigure on the left side of FIG. 4, the bar is a distance of 10 µm, and in the subfigure on the right side of FIG. 4 band represents a distance of 1 μm.

Example 6. Determination of the actual content of progesterone.

The actual progesterone content of the spray-dried progesterone + SYLOID® particles in Example 5 was determined by monitoring the progesterone release for about 7 days (assuming 100% of the encapsulated progesterone was released). 3x10 mg of each batch of progesterone-loaded particles were weighed into small glass vials and 20 ml of ethanol water (45/55 (v/v)) was added to the vials. The dispersions were stirred at 400 rpm and room temperature for about 7 days. The samples were then centrifuged at 15,000 rpm for 10 minutes and diluted. The mass concentration of the samples was determined using ultraviolet spectroscopy at 23 043077 at 247 nm.

The actual progesterone content and loading efficiency were calculated and presented in Table 1. 4.

Table 4

Comparison of Theoretical and Actual Progesterone Loading in SYLOID® Particles

The consignment SYLOID® Theoretical Progesterone Load (%) Actual Progesterone Load (%) Loading Efficiency (%) MetP 106 244FP 30.0 24.8±0.3 82.9 MetP_107 244FP 40.0 37.1±0.5 92.8 MetP 108 244FP 50.0 47.4 ± 1.2 95.0 MetP_109 244FP 60.0 58.0±0.6 96.7 MetP_111 72FP 30.0 21.4±0.8 71.6 MetP_112 72FP 40.0 31.1±0.4 77.8 MetP 113 72FP 50.0 42.1±0.6 84.4 MetP_114 72FP 60.0 57.5 ± 1.0 95.8

Example 7 Thermal behavior of encapsulated progesterone.

The thermal behavior of the spray-dried progesterone + SYLOID® particles in Example 5 was evaluated by differential scanning calorimetry. All samples were measured twice from 50° C. to 180° C. with a heating and cooling rate of 10 K/min on a DSC 200 F3 MAIA® (Netzch). Progesterone dissolved in ethanol was spray dried under the same conditions as progesterone + SYLOID® particles and used as a reference. Non-spray dried progesterone and spray-dried SYLOID® 72FP particles or SYLOID® 244FP particles without progesterone were also used as reference. The DSC curves for the references are shown in FIG. 5. For standards of progesterone, the melting temperatures (maximum temperature), glass transition temperature (beginning) and recrystallization (maximum temperature) of two heating cycles were determined and they were given in table. 5.

Table 5

Thermal behavior of progesterone based on DSC curves obtained with reference samples

Progesterone 1. Melting point when heated (°C) 2. Glass transition temperature when heated (°C) 2. Recrystallization temperature (°C) 2. Melting point (°C) without spray drying 133.1 7.7 59.2 126.3 spray dried 126 6.9 35.4 125.1

The thermal behavior of spray-dried progesterone + SYLOID® 244FP particles is demonstrated using the DSC measurements depicted in FIG. 6. In FIG. 6 shows that in formulations based on SYLOID® 244FP with an actual loading of 37% progesterone, the melting peak begins to appear at a temperature slightly below 100°C (MetP_107). Without being limited by theory, it is believed that this peak is a polymorphic form (eg, V-form) of progesterone. In FIG. 6 also shows that with increasing progesterone, growth peaks were detected at 96.5°C (MetP_108) and 99.2°C (MetP_109).

The thermal behavior of spray-dried progesterone + SYLOID® 72FP particles is demonstrated using the DSC measurements depicted in FIG. 7. In FIG. 7 shows that in compositions based on SYLOID® 72FP with an actual loading of 42% (MetP_107), the shoulder appears at temperatures below 100°C. In FIG. 7 also shows a melting point of 125°C in the first heating cycle and a peak at about 100°C in the second cycle for compositions that have an actual progesterone loading of 57.5% (MetP_114). Without being limited by theory, it is believed that these two melting points are due to the presence of crystalline forms of progesterone II and V.

Example 8 Progesterone Loaded Ordered Mesoporous Silica.

Progesterone was impregnated onto a powder composed of ordered mesoporous silica (OMS-7) using either 200 mg/mL progesterone in methylene chloride or 100 mg/mL solutions of progesterone in acetone to give loadings of 30, 35, and 40% w/w. . progesterone. After impregnation, the loaded silica powders were dried under vacuum for at least 24 hours at 40° C. to remove excess solvent. The morphology of the samples was assessed using differential scanning calorimetry thermograms, which are depicted in FIG. 8. In FIG. 8 shows that the samples prepared using methylene chloride appeared to be amorphous while the samples prepared using acetone were in crystalline form.

- 24 043077

In a separate experiment, progesterone was loaded onto OMS-7 at target concentrations of 20 and 40% w/w. using methylene chloride and the samples were dried as described above. The actual progesterone content was determined to be 20.2±0.2% w/w. (n = 3) and 38.3±0.9% wt./wt. (n=3) respectively. The diffraction scanning calorimetry thermograms show that progesterone in all samples is in amorphous form, as depicted in FIG. 9.

Nitrogen physical adsorption experiments confirmed that progesterone is adsorbed in the pores of OMS-7. In particular, the data demonstrate a consistent decrease in pore volume and surface area after progesterone loading. These results are summarized in Table. 6 and visually depicted in Fig. 10 where OMS-7, batch 39 is OMS-7 without progesterone, Prog-OMS-7-20% is OMS-7 with about 20% progesterone and Prog-OMS-7-40% is OMS-7 containing about 40% progesterone. The pore size distribution was calculated from the branches of the desorption isotherm using the Barrett-Joyner-Halenda (BJH) model. The total surface area was calculated using the Brunauer-Emmett-Teller (BET) model. The total pore volume was obtained directly from the isotherm at p/p ₀ = 0.95. The data suggest a progressive decrease in pore diameter with loading, suggesting layered deposition of progesterone on the surface of OMS-7. Without being limited by theory, it is believed that progesterone interacts with both OMS-7 and other fragments of progesterone, for example, as a result of capillary forces or van der Waals interactions.

Table 6

Porosity data based on nitrogen physical adsorption experiments

Sample Total pore volume (cm ³ /g) Total surface area (m ² /g) Average pore diameter (nm) OMS-7 Batch 39 1.14 925 6.6 Prog-OMS-7-20% 0.80 509 6.2 Prog-OMS-7-40% 0.48 286 5.2

Example 9 Testosterone Loaded Ordered Mesoporous Silica.

Testosterone was impregnated on a powder composed of ordered mesoporous silica (OMS-7) using either 200 mg/mL testosterone in ethanol or 100 mg/mL solutions of progesterone in acetone to give loadings of 30%, 35%, and 40% w/w. . testosterone. After impregnation, the loaded silica powders were dried under vacuum for at least 24 hours at 40° C. to remove excess solvent. The morphology of the samples was assessed using differential scanning calorimetry thermograms, which are depicted in FIG. 11. In FIG. 11 shows that the samples prepared using methylene chloride appeared to be amorphous while the samples prepared using ethanol were in crystalline form.

In a separate experiment, testosterone was loaded onto OMS-7 at target concentrations of 20 and 40% w/w. using methylene chloride and the samples were dried as described above. The actual testosterone content was determined to be 20.1±0.4% w/w. (n=3) and 37.9±1.9% w/w. (n=3) respectively. The diffraction scanning calorimetry thermograms show that testosterone in all samples is in amorphous form, as depicted in FIG. 12.

Nitrogen physical adsorption experiments confirmed that testosterone is adsorbed into the pores of OMS-7. In particular, the data demonstrate a consistent decrease in pore volume and surface area after progesterone loading. These results are summarized in Table. 7 and visually depicted in Fig. 13 where OMS-7, batch 39 is OMS-7 without testosterone, Test-OMS-7-20% is OMS-7 with about 20% testosterone and Test-OMS-7-40% is OMS-7 containing about 40% testosterone. The pore size distribution was calculated from the branches of the desorption isotherm using the Barrett-Joyner-Halenda (BJH) model. The total surface area was calculated using the Brunauer-Emmett-Teller (BET) model. The total pore volume was obtained directly from the isotherm at p/p ₀ =0.95. The data show a progressive decrease in pore diameter with loading, indicative of layer-by-layer deposition of testosterone on the surface of OMS-7.

Table 7

Porosity data based on nitrogen physical adsorption experiments

Sample Total pore volume (cm ³ /g) Total surface area (m ² /g) Average pore diameter (nm) OMS-7 Batch 39 1.14 925 6.6 TecT-OMS-7-20% 0.82 518 6.2 TecT-OMS-7-40% 0.46 271 5.2

Example 10 Progesterone based gel compositions.

Progesterone-based gel formulations with encapsulated progesterone were prepared as

- 25 043077 is set out in table. 8. In the case of composition 1, additional colloidal anhydrous silica was added to increase the viscosity, resulting in a composition with a content of components that exceeded 100% (wt% in composition 1 in the amount of 102%).

Table 8

Gel compositions based on progesterone

Composition 1 Composition 2 Component Component content (%) Component content (%) Procedure Castor oil 70.3 76.8 Air bubbles and heating were avoided during manufacture. Oleoylpolyoxyglycerides 4.0 4.0 Added to castor oil and mixed for 1 min at 13,000 rpm micronized progesterone 6.4 4.6 Added and mixed for 2 min at 13,000 rpm Progesterone adsorbate 40% 17.3 8.6 Added and homogenized by hand; mixed for 2 min at 13,000 rpm colloidal anhydrous silica 2.0 6.0 Added and homogenized by hand; mixed for 10 min at 13,000 rpm

Example 11 Testosterone based gel compositions.

Gel compositions based on testosterone with encapsulated testosterone were obtained as described in table. 9.

Table 9

Gel compositions based on testosterone

Composition 1 Composition 2 Component Component content (%) Component content (%) Procedure Castor oil 76.08 83.56 Air bubbles and heating were avoided during manufacture. Testosterone adsorbate 20% 15.92 - Added to castor oil and mixed for 2 min at 13,000 rpm Testosterone adsorbate 40% - 8.44 Added to castor oil and mixed for 2 min at 13,000 rpm Oleoylpolyoxyglycerides 4.00 4.00 Added and mixed for 2 min at 13,000 rpm colloidal anhydrous silica 4.00 4.00 Added and homogenized by hand; mixed for 10 min at 13,000 rpm

Example 12 Spray Drying of Testosterone.

To study the extent to which the active substance testosterone was changed by the spray process, it was spray dried in pure ethanol. For this purpose, 0.214 g of testosterone was dissolved in 50 ml of ethanol. This concentration is that used to load 30% testosterone. The solutions were sprayed into a Mini Spray Dryer using a closed suction system. Settings were 10% pump power, 100% aspirator power, dispersive

- 26 043077 gas at 45 mm and nozzle cleaner were kept constant at 1. Variable parameters are presented in table. 10.

Table 10

Inlet temperature Tin in spray-drying experiments using testosterone batches and their yield

Testosterone T _in (°C) Exit (%) First delivery (MetP 99) 110 19.9 Second delivery (MetP 103) 81 10.9

The yield of pure testosterone from spray drying was relatively low, probably due to the large amounts of testosterone found in the cyclone, i. not precipitated into the product collection vessel. Scanning electron microscope photographs (SEM images) are shown in FIG. 14 which show that testosterone is present in particulate form after spray drying. In FIG. 1. delivery is the first batch of testosterone and 2. delivery is the second batch of testosterone.

Example 13 Loading testosterone into polymer matrices.

Compositions were prepared using testosterone encapsulated in the presence of the following polymers: polylactide, chitosan or gelatin.

Loading polylactide.

Polylactide polymers RESOMER® 202H and RESOMER® 202S (Evonik) were dissolved in dichloromethane and testosterone was added at a content of 10% or 30% based on the total weight of testosterone + RESOMER®. The solutions were sprayed into a Mini Spray Dryer using a dual flow nozzle in a closed suction system. During this stage, the aspirator power was kept constant at 100%, dispersion gas at 50 mm and nozzle cleaner at 1. The temperatures T-, n were obtained based on the available room temperature. The output obtained using these experiments is presented in table. eleven.

Table 11

Parameters of Spray Drying Experiments Using Polylactide and Obtained Yield

The consignment Material Amount of PLA (%) in dichloromethane solution Theoretical Load (testosterone) (%) Download speed (%) Tp (°C) Exit (%) MetP 05 202H 1 14 50 4.8 MetP_02 202H 1 - 14 60 4.7 MetP 06 202S 1 - 14 50 3.6 MetP_07 202S 1 - 14 60 4.0 MetP 27 202H 5 - 14 50 10.2 MetP 28 202H 5 10 14 50 4.2 MetP 45 202H 10 - 14 50 25.3 MetP_60 202H 10 - 24 50 53.1 MetP_61 202H 10 - 14 25 63.8 MetP 74 202H 10 10 14 29 60.4 MetP 75 202H 10 thirty 14 28 52.2 MetP_85* 202H 10 thirty 14 38 44.1

*MetP_85 was received in the same way as MetP_75 but in double the lot size.

Yield increased from 4.8% to 25.3% by increasing the amount of PLA added, and from 25.3% to 63.8% by further lowering the Tin inlet temperature. Without being limited by theory, it is believed that the increase in deposition of particles in the cyclone could be due to the low glass transition temperature of polylactides and initially high temperatures. A slight decrease in yield to 52.2% was due to the addition of testosterone to the polymer solution.

Particle morphology is depicted in the SEM images in FIG. 15A-C. In initial experiments, it was shown that non-aggregated, more homogeneous particles could be obtained using RESOMER® 202H (MetP_05/MetP_02), in contrast to RESOMER® 202S (MetP_06/MetP_07), possibly due to differences in glass transition temperatures (Tg) of the two amorphous polylactides . For further experiments RESOMER® 202H was used with a higher Tg value than RESOMER® 202S.

Increasing the amounts of PLA added by 5% (MetP_27) and 10% (MetP_45) resulted in an increase in particle size and size distribution. Increasing the pumping speed of the spray solution (MetP_60) and lowering the inlet temperature (MetP_61) did not significantly affect the morphology. The addition of testosterone (10%: MetP_74, 30%: MetP_75) also had no significant effect. Doubling the amount of composition obtained (MetP_85) seemed to result in an additional increase in particle size.

Loading chitosan.

A chitosan solution was prepared by dissolving 0.5 g of pharmaceutical grade 95/200 chitosan (deacetylation rate 95%, viscosity in 1% acetic acid: 151-350 mPa) in 50 ml of 2% acetic acid. In the case of control experiments, 50 ml of ethanol was added to the chitosan solution.

- 27 043077

In the case of compositions based on testosterone, 48 ml of ethanol was added to the chitosan solution; testosterone was dissolved in 2 ml of ethanol and then added to the chitosan/ethanol solution. The solutions were spray dried in a Mini Spray Dryer using a dual flow nozzle in a closed suction system and with an agitation speed of 200 rpm. Drying settings were as follows: inlet temperature 140° C., 10% pump power, 100% aspirator power, dispersion gas at 50 mm and nozzle cleaner were held constant at 1. The yield obtained from these experiments is shown in Table 1. 12.

Table 12

Parameters of Spray Drying Experiments Using Chitosan and the Yield Obtained

The consignment Theoretical Load (testosterone) (%) Exit [%] MetP 40 - 72.4 MetP_41 10 60.0 MetP_42 thirty 68.6

The yield of the obtained particles ranged from 60.0 to 72.4%. Particle morphology is depicted in the SEM images in FIG. 16 which show particles with a wide size distribution.

In separate experiments, chitosan was electrostatically crosslinked with tripolyphosphate (TPP) in order to increase the stability of the material and thus induce a delay effect (ie, a sustained release effect). To do this, a 2% TPP solution (2% acetic acid and ethanol in a ratio of 1:1, v/v) was added to the chitosan solution. However, the chitosan solution immediately agglomerated upon the addition of TPP, the solution could not be sprayed in one phase using a dual flow nozzle.

In order to eliminate this pre-crosslinking in the next step, an attempt was made to obtain crosslinking in situ, that is, crosslinking during the spraying process. For this purpose, a three-stream nozzle was used for spray drying to simultaneously spray chitosan and TPP solution in one stream. Various spray parameters were varied for this purpose, but they could not be set during the feasibility study in such a way that crosslinking could be carried out with a three-stream nozzle.

Microencapsulation of gelatin.

Three different fish gelatins were used to encapsulate testosterone, which differ in bloom: F15 (Bloom grade 150), F20 (Bloom grade 200) and F25 (Bloom grade 300).

To obtain unloaded gelatin particles, gelatin was dissolved in water and sprayed as (i) a single phase or (ii) an emulsion of water and dichloromethane. In the case of MetP_08-MetP_10 in Table. 13A 0.5 g of each gelatin was dissolved in 50 ml of water; in the case of MetP_11-MetP_13 in Table. 13A 0.5 g of each gelatin was dissolved in 47.5 ml of water. The mixtures were stirred in an incubation shaker at 37°C to achieve complete dissolution and then brought to room temperature. In the case of MetP_11-MetP_13, 0.175 g of TWEEN® 20 and 2.5 ml of dichloromethane were also added. Then the mixtures were homogenized using a rotor-stator unit for 10 minutes at 30,000 rpm, while cooling it with ice.

Thereafter, the gelatin solutions and emulsions were sprayed into a Mini Spray Dryer using a dual flow nozzle in a closed suction system. The settings were kept constant with aspirator power 100%, dispersion gas at 45 mm, nozzle cleaner at 1, pump power 10% and inlet temperature T _in 135°C. Variable parameters are shown in table. 13A.

Table 13A

Overview of gelatin particles spray dried in a single phase system versus spray dried in emulsion

The consignment Gelatin Experiment Exit [%] MetP_08 F15 single phase 73.2 MetP 09 F20 single phase 71.5 MetP_10 F25 single phase 79.1 MetP 11 F15 Emulsion 3.0 MetP_12 F20 Emulsion 4.3 MetP_13 F25 Emulsion 12.8

The output depended on the type of system to be sprayed; thus, the yield for gelatin particles sprayed in emulsion was lower than for gelatin particles sprayed as a single phase. Without being limited by theory, it is believed that reducing the emulsifier content can lead to an increase in yield.

Particle morphology is depicted in the SEM images in FIG. 17A-B. Particles sprayed as a single phase (clear gelatin/water solution) and particles sprayed as an emulsion showed different morphologies. In particular, agglomerates were obtained from the finer primary particles in the form of an emulsion during spray-drying processes, while individual particles with a relatively broad particle size distribution were obtained using single-phase spraying.

LUTROL® F68 emulsifiers and sodium oleate have been investigated as substitutes for TWEEN® 20 in

- 28 043077 compositions obtained with gelatin F25. Casein was also investigated as an emulsifier, however, it did not dissolve in either water or dichloromethane. The parameters of the Mini Spray Dryer remained unchanged from the last experiments, and the variable parameters are shown in Table 1. 13V.

Table 13B

Variable Emulsifier Emulsifier Variable Emulsifier Emulsion Spray Drying Experiment Parameters and Obtained Yield

The consignment Gelatin emulsifying agent Emulsifying agent (g) Exit (%) MetP_14 F15 TWEEN® 20 0.08 3.4 MetP_15 F15 TWEEN® 20 0.04 4.2 MetP 16 F20 TWEEN® 20 0.08 3.8 MetP 17 F20 TWEEN® 20 0.04 3.7 MetP_18 F25 TWEEN® 20 0.08 2.8 MetP_19 F25 TWEEN® 20 0.04 14.0 MetP 23 F25 Sodium oleate 0.04 46.9 MetP_24 F25 LUTROL® F68 0.04 3.2

Although a relatively high yield was obtained using sodium oleate as the emulsifier, the emulsifier thickened shortly after emulsification. After spraying, a gel-like residue also remained in the collection vessel. For the most part, reducing the amount of emulsifier or changing the emulsifier used did not significantly change the yield. Without being limited by theory, it is believed that the output in the table. 13 was increased by spray drying the compositions in one phase.

Likewise, decreasing TWEEN® 20 also had no effect on particle morphology. The particle morphology with sodium oleate and LUTROL® is shown in the SEM images in FIG. 18.

Single-phase spray drying of testosterone-based formulations.

To determine the optimal water/ethanol mixture for single phase spraying of both testosterone and gelatin, which have different solubility properties, the compositions were sprayed in various ethanol/water mixtures. Solutions of gelatin were sprayed into a mixture of ethanol/water with ratios of 40/60 v/v, 45/55 v/v. and 50/50 rev/rev. All batches of gelatin were stable in 40/60 and 45/55 mixtures. Gelatin F15 was also stable at 50/50 v/v, however gelatin F20 and F25 previously dissolved in water precipitated out of solution at 50/50 v/v.

In each of the experiments summarized in Table. 14, 0.5 g of gelatin was used. Different amounts of water were added to the gelatin for different mixing ratios (20 ml in the case of 40/60, 22.5 ml in the case of 45/55 and 25 ml in the case of 50/50). The dissolution of the gelatin occurred at 37° C. in an incubation shaker at 200 rpm for at least an hour. Then the solution was brought to room temperature by stirring with a magnetic stirrer at 500 rpm and each of the required amounts of ethanol was added to establish the appropriate mixing ratio. To load testosterone, a small amount of ethanol was added to the gelatin solution, and then the dissolved testosterone was added in order to obtain the appropriate mixing ratio.

The solutions were then sprayed into a Mini Spray Dryer using a dual flow nozzle in a closed suction system. The settings were kept constant with aspirator power 100%, dispersion gas at 45 mm, nozzle cleaner at 1, pump power 10% and inlet temperature T _in 135°C. Variable parameters are presented in table. 14.

Table 14

Parameters of Spray Drying Experiments Using Gelatin in Various Ethanol/Water Mixtures

The consignment Gelatin EUN/H2O [volume/volume] Theoretical Load (testosterone) (%) Exit [%] MetP 29 F15 40/60 - 34.1 MetP_30 F20 40/60 - 59.1 MetP 31 F25 40/60 - 62.5 MetP_32* F15 40/60 10 28.1 MetP 33 F20 40/60 10 32.8 MetP 26 F25 40/60 10 46.6 MetP 53 F15 45/55 - 55.5 MetP_54 F20 45/55 - 51.6 MetP_55 F25 45/55 - 55.4 MetP 56 F15 45/55 20 29.1 MetP 43 F20 45/55 20 23.0 MetP_44 F25 45/55 20 31.3 MetP_34 F15 50/50 - 61.2 MetP 37 F15 50/50 thirty 5.4

Note: The spray dryer was leaking, so the spraying process was stopped before completion.

The yield was significantly improved compared to spraying in the form of an emulsion. The yield for unloaded gelatin particles was higher than that for gelatin particles loaded with testosterone.

Possibly due to the higher ethanol content in compositions with an ethanol/water ratio

- 29 043077

45/55 rev/rev it was also possible to achieve a 20% higher theoretical testosterone load.

In a mixture of 40/60 v/v. ethanol/water was only possible with a 10% loading of testosterone, which was potentially due to its poor solubility. In the case of F15 gelatin (MetP_34 and MetP_37) it was possible to use a mixture of ethanol/water 50/50 v/v and thus achieve a theoretical loading of 30% (MetP_37).

In FIG. 19A-E are SEM images of gelatin particles that were sprayed into an ethanol/water mixture. In the case of particles prepared in a 40/60 v/v ethanol/water mixture, no distinct differences were observed in particle size distributions between different experimental approaches. Only the particles obtained from the unloaded approach using F15 (MetP_29) gelatin were slightly smaller. In SEM images of particles loaded with testosterone, obtained using a mixture of ethanol/water 45/55 v/v. (MetP_56, MetP_43 and MetP_44) detected bacteria, indicating the importance of using sterile gelatin under sterile conditions. Compositions made in ethanol/water 50/50 v/v do not show significant differences compared to particles made using different mixing ratios.

At all water/ethanol ratios, a broad particle size distribution was observed. The difference in surface morphology between unloaded and testosterone loaded gelatin particles was observed at all ethanol/water mixing ratios. In particular, the smaller particles of individual unloaded batches were characterized by the formation of dents, while this was not observed in the case of smaller particles loaded with testosterone.

Example 14 Loading Testosterone into Porous Silica Microparticles.

Various mesoporous silica particles (SYLOID® from Grace) were used to encapsulate testosterone. The properties of mesoporous silica particles are given in Table 1. 15. Particle morphology is depicted in the SEM images of FIG. 20A-B.

Table 15

SYLOID® particles, particle size, pore volume and specific surface area

Particles Average particle size (µm) Average pore volume (ml/g) Specific surface area (m ² /g) SYLOID® XDP6035 35.1 0.98 k.A. SYLOID® XDP3050 48-66 >1.70 ml/g 320 SYLOID® XDP3150 120-170 >1.70 ml/g 320 SYLOID® 244FP 3.4 1.6 300 AL-1FP/63FP 7.5 0.4 700 m2/g

The active ingredient testosterone came from two separate batches (called first delivery and second delivery). Loading experiments were performed with both deliveries. The SYLOID® particles were dispersed in ethanol at a level of 1% (ie 1 g per 100 ml). In the case of formulations with testosterone, testosterone (either 10% or 30% based on total weight, ie testosterone + SYLOID®) was dissolved in a portion of the ethanol and then added to the particle dispersion system. Particle mixtures were agitated with a magnetic stirrer at 500 rpm and then sprayed with a dual flow nozzle in a closed suction system using a B-290 Mini Spray Dryer (Buchi).

The Mini Spray Dryer parameters were held constant with inlet temperature 110° C., pump power 10%, aspirator power 100%, dispersion gas at 45 mm and nozzle cleaner at 1. The solution was agitated at 200 rpm during the spraying process. Variable parameters are shown in table. 16.

Table 16

Parameters of spray drying experiments with SYLOID® particles and their yield

The consignment SYLOID® Batch volume (ml) Incubation time (h) Theoretical Testosterone Load (%) Exit (%) MetP_46 244FP 50 1 60.1 MetP_47 244FP 50 1 10 62.8 MetP_48 244FP 50 1 thirty 62.0 MetP 49 XDP6035 50 1 - 54.8 MetP 50 XDP6035 50 1 10 94.7 MetP_51 XDP6035 50 1 thirty 63.0 MetP_57 244FP 100 1 thirty 56.1 MetP 62 XDP6035 100 1 thirty 66.0 MetP 62A XDP6035 100 1 thirty 66.2 MetP 79A* 244FP 50 1:45 10 41.4 MetP_79B 244FP 50 3:35 10 51.7 MetP_79C 244FP 50 24:20 10 59.5 MetP_86 244FP 100 -24 thirty 63.2

It was not possible to complete spray drying because the vial in the spray dryer was leaking.

- 30 043077

In the case of SYLOID® 244FP (MetP_46-MetP_48), the presence of testosterone did not significantly affect the yield. For the larger particles SYLOID® XDP6035 (MetP_49-MetP_51) the yield was variable but still satisfactory.

In the case of MetP_79A-MetP_79C, the incubation period of the SYLOID® particles with testosterone was changed prior to spray drying to allow additional time for adsorption of testosterone, if necessary. MetP_62 and MetP_62A were spray dried under similar conditions and showed a high level of reproducibility in the spray drying process. The yield was 66.0% and 66.2%, respectively.

Particle morphology is depicted in the SEM images in FIG. 21A-E. SEM images of SYLOID® XDP6035 particles nebulized in the presence of testosterone (MetP_50 and MetP_51) showed both large particles (characteristic of the particle lot) and smaller particles. Without being limited by theory, it is believed that smaller particles may be formed from fragments of Syloid® particles formed during the spraying process, or consisting of particles of testosterone. Due to the small particle size of SYLOID® 244FP (MetP_46-MetP_48) it was not possible to determine from the SEM images whether testosterone was present alone. However, in differential scanning calorimetry experiments, MetP_51 has been shown to contain crystalline testosterone.

Testosterone Loading - Second Delivery (i.e. Second Batch)

SYLOID® 244FP and Aerosil® 200 particles were used to encapsulate testosterone. Particles of SYLOID® or AEROSIL® were dispersed in ethanol at a level of 1% (ie 1 g per 100 ml). In testosterone formulations, testosterone (either 30% or 40% based on total weight, eg testosterone + SYLOID®) was dissolved in a portion of the ethanol and then added to the particle dispersion system. Particle mixtures were agitated with a magnetic stirrer at 500 rpm and then sprayed with a dual flow nozzle in a closed suction system using a B-290 Mini Spray Dryer (Buchi). The inlet temperature was changed and lowered to 81°C. In one experiment, a mixture of ethanol/water 50/50 v/v. used as a continuous phase instead of ethanol to enhance testosterone adsorption, if necessary. The Mini Spray Dryer parameters were kept constant with pump power 10%, aspirator power 100%, dispersion gas at 45 mm and nozzle cleaner at 1. The solution was agitated at 200 rpm during the spraying process. Variable parameters are shown in table. 17.

Table 17

Parameters of testosterone spray drying experiments (second delivery) and their yield

The consignment Particles Solvent Theoretical Testosterone Load (%) Tin (°C) Exit (%) MetP 92 244FP ethanol thirty 110 58.9 MetP 93 244FP ethanol thirty 81 67.4 MetP_94 244FP ethanol 40 81 67.3 MetP_95 244FP Ethanol/H2O 50/50 (v/v) thirty 110 71.8 MetP 102 AEROSIL® 200 ethanol thirty 81 45.2

The yield obtained using SYLOID® particles was 58.9% to 71.8% and the yield obtained using AEROSIL® 200 was 45.2%. The morphology of the loaded SYLOID® particles is depicted in the SEM images in FIG. 22. Particle morphology and particle size distribution of two different batches of particles do not show significant differences. In FIG. 23 shows SEM images of testosterone in spray-dried AEROSIL® 200 particles. Small primary particles of Aerosil® formed spherical agglomerates upon spray drying.

Loading SYLOID® particles with oil.

Mesoporous silica particles 244FP, XDP6035 and XDP3050 (SYLOID®, from Grace) were used to encapsulate testosterone. Various oils were used to load these particles, in which testosterone exhibited different solubility. The solubility of testosterone in castor oil, linalool, TRANSCUTOL® HP and CAPRYOL™ PGMC is shown in Table 1. 18.

Table 18

Solubility of testosterone in various oils

Oil Solubility in oil (%) Castor oil 4.0 Linalool 12.5 TRANSCUTOL® HP 6.5 CAPRYOL™ PGMC 6.0

The miscibility of castor oil with each of the other oils was investigated. In the initial experiments, mixtures of 50/50 were obtained; those. 1 g of castor oil was mixed with 1 g of each oil (linalool, CAPRYOL™, TRANSCUTOL®). All three oils were found to be miscible with castor oil. Spontaneous separation occurred with all three samples, with only one phase visible after about five minutes. Thus, the oils can also be used as mixtures.

The adsorption capacity of SYLOID® particles was studied by mixing SYLOID® 244FP, XDP3050 and XDP6035 with castor oil, linalol, TRANSCUTOL® MCAPRYOL™. The maximum soluble amount of testosterone (under test conditions) was dissolved in 2.5 g of each oil using a vortex mixer and shaker at 1000 rpm. The periods of complete dissolution of testosterone are shown in table. 19.

Table 19

Solubility time of testosterone in different oils

Oil Testosterone (g) Time (min) Castor oil 0.10 >300 Linalool 0.31 15-20 TRANSCUTOL® 0.16 ~5 CAPRYOL™ 0.15 ~60

A particle/oil ratio of 1:1.5 was used in the case of testosterone loading of the Syloid® PARTICLES with oil. 0.75 g of each oil loaded with testosterone and 0.5 g of each of the SYLOID® particles were mixed and stirred with a magnetic stirrer at 700 rpm for ten minutes. The mixture was also mixed by hand with a spatula and then mixed again for 10 minutes at 700 rpm. The properties of various compositions are set out in table. 20.

Table 20

Experimental batches of various particle/oil mixtures in a ratio of 1:1.5

The consignment Oil SYLOID® Texture after loading MetP 80 R Castor oil 244FP Powder MetP 80L Linalool 244FP Powder MetP 80T TRANSCUTOL® 244FP Powder MetP 80 C CAPRYOL™ 244FP Powder MetP 81R Castor oil XDP6035 sticky MetP 81L Linalool XDP6035 sticky MetP_81_T TRANSCUTOL® XDP6035 sticky MetP 81C CAPRYOL™ XDP6035 sticky MetP 82R Castor oil XDP3050 Powder MetP 82L Linalool XDP3050 Powder MetP 82T TRANSCUTOL® XDP3050 Powder MetP 82C CAPRYOL™ XDP3050 Powder

The SYLOID® XDP6035 particles did not completely adsorb the oil and formed a sticky mass, possibly due to their small pore volumes. SYLOID® 244FP and XDP3050 particles were powdery after testosterone loading. In FIG. 24 shows the textures of the compositions in table. 20.

To evaluate the effect of particle/oil ratio on loading rate, 1.5 g of each oil was mixed with SYLOID® particles at a particle/oil ratio of 1:3 and mixed with a magnetic stirrer at 700 rpm for ten minutes.

The mixture was mixed by hand with a spatula and then mixed for another ten minutes at 700 rpm. The properties of various compositions are set out in table. 21.

Table 21

Experimental batches of various particle/oil mixtures in a ratio of 1:3

The consignment Oil SYLOID® Texture after loading MetP 83R Castor oil 244FP sticky, glassy MetP_83_L Linalool 244FP Sticky, transparent MetP_83_T TRANSCUTOL® 244FP sticky, glassy MetP 83 C CAPRYOL™ 244FP sticky, glassy MetP 84 R Castor oil XDP3050 solid gel MetP 84L Linalool XDP3050 Transparent gel MetP 84T TRANSCUTOL® XDP3050 Clear, hard gel MetP_84_C CAPRYOL™ XDP3050 Clear, hard gel

At a particle/oil ratio of 1:3, the loaded particles were no longer powdery, as shown in Table 1. 21 and 25, and it is believed that the oil was not located in the pores of the particle. Moreover, only 9.4% testosterone peak loading was achieved at particle/oil ratio due to the maximum testosterone solubility in linalool.

Example 15 Synthesis of Testosterone Loaded Core/Shell Particles.

Core/shell particles of mesoporous silica and gelatin were synthesized to evaluate the ability to produce particles with enhanced delayed action (ie, sustained release of testosterone). Without being limited by theory, it is believed that unloaded gelatin can function as a barrier to delay the release of testosterone, while when using testosterone-loaded gelatin, gelatin can act as a substrate for testosterone.

In the case of an unloaded gelatin matrix coating, 0.5 g of F15 gelatin was mixed with 27.5

- 32 043077 ml of water and stirred at 200 rpm in an incubation shaker at 37°C until complete dissolution. 22.5 ml of ethanol was added to form an ethanol/water ratio of 45/55 v/v, the mixture was shaken for about an hour on an incubation shaker, stirred with a magnetic stirrer at 500 rpm and then brought to room temperature. In the case of the testosterone-loaded gelatin matrix, the gelatin was dissolved in water similarly to unloaded gelatin. 0.125 g of testosterone was dissolved in 2 ml of ethanol and added to the gelatin mixture. Then, 20.5 ml of ethanol was added to the gelatin mixture.

Pre-sprayed testosterone-loaded SYLOID® particles (0.25 g testosterone from Example 1) at 30% theoretical testosterone loading were then added to each of the gelatin solutions and mixed in the gelatin matrix. The slurry was stirred at 500 rpm until spray dried.

The particles were spray dried using a Mini Spray Dryer in a closed system with suction while stirring was continued at 500 rpm with a magnetic stirrer. Inlet temperature T _in 135°C, dispersion gas 45 mm, aspirator power level 100%, pump power level 10% and nozzle cleaner at 1 were constant. Variable parameters are shown in table. 22.

Table 22 Parameters and results of spray drying experiments using a two-flow nozzle

Batch core/shell Particle SYLOID® Lot SYLOID® Theoretical Testosterone/Gelatin Load (%) Exit (%) MetP 58 244FP MetP 57 - 70.9 MetP 59 244FP MetP 57 20 93.6 MetP 63 XDP6035 MetP 62 - 68.7 MetP_63A XDP6035 MetP_62 - 71.3 MetP 64 XDP6035 MetP 62 20 69.1 MetP 64A XDP6035 MetP 62 20 24.8 MetP_88 244FP MetP_57 20 41.3

In the case of MetP_64A and MetP_88, relatively large amounts of particles were adsorbed by the cyclone during spraying, possibly explaining the lower yield in the case of these compositions (24.8 and 41.3%, respectively). The particles are depicted in the SEM images in FIG. 26A-B. The differences compared to pure testosterone-loaded SYLOID® particles (see Example 12; Fig. 14) are clear.

In the case of spray-dried SYLOID® 244FP particles, predominantly spherical particles resulted from spray drying in the presence of gelatin. Very few particles were still characterized by open pores, and irregularly shaped SYLOID® particles were only slightly visible. Coatings are believed to have been successfully achieved through the use of gelatin.

In the case of spray-dried SYLOID® XDP6035 particles (MetP_63, 63A, 64 and 64A), large SYLOID® particles appeared separately from the gelatin particles. Thus, the 35.1 µm SYLOID® particle size was considered unsuitable for spray drying or coating of testosterone-based compositions under the conditions studied.

Rod-shaped structures also appeared on SEM images of some compositions (MetP_59, MetP_64A and MetP_88) indicating the presence of bacteria, indicating the importance of using sterile starting materials and sterile manufacturing conditions.

Synthesis of core/shell particles using a three-stream nozzle.

Experiments in the case of loading SYLOID® particles with testosterone and simultaneously coating them with gelatin were carried out in a one-stage process using a three-stream nozzle.

To obtain nuclear particles, 0.5 g of SYLOID® particles in 50 ml of ethanol were stirred at 500 rpm for at least one hour. In the case of testosterone loaded particles, 0.214 g of testosterone was dissolved in ethanol.

To obtain the shell gelatin F15 was dissolved in 45/55 v/v. solution of ethanol and water. First, 82.5 ml of water was added and the gelatin solution was shaken in an incubation shaker at 37°C until complete dissolution. Then 67.5 ml of ethanol with 0.375 g of testosterone was added and mixed.

The suspension of SYLOID® particles (core) was transferred using an external pump, while the gelatin solution (shell) was transported using an internal pump to a three-stream nozzle. 50 ml of core solution was used for every 150 ml of shell solution; the excess shell solution was synthesized so that about 45 ml remained after spraying. In the case of MetP_72, the solutions were sprayed using an appropriate other pump.

The Mini Spray Dryer parameters were held constant during the 3-stream nozzle experiments with a temperature of 135° C., aspirator power of 100%, dispersion gas of 45 mm, and nozzle cleaner 0 (since it was not available on the 3-stream nozzle). Spray drying was performed in a closed suction system. The SYLOID® suspensions were agitated at 200 rpm during spray drying. Variable parameters are shown in table. 23.

- 33 043077

Table 23

Parameters and results of spray drying experiments using a three-stream nozzle

The consignment SYLOID® Theoretical loading of the core with testosterone (%) Theoretical shell loading with testosterone (%) Internal download speed(%) External loading speed (ml/min) Exit(%) MetP_65 244FP - 12 (4 ml/min) 2 72.0 MetP 66 XDP6035 - - 12 2 53.0 MetP_72 XDP6035 - - 6(2ml/min) 4 43.1 MetP 76 244FP thirty - 12 2 67.3 MetP_77 244FP thirty 20 12 2 61.2

In the case of experiments using SYLOID® 244FP complications were not observed. At the same time, slightly larger particles of SYLOID® XDP6035 (MetP_66) clogged the tube of the external peristaltic pump. For this reason, each solution was sprayed with a different pump (MetP_72). Although the final sputtering procedure was smooth, the yield was lower than with the other formulations.

As depicted in the SEM images in FIG. 27A-B, MetP_66 and MetP_72 had larger fragments (SYLOID® XDP6035) and smaller gelatin particles. The open pore structure of the SYLOID® particles was still present even with the smaller SYLOID® 244FP particles (see MetP_65, MetP_76 and MetP_77). The degree to which the particles were coated with gelatin despite this was not evaluated.

Particle size determination by laser refraction.

The particle sizes were measured in the case of various compositions obtained in accordance with some of the previous examples. The measuring cell for dry samples Scirocco offers a means for testing powdered samples, however the required sample sizes are quite large and thus the measurement method is not suitable for this purpose. Thus, particle sizes were determined using a Mastersizer 2000 (Malvern). These compositions are shown in table. 24. Polylactide particles could not be characterized with the Mastersizer due to dispersive behavior in ethanol. The samples were dispersed in ethanol and examined in a measuring cell for Hydro 2000 μP dispersions (pumping speed 2500 rpm, ultrasound 30%). Without being limited by theory, it is believed that the particles are in a swollen state caused by their dispersion in ethanol, which affects the observed particle sizes.

Table 24

Results of particle size measurement by laser diffraction (measuring cell Hydro 2000 μP)

The consignment Material d(0.1) (µm) d(0.5) (µm) d(0.9) (µm) MetP. 40 Chitosan 95/200 0.194 5.143 15.437 SYLOID® 244FP 0.106 0.831 4.177 MetP. .53 Gelatin 0.120 1.946 7.445

Particle loading definition.

The actual testosterone loading of the various spray dried particles was determined. Because the loading material (silica) in the testosterone-loaded SYLOID® particles cannot be removed by solvent treatment, the release experiment was run over a longer period (> seven days). Percent load calculations were made on the assumption that 100% testosterone was released for >7 days.

About 10 mg of each of the loaded particles were weighed into a small glass container with the addition of 20 ml of 45/55 v/v. ethanol/water mixtures using a volumetric pipette. Then this dispersion was stirred with a magnetic stirrer for a certain period (> seven days) at room temperature. After an appropriate release period, samples were taken and centrifuged at 15,000 rpm using a benchtop centrifuge for 10 minutes to remove the Syloid® particles from the solution. Then the samples were diluted so that they were in the calibration interval.

The mass concentration of standards and samples was determined using UV/VIS spectrometry (multi-mode microplate reader Synergy 2 from BIOTEK® Instruments). A 96-well quartz microtiter plate was used, into which 200 μl of standard or sample was pipetted into each well. Concentrations were determined using three ratings and loading levels calculated assuming 100% release. Load levels determined for various testosterone-loaded particles are shown in Table 1. 25.

- 34 043077

Table 25

Results for Testosterone Loaded Particles

The consignment Material Testostero H Dried * Theoretical load (%) Defined load (%) MetP_57 SYLOID® 244FP First delivery No 29.9 25.3 MetP_59 MetP_57 in F15 gelatin First delivery No 22.9 18.2 MetP_59 MetP_57 in F15 gelatin First delivery Yes 22.9 20.4 MetP_76 SYLOID® 244FP in F15 gelatin First delivery Yes 14.3 11.8 MetP_77 SYLOID® 244FP in F15 gelatin First delivery Yes 26.7 24.6 MetP_86 SYLOID® 244FP First delivery Yes 30.0 28.0 MetP_88 MetP_86 in gelatin F15 First delivery Yes 22.9 22.6 MetP_92 SYLOID® 244FP Second delivery No 30.0 27.0 MetP_92 SYLOID® 244FP Second delivery Yes 30.0 23.9 MetP_93 SYLOID® 244FP Second delivery Yes 29.9 26.5 MetP_94 SYLOID® 244FP Second delivery Yes 40.0 34.2 MetP_96 Gelatin F15 Second delivery No 30.1 29.7 MetP_10 2 AEROSIL® 200 Second delivery Yes 29.5 28.7

* Drying in a vacuum desiccator.

Comparison of theoretical load levels with actual load levels showed a high recovery rate. The largest deviations from the theoretical value were observed in the cases of MetP_92 at 6.1% and Met_94 at 5.8%. In the case of the remaining samples, the absolute percentage differences ranged from 0.8 to 4.7%. Thus, the efficiency of testosterone loading is quite high and ranges from 79.5 to 98.7%.

Development of nasal gels.

Nasal gels were prepared using castor oil, testosterone, LABRAFIL® and Aerosil® 200. To prepare gels, castor oil and appropriate amounts of testosterone, LABRAFIL® and Aerosil® 200 were added sequentially. Gels were prepared using a rotary stator unit (up to 100 g) or ball mill (Precellys, 1-4 g). Experiments were also carried out with Dispermat, which offers a means of preparing gels in the 30-40 g range (data not shown). Different amounts of nasal gel were obtained using different dispersion capabilities.

Nasal gels were initially prepared according to the nasal gel formula in Table 1. 26.

Table 26

The composition of the original composition of the nasal gel

Amount of castor oil (%) Amount of testosterone (%) Amount of LABRAFIL® (%) Amount of AEROSIL® 200 (%) 89.70 2.30 4.00 4.00

The content of the various nasal gel compositions obtained is shown in Table 1. 27. Higher amounts were obtained by homogenization using a rotor-stator mixing device (nasal gel 03). Each sample was mixed at 13,000 rpm for 2x2 minutes after the addition of testosterone and LABRAFIL®. After the addition of AEROSIL® 200, premixing was first carried out using a glass rod and then by homogenization at 13,000 rpm for 20 minutes.

- 35 043077

Table 27

The number of components in compositions obtained without SYLOID® particles

nasal gel Amount of castor oil (g) Amount of testosterone (g) Amount of LABRAFIL® (g) Amount of AEROSIL® 200 (g) 03 89.70 2.30 4.00 4.00 05(A) 2.240 0.060 0.100 0.100 05 (V) 2.240 0.060 0.100 0.100 06(A) 3.360 0.090 0.150 0.150 06 (B) 3.360 0.090 0.150 0.150

Smaller batches were made using a ball mill (Precellys) starting with the nasal gel, batch 05, so that small amounts of loaded particles could be administered. A fast and gentle mixing and dissolution process was used to prepare the gel: in this mixing process, 7 ml plastic containers were used which contained two zirconia beads (diameter 6.8 mm); a vortex mixer was used to premix the components (castor oil, testosterone and LABRAFIL®) for 10 minutes; then AEROSIL® 200 was added and homogenization was carried out in a ball mill at 4000 rpm for 3x30 minutes with pauses of 2x30 s. The percentage of substances in the nasal gel formula is shown in Table. 28.

Table 28

Percentage of components in formulations made without SYLOID® particles

Component Quantity(%) Castor oil 90.00 T testosterone 2.00 LABRAFIL® 4.00 AEROSIL® 200 4.00

Nasal gel, batch 07 (A) in the table. 29 was obtained in accordance with the formula of the nasal gel in table. 28. SYLOID® particles were used to prepare nasal gel, lots 07 (B) and 07 (C).

Table 29

The number of components in compositions obtained using SYLOID® particles

nasal gel Amount of castor oil (g) Amount of testosterone (g) Amount of LABRAFIL® (g) Amount of AEROSIL® 200 (g) Amount of SYLOID® 244FP (g) 07 (A) 3.375 0.075 0.150 0.150 - 07(B) 3.375 0.075 0.150 - 0.150 07(C) 3.375 0.075 0.150 0.150 0.150

The gelling behavior of SYLOID® 244FP was compared to that of AEROSIL® 200 based on the formulations in Table. 29. Lot flow was determined using a stick test to determine if AEROSIL® 200 could be replaced with SYLOID® 244FP. The rod study (see FIG. 28) showed that the amounts of SYLOID® 244FP present in formulation 07 (B) (on the right side of FIG. 28) were insufficient to induce comparable gelling behavior in the case of 4% Aerosil® 200 ( on the left side of Fig. 28). Additional experiments showed that gelling behavior similar to 4% AEROSIL® 200 occurred at a ratio of 8-10% in the case of SYLOID® 244FP.

Nasal Gel Development with Testosterone-Loaded Particles Nasal gels with testosterone-loaded porous particles (adsorbate) were developed with 11 mg of testosterone adsorbate (6.75 mg in solution and 4.25 mg from adsorbate). The formula is set out in Table. 30, in which the total amount was kept constant.

Table 30

Composition of the nasal gel (constant total volume)

Component Quantity(%) Castor oil Changed (added) Testosterone (dissolved) 4.50 LABRAFIL® 4.00 AEROSIL® 4.00 Adsorbate changing Testosterone (adsorbate) 2.8

The preparation of a nasal composition should optimally combine the alternative problems of maintaining a constant total amount and minimizing the solubility of the active substance. If the total amount is held constant, the inclusion of SYLOID® particles would reduce the amount of added castor oil, which may affect the solubility of testosterone in castor oil. On the other hand, if the amount of castor oil remains constant (and does not affect the solubility of testosterone), the addition of SYLOID® would make it so that the ratios do not remain constant, thereby changing the composition of the composition.

With this in mind, in this feasibility study, as the first stage,

- 36 043077 nasal gels containing constant amounts of castor oil. These compositions are shown in table.

and they were synthesized using a ball mill (Precellys).

Table 31

Nasal gel compositions with a constant amount of castor oil

Gel Number of places in castor oil (g) Number of places in the tester she (g) Amount of LABRAFI L® (g) Amount of AEROSIL ® 200 (g) Loaded particles (adsorbate) Charge Quantity (matrix ) (g) Theoretical amount of testosterone (g) yu, 4 0.867 0.039 0.0347 0.0347 MetP_ 88 0.0847 0.0246 yu, 5 0.867 0.039 0.0347 0.0347 MetP_ 86 0.0578 0.0246 yu, 6 0.867 0.039 0.0347 0.0347 MetP_ 87 0.0976 0.0246 yu, 7 0.867 0.039 0.0347 0.0347 MetP_ 85 0.0578 0.0246

In the compositions shown in table. 31, all components of the nasal gels were kept constant relative to their masses, with the exception of the loaded particle matrix. Formulation 10.4 used SYLOID® 244FP particles theoretically loaded with 30% testosterone and subsequently coated with gelatin (MetP_88). Formulation 10.5 used SYLOID® 244FP particles theoretically loaded with 30% (MetP_88). Formulation 10.6 used particles loaded with F15 gelatin (MetP_87, theoretical loading level 20%), while composition 10.7 used PLA (MetP_85, theoretical loading level 30%).

In separate experiments designed to maintain a constant total amount of nasal synthesis gels, the gels were prepared based on the formula shown in Table 1. 30, in which the compositions were homogenized using a ball mill (Precellys).

Nasal gel 11 with the formula shown in table. 32 was taken as a reference, i. e. without the addition of particles loaded with active substances (thus without adsorbate).

Table 32

Reference nasal gel composition

nasal gel Amount of castor oil (g) Amount of testosterone (g) Amount of LABRAFIL® (g) Amount of AEROSIL® 200 (g) eleven 2.625 0.135 0.120 0.120

Release experiments were also performed using the nasal gels shown in Table 1. 33.

Table 33

Nasal gel compositions

Gel Amount of castor oil (g) Number of tester it (g) Amount of LABRAFI L® (g) Amount of AEROSIL ® 200 (g) Loaded particles (adsorbate) Charge Amount of matrix (g) Theoretical amount of testosterone (g) 12.1 0.78043 0.04500 0.04000 0.04000 MetP_ 85 0.06623 0.02834 12, 2 0.78059 0.04500 0.04000 0.04000 MetP_ 86 0.06609 0.02832 12, 3 0.73397 0.04500 0.04000 0.04000 MetP_ 87 0.11282 0.02821 12, 4 0.75133 0.04500 0.04000 0.04000 MetP_ 88 0.09534 0.02833

To show the problems in the preparation of the nasal gel, the formulation of the two nasal gel formulations is depicted in FIG. 29. Based on the solubility results, testosterone has a solubility of about 4% in castor oil (leftmost column in FIG. 29). In the case of the embodiment shown in FIG. 29 with a constant amount of castor oil, an insoluble portion of 0.3% testosterone will be present (top of middle column). The upper part of the rightmost column corresponds to the amount of testosterone introduced by the adsorbate (particulate testosterone).

However, if the total amount is constant (see FIG. 30), the amount of castor oil must be reduced by an amount corresponding to the amount of adsorbate added. This means that the proportion of undissolved testosterone increases as a function of particle loading in the range of 1 to 2% (top of the two middle columns; middle of the rightmost column). Fig. 29 and 30 together demonstrate the difficulty in obtaining a formula that avoids the appearance of insoluble testosterone.

Example 16 Measurements Obtained by Differential Scanning Calorimetry.

- 37 043077

The melting behavior of the samples was examined using dynamic differential scanning calorimetry to determine the crystallinity of testosterone. Two heating curves (heating rate: 5 K/min/cooling rate: 20 K/min) were recorded for each on a DSC 200 F3 MAIA® dynamic differential calorimeter (Netzsch) in the temperature range from to 200° C. in an inert atmosphere (nitrogen, 40 ml/min).

Without being limited by theory, it is believed that the thermal history is influenced by the processing procedure, in this case spray drying, and can be distinguished between the first and second heating curves. Thus, the second heating curve provides initial material specific data. However, in this project, the first heating indicates whether testosterone is present in crystalline or amorphous form in the individual particle compositions.

Raw batches of testosterone from different deliveries were compared. These DSC curves are depicted in Fig. 31. On first heating, testosterone melts peak at 155.3°C (first delivery) and at 155.2°C (second delivery). The melting peak on the second heating shifted slightly to 154.4°C (first delivery) and 154.2°C (second delivery). In addition, a glass transition was detected at about 40°C and a recrystallization peak in the case of (first delivery) at 97.9°C (maximum) and second delivery of testosterone at 108.4°C (maximum).

To study the effect of spray drying on testosterone, both batches of testosterone were sprayed into pure ethanol and tested in a similar manner. These results are shown in Fig. 32. The peak of recrystallization (at 80.4 and 84.5°C) of the second heating is significantly shifted compared to untreated testosterone samples.

Polylactide (PLA) is an amorphous polymer and thus there is no melting peak with this polymer. Only a glass transition near 50°C was detected, as depicted in FIG. 33. The DSC curves of both PLA samples (non-sprayed PLA and MetP_61) differ slightly on the first heating; however, the curves for the second heating showed no difference. In the case of particles loaded with testosterone, a somewhat different processing of the curves is evident on the first heating. A broad melting peak and a recrystallization peak were detected; however, they are somewhat shifted compared to pure testosterone (melting peak maximum at 146°C and recrystallization peak maximum at 73.5°C). The presence of a melting peak in the case of testosterone indicates that this active substance is still present in crystalline form after spray drying.

DSC curves of spray-dried unloaded (MetP_53) and testosterone loaded gelatin F15 (theoretical loading level for MetP_87: 20%/theoretical loading level for MetP_96: 30%) are shown in FIG. 34. Gelatin is characterized by a broad endothermic peak that results from the evaporation of adsorbed water. The increase in the baseline is pronounced at 200°C, which, apparently, represents the initial helix-coil transition.

The distinct melting point of testosterone during the first heating is evident in the case of the loaded batch of MetP_87 gelatin particles, which decreases sharply during the second heating. A smaller additional peak appeared at <150°C. The higher theoretical testosterone loading approach of 30% (MetP_96) showed a melting peak that was smaller compared to MetP_87.

In the case of testosterone-loaded mesoporous silica particles (SYLOID® 244FP), the melting peak of testosterone near 150°C may not have been detected on either the first or second heating, as evident from the DSC curves in FIG. 35. All curves in this document have a broad endothermic peak that appears to be similar to gelatin due to the evaporation of adsorbed water.

It was assumed that testosterone was not present in crystalline form, but in amorphous form (this could be substantiated by further studies, for example, the synthesis of mixtures of testosterone and SYLOID® and the use of higher ratios of testosterone, similar to the progesterone procedure).

The DSC curves of the silica/gelatin core/shell particles are shown in FIG. 36. The intensity of the evaporation peak clearly increased in comparison with pure particles of mesoporous silica due to the presence of gelatin. MetP_76 and MetP_77 were synthesized using a three-component jet, i.e. in a one step process. Comparing the curves at a given point in time, those of testosterone-loaded SYLOID® particles with unloaded gelatin as a coating material (MetP_76) synthesized using a three-component jet with pure testosterone-loaded SYLOID® particles (MetP_86, 92 and 93, Figs. 42), they are distinguished by a more pronounced evaporation peak. The melting peak was not detected. This is meant to mean that testosterone is probably in an amorphous form. In the presence of loaded gelatin matrix (Met_77), the DSC curve is characterized by a distinct shoulder in the region from 120°C to 125°C. This shoulder could also be identified in the case of Met_88. MetP_88 had a similar composition to MetP_77 but was synthesized in two steps using a two-component jet. Moreover, apparently in

- 38 043077 In this case, two additional effects can be applied. As a result, an additional putative peak was found in the region of 53.7°C.

Non-porous silica particles (AEROSIL® 200) were spray dried as standards both as pure particles and in the presence of testosterone (30% theoretical loading level). The DSC curves of these samples are shown in Fig. 37. In this case, a small, somewhat broader melting peak is evident just below 150°C for loaded particles. This is also understandable since the primary particles do not have a porous structure.

Peak melting near 150° C. for testosterone-loaded Syloid® XDP6035 PARTICLES as depicted in FIG. 38, at a theoretical load level of 10% (MetP_50), was absent. It is to be detected starting from the theoretical utilization level of 30% (MetP_51).

Example 17 Summary of Testosterone Experiments.

Various methods of testosterone loading were evaluated. It is possible to load testosterone in polymer matrices by spray drying. In particular, loading levels of about 30% and yields of about 50% were obtained using RESOMER® 202H particles. Likewise, loading levels of about 30% and yields of about 70% were achieved using chitosan 95/500 as the encapsulating material. F15 gelatin was also loaded with approximately 20% testosterone and a yield of 30% was achieved.

The mesoporous silica particles could also be loaded by spray drying, for example with SYLOID® 244FP particles. Load levels of approximately 40% and yields of approximately 70% have been achieved. SYLOID® 244FP particles can also be loaded in the same way with oil; however, the loading rate was limited to 9.4% due to the relatively poor solubility of testosterone in linalool.

Coating of the particles was carried out using a two-flow nozzle, as well as using a three-flow nozzle. This procedure used SYLOID® 244FP particles as the core material and F15 gelatin as the coating material, achieving a loading level of about 23%. A yield of 90% was achieved using a two-stream nozzle, and a yield of 60% was achieved using a three-stream nozzle.

DSC measurements have shown that testosterone is still present in the polymer matrices, at least partially in crystalline form. The crystallite melting point at 150° C. could not be detected with testosterone-loaded Syloid® 244FP particles.

Example 18 Expanded production of testosterone-based formulations.

Extended batches of testosterone-based formulations were prepared using SILSOL™ 6035. In particular, 21 g of testosterone was dissolved in 118 g of ethanol. The testosterone solution was added at 5055°C in stages using a pump (Master Flex) to the stirred SILSOL™ 6035 solution to achieve a testosterone loading of 25-30%. The resulting mixture was substantially free of lumps. The resulting mixture was dried under vacuum in a drying chamber at a pressure of about 8 mbar and a temperature that increased from about 50 to about 80°C towards the end of the drying. For some batches, 3% polyvinylpyrrolidone (PVP) was added to the composition.

The compositions were further expanded using the protocol discussed above. In particular, compositions were obtained with a batch size of 800 g, as shown in table. 34.

Table 34 Compositions with Testosterone + SILSOL™ 6035

The consignment Lot size Mass of active substance Theoretical loading Exit Party 1 800 g 240.1 g thirty% 88% Party 2 800 g 216.3 g 27% (+3% PVP) 88%

Extended batches made with Silica XDP 3050 or 3150 as porous fillers (instead of SILSOL™ 6035) gave similar results.

Example 19 Stability of Extended Batches of Testosterone-Based Compositions.

Extended batches of testosterone-based formulations were prepared using SILSOL™ 6035 according to Example 18. The formulations were stored for 1 month at 25°C/60% RH or 30°C/65% RH. The stability of the compositions after 1 month of storage was examined using differential scanning calorimetry. In all cases, degradation-related impurities in the formulations remained essentially unchanged after 1 month of storage. Moreover, it could be assumed that the ratio of crystalline testosterone (eg, the percentage of testosterone that is in a crystalline state) in both formulations is less than 0.5% due to release, even after 1 month of storage. Moreover, the composition is essentially free of crystalline polymorphs of testosterone.

Claims (20)

1. Nasal pharmaceutical composition adapted for nasal administration, containing a porous filler and an active substance, wherein the active substance is loaded onto the surface of the porous filler located inside the pores of the porous filler, while the loaded porous filler is dispersed in a gel carrier, the gel carrier contains an oil or a mixture of oils , the porous filler contains porous silicon dioxide, and the composition contains a therapeutically effective amount of the active substance, ranging from 10 to 50% wt./wt. by weight of the composition, in a volume suitable for nasal administration, and the viscosity of the composition is from about 2000 to about 6000 mPa-s, where the term about means up to plus or minus 10% of 2000 and 6000, respectively. 2. The nasal pharmaceutical composition of claim 1, wherein the porous silica is selected from mesoporous silica, microporous silica, and macroporous silica. 3. Nasal pharmaceutical composition according to any one of claims 1, 2, where the porous silicon dioxide has pores with a maximum diameter in any dimension selected from: (i) up to 2 nm, (ii) from 2 to 50 nm, or (iii) from 50 nm or more. 4. Nasal pharmaceutical composition according to any one of claims 1-3, where the porous filler loaded with the active substance is coated with a polymer that forms a coating around the porous filler, where the polymer is selected from a linear polymer selected from polyvinylpyrrolidone, hyaluronic acid, chitosan, xanthan, alginate, polyvinyl acetate, sodium starch glycolate and combinations of any two or more of them, a cellulose-containing polymer comprising sodium carboxymethyl cellulose, a copolymer selected from polyvinylpyrrolidone/polyvinyl acetate, polyvinylpyrrolidone/polyvinyl alcohol, polyvinyl alcohol/PEG, polyvinyl caprolactam/polyvinyl acetate/polyethylene glycol, and combinations of any two or more of them, a crosslinked polymer selected from crosslinked polyvinylpyrrolidone, crosslinked sodium carboxymethylcellulose and combinations of any two or more of them, a collagen-containing polymer including gelatin and combinations of any two or more of them. 5. Nasal pharmaceutical composition according to claim 1, where the pores in the porous filler loaded with the active substance are covered with a coating. 6. Nasal pharmaceutical composition according to any one of claims 1 to 5, wherein the active substance is selected from aripiprazole, quetiapine, paliperidone, duloxetine, dopamine, testosterone, glatiramer acetate, interferon beta-1a, interferon beta-1b, fingolimod, natalizumab, dimethyl fumarate , pregnenolone, memantine, rivastigmine, donepezil, desvenlafaxine, progesterone, eszopiclone, atomoxetine, guanfacine, methylphenidate, lisdexamfetamine, recombinant tissue plasminogen activator (rt-PA), methotrexate, raltitrexide, 5-fluorouracil, telomerase inhibitor, monoclone al antibodies, midazolam, lacosamide , levetiracetam, lamotrigine, valproic acid, oxycodone, pregabalin, buprenorphine, hydrocodone, fentanyl, safinamide, ropinirole, pramipexole, levodopa, selegiline, cabergoline, istradephylline, and combinations of two or more of them. 7. Nasal pharmaceutical composition according to any one of claims 1 to 6, characterized in that the composition is a vaccine and the active substance contains an immunogen. 8. Nasal pharmaceutical composition according to any one of claims 1 to 7, containing from 10 to 40% w/w of the active substance, based on the weight of the composition. 9. Nasal pharmaceutical composition according to any one of claims 1 to 8, in which the active substance is in amorphous form. 10. Nasal pharmaceutical composition according to any one of claims 1 to 9, in which the gel carrier contains castor oil. 11. A method for preparing a nasal pharmaceutical composition adapted for nasal administration according to any one of claims 1 to 10, wherein the method includes loading the active ingredient onto a porous filler, wherein said active ingredient is loaded by adsorption of oil onto the surface of the porous filler located within the pores. the specified porous filler. 12. The method of claim 11, further comprising spray drying the co-active agent and the porous excipient after the active agent is loaded onto the porous excipient. 13. A method of vaccinating a subject against a condition, comprising nasal administration of a composition according to any one of claims 1 to 10 to a subject in need thereof, wherein: (a) the condition in question is influenza and the active substance is live attenuated influenza virus, inactivated virus or viral antigens; (b) said condition is hepatitis B and the active ingredient is hepatitis B virus (HBV), hepatitis B surface antigens (HBsAg) and/or hepatitis B core antigens (HBcAg); or - 40 043077 (c) the condition in question is meningitis and the active ingredient is a meningococcal polysaccharide vaccine (MPSV4, a polysaccharide from the surface of meningococcal bacteria), a meningococcal conjugate vaccine (MCV4, a polysaccharide chemically bound to a protein) and/or a serogroup B meningococcal vaccine (MenB, which contains four proteins taken from Neisseria meningitidis group B). 14. A method of treating a condition, comprising nasal administration of a composition according to any one of claims 1-10 to a subject in need thereof, wherein: (a) said condition is hypogonadism, female sexual dysfunction, female arousal disorder, anorgasmia, or a female libido disorder, and the active ingredient is testosterone; (b) said condition is brain damage and the active ingredient is progesterone; (c) said condition is schizophrenia and the active ingredient is aripiprazole, quetiapine or paliperidone; (d) said condition is anxiety and the active substance is duloxetine or dopamine; (e) said condition is multiple sclerosis and the active ingredient is testosterone, glatiramer acetate, interferon beta-1a, interferon beta-1b, fingolimod, natalizumab, or dimethyl fumarate; (f) said condition is Alzheimer's disease and the active ingredient is pregnenolone, memantine, rivastigmine or donepezil; (g) said condition is depression and the active ingredient is desvenlafaxine, duloxetine or dopamine; (h) said condition is insomnia and the active substance is progesterone or eszopiclone; (i) said condition is attention deficit hyperactivity disorder and the active substance is atomoxetine, guanfacine, methylphenidate, lisdexamphetamine or dopamine; (j) said condition is traumatic brain injury and the active ingredient is progesterone or recombinant tissue plasminogen activator (rt-PA); (k) said condition is a brain tumor and the active substance is methotrexate, raltitrexide, 5-fluorouracil, telomerase inhibitor or monoclonal antibodies; (l) said condition is epilepsy and the active substance is midazolam, lacosamide, levetiracetam, lamotrigine or valproic acid; (m) said condition is pain and the active ingredient is oxycodone, pregabalin, buprenorphine, hydrocodone or fentanyl; or (n) said condition is Parkinson's disease and the active ingredient is safinamide, ropinirole, pramipexole, dopamine, levodopa, selegiline, cabergoline or istradefylline. 15. Nasal pharmaceutical composition according to claim 1, containing: (a) from 0.5 to 50% w/w media based on mesoporous silica based on the weight of the composition; and from 10 to 40% wt./wt. the active ingredient based on the weight of the composition, wherein the active ingredient is loaded onto the surface of the mesoporous silica located inside the pores of the mesoporous silica; (b) 50 to 90% w/w castor oil based on the weight of the composition as an oil or mixture of oils; and (c) from 0.5 to 20% w/w. colloidal silicon dioxide based on the weight of the composition. 16. Nasal pharmaceutical composition according to claim 1, containing: (a) 6 to 11% w/w filler based on mesoporous silica based on the weight of the composition; and from 10 to 30% wt./wt. the active ingredient based on the weight of the composition, wherein the active ingredient is loaded onto the surface of the mesoporous silica located inside the pores of the mesoporous silica; (b) from 70 to 80% wt./wt. castor oil based on the weight of the composition as an oil or mixture of oils; and (c) from 0.5 to 20% w/w. viscosity adjusting agent, based on the weight of the composition. 17. A nasal pharmaceutical composition according to any one of claims 15 or 16, wherein the active ingredient is testosterone or progesterone. 18. A nasal pharmaceutical composition according to any one of claims 15 to 17, wherein the oil or mixture of oils contains the active ingredient. 19. Nasal pharmaceutical composition according to claim 1, containing: - 41 043077 (a) from 0.5 to 50% wt./wt. media based on mesoporous silica based on the weight of the composition; and from 15 to 25% wt./wt. the active ingredient based on the weight of the composition, wherein the active ingredient is loaded onto the surface of the mesoporous silica located inside the pores of the mesoporous silica; (b) 50 to 90% w/w castor oil based on the weight of the composition as an oil or mixture of oils; and (c) from 2 to 6% w/w. mixtures of oleoyl macrogoglycerides based on the weight of the composition. 20. The nasal pharmaceutical composition according to claim 19, wherein the active ingredient is testosterone or progesterone.