药学学报

Technology	Patent No.	Year	Inventor	Process parameter	Advantage	Ref.
Hydrosol	GB2200048	1988	Novartis	Rate of addition of solvent, solubility of drug in antisolvent, amount of stabilizer, ratio of solvent/antisolvent	Lower particle size can be obtained, amorphous character in final product, increase in solubility	[8]
NanoMorph	D19637517	2002	Soligs/Abbott			[9]
Nanocrystals	US5145684	1991	Elan Nanosystems	Milling speed, milling time, amount of milling media, drug amount, temperature	Easy industrial applicability, simple process, high drug loading, avoid use of organic solvent	[10]
IDD-P	US5091188 A	1992	Duncan H. Haynes	Homogenization cycle, homogenization temperature, hardness of drug	Suitable for all kind of drugs, easy reproducibility, less contamination as compared to media milling, high rate of production	[11]
Dissocubes	US5858410	1994	SkyePharma			[12]
Nanopure	PCT/EP00/06535	2000	PharmaSol			[13]
NANOEDGE	US 6607784	2003	Baxter International Inc.	Precipitation combined with homogenization	Less number of cycle and energy required to reduce the particle size	[14]
H42	WO2006094808 A3	2005	Pharmasol Gmbh	Spray-drying combined with homogenization	Able to produce particle size below 100 nm which is not feasible by any of the top-down technology, less cycle of high pressure homogenization required	[15]
H96	WO2006108637A2	2007	Pharmasol Gmbh	Freeze-drying combined with homogenization		[16]
CT	US20100047297	2010	Abbott Gmbh	Media milling combined with homogenization		[17]
ARTcrystal	US2013/0095198	2013	Pharmasol Gmbh	High-speed rotor-stator dispersion combined with homogenization		[18]

Technology

Patent No.

Year

Inventor

Process parameter

Advantage

Ref.

Hydrosol

GB2200048

1988

Novartis

Rate of addition of solvent, solubility of drug in antisolvent, amount of stabilizer, ratio of solvent/antisolvent

Lower particle size can be obtained, amorphous character in final product, increase in solubility

[8]

NanoMorph

D19637517

2002

Soligs/Abbott

[9]

Nanocrystals

US5145684

1991

Elan Nanosystems

Milling speed, milling time, amount of milling media, drug amount, temperature

Easy industrial applicability, simple process, high drug loading, avoid use of organic solvent

[10]

IDD-P

US5091188 A

1992

Duncan H. Haynes

Homogenization cycle, homogenization temperature, hardness of drug

Suitable for all kind of drugs, easy reproducibility, less contamination as compared to media milling, high rate of production

[11]

Dissocubes

US5858410

1994

SkyePharma

[12]

Nanopure

PCT/EP00/06535

2000

PharmaSol

[13]

NANOEDGE

US 6607784

2003

Baxter International Inc.

Precipitation combined with homogenization

Less number of cycle and energy required to reduce the particle size

[14]

H42

WO2006094808 A3

2005

Pharmasol Gmbh

Spray-drying combined with homogenization

Able to produce particle size below 100 nm which is not feasible by any of the top-down technology, less cycle of high pressure homogenization required

[15]

H96

WO2006108637A2

2007

Pharmasol Gmbh

Freeze-drying combined with homogenization

[16]

US20100047297

2010

Abbott Gmbh

Media milling combined with homogenization

[17]

ARTcrystal

US2013/0095198

2013

Pharmasol Gmbh

High-speed rotor-stator dispersion combined with homogenization

[18]

Technology	Patent No.	Year	Inventor	Process parameter	Advantage	Ref.
Hydrosol	GB2200048	1988	Novartis	Rate of addition of solvent, solubility of drug in antisolvent, amount of stabilizer, ratio of solvent/antisolvent	Lower particle size can be obtained, amorphous character in final product, increase in solubility	[8]
NanoMorph	D19637517	2002	Soligs/Abbott			[9]
Nanocrystals	US5145684	1991	Elan Nanosystems	Milling speed, milling time, amount of milling media, drug amount, temperature	Easy industrial applicability, simple process, high drug loading, avoid use of organic solvent	[10]
IDD-P	US5091188 A	1992	Duncan H. Haynes	Homogenization cycle, homogenization temperature, hardness of drug	Suitable for all kind of drugs, easy reproducibility, less contamination as compared to media milling, high rate of production	[11]
Dissocubes	US5858410	1994	SkyePharma			[12]
Nanopure	PCT/EP00/06535	2000	PharmaSol			[13]
NANOEDGE	US 6607784	2003	Baxter International Inc.	Precipitation combined with homogenization	Less number of cycle and energy required to reduce the particle size	[14]
H42	WO2006094808 A3	2005	Pharmasol Gmbh	Spray-drying combined with homogenization	Able to produce particle size below 100 nm which is not feasible by any of the top-down technology, less cycle of high pressure homogenization required	[15]
H96	WO2006108637A2	2007	Pharmasol Gmbh	Freeze-drying combined with homogenization		[16]
CT	US20100047297	2010	Abbott Gmbh	Media milling combined with homogenization		[17]
ARTcrystal	US2013/0095198	2013	Pharmasol Gmbh	High-speed rotor-stator dispersion combined with homogenization		[18]

Technology

Patent No.

Year

Inventor

Process parameter

Advantage

Ref.

Hydrosol

GB2200048

1988

Novartis

Rate of addition of solvent, solubility of drug in antisolvent, amount of stabilizer, ratio of solvent/antisolvent

Lower particle size can be obtained, amorphous character in final product, increase in solubility

[8]

NanoMorph

D19637517

2002

Soligs/Abbott

[9]

Nanocrystals

US5145684

1991

Elan Nanosystems

Milling speed, milling time, amount of milling media, drug amount, temperature

Easy industrial applicability, simple process, high drug loading, avoid use of organic solvent

[10]

IDD-P

US5091188 A

1992

Duncan H. Haynes

Homogenization cycle, homogenization temperature, hardness of drug

Suitable for all kind of drugs, easy reproducibility, less contamination as compared to media milling, high rate of production

[11]

Dissocubes

US5858410

1994

SkyePharma

[12]

Nanopure

PCT/EP00/06535

2000

PharmaSol

[13]

NANOEDGE

US 6607784

2003

Baxter International Inc.

Precipitation combined with homogenization

Less number of cycle and energy required to reduce the particle size

[14]

H42

WO2006094808 A3

2005

Pharmasol Gmbh

Spray-drying combined with homogenization

Able to produce particle size below 100 nm which is not feasible by any of the top-down technology, less cycle of high pressure homogenization required

[15]

H96

WO2006108637A2

2007

Pharmasol Gmbh

Freeze-drying combined with homogenization

[16]

US20100047297

2010

Abbott Gmbh

Media milling combined with homogenization

[17]

ARTcrystal

US2013/0095198

2013

Pharmasol Gmbh

High-speed rotor-stator dispersion combined with homogenization

[18]

Trade name	Drug	Company	Method	Therapeutic effect	Status
Verelan PM	Verapamil	Schwarz Pharma	Top-down (WMM)	Antiarrhythmia	Approved (FDA, 1998)
Rapamune	Sirolimus	Wyeth	Top-down (WMM)	Immunosuppre-ssant	Approved (FDA, 2000)
Focalin XR	Dexmethylphenidate hydrochloride	Novartis	Top-down (WMM)	Antipsychotic	Approved (FDA, 2001)
Avinza	Morphine sulfate	King Pharm	Top-down (WMM)	Antichronic pain	Approved (FDA, 2002)
Ritalin LA	Methylphenidate hydrochloride	Novartis	Top-down (WMM)	Antipsychotic	Approved (FDA, 2002)
Herbesser	Diltiazem	Mitsubishi Tanabe Pharma	Top-down (WMM)	Antiangina	Approved (JMH, 2002)
Zanaflex	Tizanidine hydrochloride	Acorda	Top-down (WMM)	Muscle relaxant	Approved (FDA, 2002)
Emend	Aprepitant	Merck	Top-down (WMM)	Antiemetic	Approved (FDA, 2003)
Tricor	Fenofibrate	Abbott	Top-down (WMM)	Hypercholesterolemia	Approved (FDA, 2004)
Cesamet	Nabilone	Lilly	Bottom-up (CP)	Antiemetic	Approved (FDA, 2005)
Megace ES	Megestrol acetate	Par Pharma	Top-down (WMM)	Appetite stimulant	Approved (FDA, 2005)
Triglide	Fenofibrate	Skye Pharma	Top-down (HPH)	Hypercholesterolemia	Approved (FDA, 2005)
Naprelan	Naproxen sodium	Wyeth	Top-down (WMM)	Anti-inflammation	Approved (FDA, 2006)
Theodur	Theophylline	Mitsubishi Tanabe Pharma	Top-down (WMM)	Bronchial dilation	Approved (FDA, 2008)
Invega Sustenna	Paliperidone palmitate	Janssen	Top-down (HPH)	Antidepressant	Approved (FDA, 2009)
Invega Trinza	Paliperidone palmitate	Janssen	Top-down (HPH))	Antidepressant	Approved (FDA, 2015)
Aristada	Aripiprazole lauroxil	Alkermes	Top-down (HPH)	Schizophrenia	Approved (FDA, 2015)
Panzem	2-Methoxyestradiol	EntreMed	Top-down (WMM)	Anti-tumor	Phase Ⅱ (FDA)
Semapimod	Guanylhydrazone	Ferring	Top-down (WMM)	Anti-inflammation	Phase Ⅱ (FDA)
Paxceed	Paclitaxel	Angiotech Pharmaceuticals	Top-down (HPH)	Anti-tumor	Phase Ⅱ (FDA)
Theralux	Thymectacin	Celmed BioSciences	Top-down (WMM)	Anti-tumor	Phase Ⅱ (FDA)

Trade name

Drug

Company

Method

Therapeutic effect

Status

Verelan PM

Verapamil

Schwarz Pharma

Top-down (WMM)

Antiarrhythmia

Approved (FDA, 1998)

Rapamune

Sirolimus

Wyeth

Top-down (WMM)

Immunosuppre-ssant

Approved (FDA, 2000)

Focalin XR

Dexmethylphenidate hydrochloride

Novartis

Top-down (WMM)

Antipsychotic

Approved (FDA, 2001)

Avinza

Morphine sulfate

King Pharm

Top-down (WMM)

Antichronic pain

Approved (FDA, 2002)

Ritalin LA

Methylphenidate hydrochloride

Novartis

Top-down (WMM)

Antipsychotic

Approved (FDA, 2002)

Herbesser

Diltiazem

Mitsubishi Tanabe Pharma

Top-down (WMM)

Antiangina

Approved (JMH, 2002)

Zanaflex

Tizanidine hydrochloride

Acorda

Top-down (WMM)

Muscle relaxant

Approved (FDA, 2002)

Emend

Aprepitant

Merck

Top-down (WMM)

Antiemetic

Approved (FDA, 2003)

Tricor

Fenofibrate

Abbott

Top-down (WMM)

Hypercholesterolemia

Approved (FDA, 2004)

Cesamet

Nabilone

Lilly

Bottom-up (CP)

Antiemetic

Approved (FDA, 2005)

Megace ES

Megestrol acetate

Par Pharma

Top-down (WMM)

Appetite stimulant

Approved (FDA, 2005)

Triglide

Fenofibrate

Skye Pharma

Top-down (HPH)

Hypercholesterolemia

Approved (FDA, 2005)

Naprelan

Naproxen sodium

Wyeth

Top-down (WMM)

Anti-inflammation

Approved (FDA, 2006)

Theodur

Theophylline

Mitsubishi Tanabe Pharma

Top-down (WMM)

Bronchial dilation

Approved (FDA, 2008)

Invega Sustenna

Paliperidone palmitate

Janssen

Top-down (HPH)

Antidepressant

Approved (FDA, 2009)

Invega Trinza

Paliperidone palmitate

Janssen

Top-down (HPH))

Antidepressant

Approved (FDA, 2015)

Aristada

Aripiprazole lauroxil

Alkermes

Top-down (HPH)

Schizophrenia

Approved (FDA, 2015)

Panzem

2-Methoxyestradiol

EntreMed

Top-down (WMM)

Anti-tumor

Phase Ⅱ (FDA)

Semapimod

Guanylhydrazone

Ferring

Top-down (WMM)

Anti-inflammation

Phase Ⅱ (FDA)

Paxceed

Paclitaxel

Angiotech Pharmaceuticals

Top-down (HPH)

Anti-tumor

Phase Ⅱ (FDA)

Theralux

Thymectacin

Celmed BioSciences

Top-down (WMM)

Anti-tumor

Phase Ⅱ (FDA)

Trade name	Drug	Company	Method	Therapeutic effect	Status
Verelan PM	Verapamil	Schwarz Pharma	Top-down (WMM)	Antiarrhythmia	Approved (FDA, 1998)
Rapamune	Sirolimus	Wyeth	Top-down (WMM)	Immunosuppre-ssant	Approved (FDA, 2000)
Focalin XR	Dexmethylphenidate hydrochloride	Novartis	Top-down (WMM)	Antipsychotic	Approved (FDA, 2001)
Avinza	Morphine sulfate	King Pharm	Top-down (WMM)	Antichronic pain	Approved (FDA, 2002)
Ritalin LA	Methylphenidate hydrochloride	Novartis	Top-down (WMM)	Antipsychotic	Approved (FDA, 2002)
Herbesser	Diltiazem	Mitsubishi Tanabe Pharma	Top-down (WMM)	Antiangina	Approved (JMH, 2002)
Zanaflex	Tizanidine hydrochloride	Acorda	Top-down (WMM)	Muscle relaxant	Approved (FDA, 2002)
Emend	Aprepitant	Merck	Top-down (WMM)	Antiemetic	Approved (FDA, 2003)
Tricor	Fenofibrate	Abbott	Top-down (WMM)	Hypercholesterolemia	Approved (FDA, 2004)
Cesamet	Nabilone	Lilly	Bottom-up (CP)	Antiemetic	Approved (FDA, 2005)
Megace ES	Megestrol acetate	Par Pharma	Top-down (WMM)	Appetite stimulant	Approved (FDA, 2005)
Triglide	Fenofibrate	Skye Pharma	Top-down (HPH)	Hypercholesterolemia	Approved (FDA, 2005)
Naprelan	Naproxen sodium	Wyeth	Top-down (WMM)	Anti-inflammation	Approved (FDA, 2006)
Theodur	Theophylline	Mitsubishi Tanabe Pharma	Top-down (WMM)	Bronchial dilation	Approved (FDA, 2008)
Invega Sustenna	Paliperidone palmitate	Janssen	Top-down (HPH)	Antidepressant	Approved (FDA, 2009)
Invega Trinza	Paliperidone palmitate	Janssen	Top-down (HPH))	Antidepressant	Approved (FDA, 2015)
Aristada	Aripiprazole lauroxil	Alkermes	Top-down (HPH)	Schizophrenia	Approved (FDA, 2015)
Panzem	2-Methoxyestradiol	EntreMed	Top-down (WMM)	Anti-tumor	Phase Ⅱ (FDA)
Semapimod	Guanylhydrazone	Ferring	Top-down (WMM)	Anti-inflammation	Phase Ⅱ (FDA)
Paxceed	Paclitaxel	Angiotech Pharmaceuticals	Top-down (HPH)	Anti-tumor	Phase Ⅱ (FDA)
Theralux	Thymectacin	Celmed BioSciences	Top-down (WMM)	Anti-tumor	Phase Ⅱ (FDA)

Trade name

Drug

Company

Method

Therapeutic effect

Status

Verelan PM

Verapamil

Schwarz Pharma

Top-down (WMM)

Antiarrhythmia

Approved (FDA, 1998)

Rapamune

Sirolimus

Wyeth

Top-down (WMM)

Immunosuppre-ssant

Approved (FDA, 2000)

Focalin XR

Dexmethylphenidate hydrochloride

Novartis

Top-down (WMM)

Antipsychotic

Approved (FDA, 2001)

Avinza

Morphine sulfate

King Pharm

Top-down (WMM)

Antichronic pain

Approved (FDA, 2002)

Ritalin LA

Methylphenidate hydrochloride

Novartis

Top-down (WMM)

Antipsychotic

Approved (FDA, 2002)

Herbesser

Diltiazem

Mitsubishi Tanabe Pharma

Top-down (WMM)

Antiangina

Approved (JMH, 2002)

Zanaflex

Tizanidine hydrochloride

Acorda

Top-down (WMM)

Muscle relaxant

Approved (FDA, 2002)

Emend

Aprepitant

Merck

Top-down (WMM)

Antiemetic

Approved (FDA, 2003)

Tricor

Fenofibrate

Abbott

Top-down (WMM)

Hypercholesterolemia

Approved (FDA, 2004)

Cesamet

Nabilone

Lilly

Bottom-up (CP)

Antiemetic

Approved (FDA, 2005)

Megace ES

Megestrol acetate

Par Pharma

Top-down (WMM)

Appetite stimulant

Approved (FDA, 2005)

Triglide

Fenofibrate

Skye Pharma

Top-down (HPH)

Hypercholesterolemia

Approved (FDA, 2005)

Naprelan

Naproxen sodium

Wyeth

Top-down (WMM)

Anti-inflammation

Approved (FDA, 2006)

Theodur

Theophylline

Mitsubishi Tanabe Pharma

Top-down (WMM)

Bronchial dilation

Approved (FDA, 2008)

Invega Sustenna

Paliperidone palmitate

Janssen

Top-down (HPH)

Antidepressant

Approved (FDA, 2009)

Invega Trinza

Paliperidone palmitate

Janssen

Top-down (HPH))

Antidepressant

Approved (FDA, 2015)

Aristada

Aripiprazole lauroxil

Alkermes

Top-down (HPH)

Schizophrenia

Approved (FDA, 2015)

Panzem

2-Methoxyestradiol

EntreMed

Top-down (WMM)

Anti-tumor

Phase Ⅱ (FDA)

Semapimod

Guanylhydrazone

Ferring

Top-down (WMM)

Anti-inflammation

Phase Ⅱ (FDA)

Paxceed

Paclitaxel

Angiotech Pharmaceuticals

Top-down (HPH)

Anti-tumor

Phase Ⅱ (FDA)

Theralux

Thymectacin

Celmed BioSciences

Top-down (WMM)

Anti-tumor

Phase Ⅱ (FDA)

Combinative technology	Pretreatment (bottom-up)	Particle size reduction technology	Drug	Mean particle size/nm	Size reduction process (top-down)	Ref.
Nanoedge	Microprecipitation	HPH	Prednisolone	640	68.95 MPa for 15 min	[34]
Nanoedge	Microprecipitation	HPH	Glabridin	149.2	68.95 MPa for 30 min	[35]
Nanoedge	Microprecipitation	HPH	Herpetrione	243		[36]
Nanoedge	Microprecipitation	HPH	10-Hydroxycamptothecin	22	68.95 MPa for 30 min	[37]
H69	Cavi-precipitation	HPH	Prednisolone	787	150 MPa for 6 min	[38]
H69	Cavi-precipitation	HPH	Ursodeoxycholic acid	372	60 MPa for 10 cycles	[39]
H96	Freeze-drying	HPH	Aprepitant	35.82	150 MPa for 5 cycles	[40]
H42	Spray-drying	HPH	Hydrocortisone acetate	281	150 MPa for 20 cycles	[41]
H96	Freeze-drying	HPH	Glibenclamide	355	150 MPa for 20 cycles	[42]
PLH	Precipitation-freeze-drying	HPH	Clarithromycin	444	150 MPa for 5 cycles	[43]
CT	Pearl milling	HPH	Hesperidin	599	100 MPa for 5 cycles	[44]
CT	Pearl milling	HPH	Nicergoline	353	150 MPa for 10 cycles	[45]
MRT	Microfluids reaction	HPH	Norfloxacin	170	138 MPa	[46]
ART crystals	ART MICCRA	HPH	Rutin	431	50 MPa for 5 cycle	[18]

Combinative technology

Pretreatment (bottom-up)

Particle size reduction technology

Drug

Mean particle size/nm

Size reduction process (top-down)

Ref.

Nanoedge

Microprecipitation

HPH

Prednisolone

640

68.95 MPa for 15 min

[34]

Nanoedge

Microprecipitation

HPH

Glabridin

149.2

68.95 MPa for 30 min

[35]

Nanoedge

Microprecipitation

HPH

Herpetrione

243

[36]

Nanoedge

Microprecipitation

HPH

10-Hydroxycamptothecin

68.95 MPa for 30 min

[37]

H69

Cavi-precipitation

HPH

Prednisolone

787

150 MPa for 6 min

[38]

H69

Cavi-precipitation

HPH

Ursodeoxycholic acid

372

60 MPa for 10 cycles

[39]

H96

Freeze-drying

HPH

Aprepitant

35.82

150 MPa for 5 cycles

[40]

H42

Spray-drying

HPH

Hydrocortisone acetate

281

150 MPa for 20 cycles

[41]

H96

Freeze-drying

HPH

Glibenclamide

355

150 MPa for 20 cycles

[42]

PLH

Precipitation-freeze-drying

HPH

Clarithromycin

444

150 MPa for 5 cycles

[43]

Pearl milling

HPH

Hesperidin

599

100 MPa for 5 cycles

[44]

Pearl milling

HPH

Nicergoline

353

150 MPa for 10 cycles

[45]

MRT

Microfluids reaction

HPH

Norfloxacin

170

138 MPa

[46]

ART crystals

ART MICCRA

HPH

Rutin

431

50 MPa for 5 cycle

[18]

Combinative technology	Pretreatment (bottom-up)	Particle size reduction technology	Drug	Mean particle size/nm	Size reduction process (top-down)	Ref.
Nanoedge	Microprecipitation	HPH	Prednisolone	640	68.95 MPa for 15 min	[34]
Nanoedge	Microprecipitation	HPH	Glabridin	149.2	68.95 MPa for 30 min	[35]
Nanoedge	Microprecipitation	HPH	Herpetrione	243		[36]
Nanoedge	Microprecipitation	HPH	10-Hydroxycamptothecin	22	68.95 MPa for 30 min	[37]
H69	Cavi-precipitation	HPH	Prednisolone	787	150 MPa for 6 min	[38]
H69	Cavi-precipitation	HPH	Ursodeoxycholic acid	372	60 MPa for 10 cycles	[39]
H96	Freeze-drying	HPH	Aprepitant	35.82	150 MPa for 5 cycles	[40]
H42	Spray-drying	HPH	Hydrocortisone acetate	281	150 MPa for 20 cycles	[41]
H96	Freeze-drying	HPH	Glibenclamide	355	150 MPa for 20 cycles	[42]
PLH	Precipitation-freeze-drying	HPH	Clarithromycin	444	150 MPa for 5 cycles	[43]
CT	Pearl milling	HPH	Hesperidin	599	100 MPa for 5 cycles	[44]
CT	Pearl milling	HPH	Nicergoline	353	150 MPa for 10 cycles	[45]
MRT	Microfluids reaction	HPH	Norfloxacin	170	138 MPa	[46]
ART crystals	ART MICCRA	HPH	Rutin	431	50 MPa for 5 cycle	[18]

Combinative technology

Pretreatment (bottom-up)

Particle size reduction technology

Drug

Mean particle size/nm

Size reduction process (top-down)

Ref.

Nanoedge

Microprecipitation

HPH

Prednisolone

640

68.95 MPa for 15 min

[34]

Nanoedge

Microprecipitation

HPH

Glabridin

149.2

68.95 MPa for 30 min

[35]

Nanoedge

Microprecipitation

HPH

Herpetrione

243

[36]

Nanoedge

Microprecipitation

HPH

10-Hydroxycamptothecin

68.95 MPa for 30 min

[37]

H69

Cavi-precipitation

HPH

Prednisolone

787

150 MPa for 6 min

[38]

H69

Cavi-precipitation

HPH

Ursodeoxycholic acid

372

60 MPa for 10 cycles

[39]

H96

Freeze-drying

HPH

Aprepitant

35.82

150 MPa for 5 cycles

[40]

H42

Spray-drying

HPH

Hydrocortisone acetate

281

150 MPa for 20 cycles

[41]

H96

Freeze-drying

HPH

Glibenclamide

355

150 MPa for 20 cycles

[42]

PLH

Precipitation-freeze-drying

HPH

Clarithromycin

444

150 MPa for 5 cycles

[43]

Pearl milling

HPH

Hesperidin

599

100 MPa for 5 cycles

[44]

Pearl milling

HPH

Nicergoline

353

150 MPa for 10 cycles

[45]

MRT

Microfluids reaction

HPH

Norfloxacin

170

138 MPa

[46]

ART crystals

ART MICCRA

HPH

Rutin

431

50 MPa for 5 cycle

[18]

药物纳米晶体制备技术30年发展回顾与展望

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岳鹏飞 ^* , 刘阳 , 谢锦 , 陈颖翀 , 杨明 ^*

药学学报 | 综述 2018,53(4): 529-537

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药学学报 | 综述 2018, 53(4): 529-537

药物纳米晶体制备技术30年发展回顾与展望

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岳鹏飞^*, 刘阳, 谢锦, 陈颖翀, 杨明^*

作者信息

江西中医药大学, 现代中药制剂教育部重点实验室, 创新药物与高效节能降耗制药设备国家重点实验室, 江西南昌 330004

通讯作者:

* 岳鹏飞, Tel/Fax:86-791-87118658, E-mail:ypfpharm@126.com;

杨明, E-mail:yangming16@126.com

Review and prospect on preparation technology of drug nanocrystals in the past thirty years

Peng-fei YUE^*, Yang LIU, Jin XIE, Ying-chong CHEN, Ming YANG^*

Affiliations

Key Laboratory of Modern Preparation of Traditional Chinese Medicine, Ministry of Education, State Key Laboratory of Innovative Drug and High Efficiency and Energy Saving Pharmaceutical Equipment, Jiangxi University of Traditional Chinese Medicine, Nanchang 330004, China

出版时间: 2018-04-12 doi: 10.16438/j.0513-4870.2017-0920

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摘要

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纳米晶体是难溶性药物给药系统研究的热点。纳米晶体不同于载体纳米粒，其药物并非包载于高分子材料中，同时纳米晶体也不同于固体分散体，其内部有药物晶体存在。纳米晶体制备工艺简单，为改善难溶性药物的溶解度与生物利用度提供了一种有效的技术方法，极具产业化应用与发展潜力。本文将对纳米晶体技术的发展历程进行回顾，以纳米晶体制备技术方法的发展为主线进行综述，并对其存在的问题进行分析与展望，期望为药物纳米晶体制剂的研发提供借鉴。

关键词

纳米晶体 / 制备技术 / bottom-up技术 / top-down技术 / 组合技术

Abstract

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Nanocrystals is a hot topic of poorly soluble drug delivery system under development. Nanocrystals is different from the nanoparticles for drug unloading in polymer materials, and nanocrystals is different from solid dispersion system, in which the drug maintains crystals state. Nanocrystals has a simple preparation process, represents an effective technology in the improvement of solubility and bioavailability of poorly soluble drugs, and has a very promising industrialization application and development potential. In this paper, we retrospect the development history of drug nanocrystals technology, review development of the preparation methods of nanocrystals, and analyze the existing problems to provide a reference to the development of drug nanocrystals preparation.

Key words

nanocrystal / preparation technology / bottom-up / top-down / combinative technology

引用本文

岳鹏飞, 刘阳, 谢锦, 陈颖翀, 杨明. 药物纳米晶体制备技术30年发展回顾与展望. 药学学报, 2018 , 53 (4) : 529 -537 . DOI: 10.16438/j.0513-4870.2017-0920

Peng-fei YUE, Yang LIU, Jin XIE, Ying-chong CHEN, Ming YANG. Review and prospect on preparation technology of drug nanocrystals in the past thirty years[J]. Acta Pharmaceutica Sinica, 2018 , 53 (4) : 529 -537 . DOI: 10.16438/j.0513-4870.2017-0920

正文

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纳米技术与药学相结合, 从而衍生出纳米药物。根据纳米药物存在形式的不同可分为纳米载体药物(借助于载体材料使药物分散在载体中纳米化, 如纳米粒、纳米脂质载体、纳米乳)与纳米晶体药物(药物本身纳米化)。纳米载体药物属载体型纳米系统^[1], 药物包裹于载体材料, 制备工艺复杂、载药量较低、稳定性差; 而药物纳米晶体技术是纯药物纳米胶态分散体系, 不需要载体材料, 制备工艺简单, 载药量高。纳米晶体技术最早由爱尔兰Elan公司开发, 于1991年首次提出了纳米晶体(nanocrystals)的概念, 而事实上药剂学家普遍认为纳米晶体技术本质上是由1988年研发的Hydrosols技术发展而来。纳米晶体技术为改善难溶性药物的溶解度与生物利用度提供了一种有效的技术方法, 极具产业化应用与发展潜力^[2]。本文将对纳米晶体技术的发展历程进行回顾, 以纳米晶体制备技术方法的发展过程为主线进行综述, 并对其存在的问题进行分析与展望, 期望为药物纳米晶体制剂的开发与应用提供借鉴。

1 药物纳米晶体技术发展历程

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药物纳米晶体通常是在高强度机械力作用下将药物粉碎至纳米级别, 并在少量稳定剂作用下形成的纳米胶态颗粒, 可显著提高药物的可润湿性、饱和溶解度及溶出速度, 凭借巨大的表面积, 可增强与生物膜的黏附性, 延长黏附时间和滞留时间, 提高药物的生物利用度^[3]。其作为一种中间制剂技术, 被广泛应用于口服、吸入、鼻腔、经皮和注射等给药途径制剂的制备^[4-7]。表 1概述了纳米晶体制备技术授权专利的相关信息^[8-18]。纳米晶体的制备方法按照原理通常可分为3类: Top-down技术和Bottom-up技术及二者联用技术, 联用技术又分为NanoEdge和SmartCrystal技术, 其中SmartCrystal技术包含了不同的专利, 由数种技术组合而得(H69:即沉淀-高压均质组合技术; H42:即喷干技术与高压均质技术联用; H96:即冻干技术与高压均质技术联用; CT:介质研磨法-高压均质组合法), 可以最大限度地减小药物纳米晶体的粒径。可见纳米晶体从1988年诞生, 截止目前历经30年的创新发展, 形成了10多项制备关键技术, 并逐步走向成熟, 已有17个药物制剂品种先后获得FDA批准上市。

2 药物纳米晶体制备技术的发展概况

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2.1 Bottom-up技术

Bottom-up技术系指将含有药物的良溶剂加入到另一种不良溶剂中, 使药物浓度过饱和而析出结晶的方法, 根据技术原理可分为微量沉淀法、超临界流体法等^[19]。

2.1.1 微量沉淀法

微量沉淀法是将溶有难溶性药物的良溶剂溶液加入到可混溶的不良溶剂中, 通过控制析晶条件来制备纳米晶体。该方法的优点是对仪器的要求不高, 成本低, 操作简单, 可一步完成, 制得的粒子粒径小, 分布窄。晶核形成和成长是析晶过程中两个关键步骤, 不稳定的粒子易发生重结晶, 导致晶体的聚集、沉降, 从而影响药物的稳定性。其缺点是由于制备过程中使用了有机溶剂, 存在有机溶剂残留问题, 所以在制备后需要将有机溶剂除去, 导致较高的生产成本, 且不适用于既不溶于水又不溶于非水溶剂的药物^[20]。Hydrosols与Nanomorph技术均是微量沉淀技术, 区别在于药物纳米晶体存在形式不同。Hydrosols技术即是最早利用微量沉淀原理制备纳米晶体的技术方法, 于1988年由Sucker等研发^[8], 现被Novartis公司拥有^[21]。而Nanomorph技术是利用微量沉淀法制备无定型纳米晶体的技术方法, 最早由Auweter等研发^{[22, 23]}, 然而, 至今为止市场上采用微量沉淀法制备的纳米晶体产品很少。

2.1.2 超临界流体法

超临界流体法系指将药物溶解在超临界液体(如CO₂)中, 当该液体通过微小孔径的喷嘴减压雾化时, 随着超临界液体的迅速气化从而析出纳米晶体粒子。其优点在于技术简单, 成本较低, 使用了对环境无害的溶剂, 可制备出高纯度的无任何有机溶剂残留的纳米晶体, 而其缺点在于超临界流体消耗大, 且不适用于在超临界流体中不溶解的药物。Zhang等^[24]采用超临界流体快速膨胀法制备了152~863 nm的阿托伐他汀钙纳米晶体。

2.1.3 酸碱汽化泡腾辅助沉淀法

酸碱汽化泡腾辅助沉淀法系指利用酸碱溶液中和反应产生二氧化碳, 利用汽化泡腾作用控制溶液药物微小晶体的形成而制备药物纳米晶体的方法。通常将药物溶于含有弱酸(柠檬酸、枸橼酸等)的溶液中作为酸相, 弱碱(碳酸氢钠)等溶于含有稳定剂的溶液中作为碱相, 然后酸相缓慢加入到碱相中反应产生二氧化碳, 同时汽化泡腾辅助作用下析出药物纳米晶体^[25]。该法制备工艺简单, 成本较低, 但要求药物不能被酸碱破坏, 且可能会使用有机溶剂。Wang等^[26]利用酸碱汽化泡腾辅助沉淀法制备了他克莫司纳米晶体混悬液, 药物、稳定剂、柠檬酸与碳酸氢钠的质量比例为1:1:1:1.2, 制备的他克莫司纳米晶体的粒径为(348.2 ± 16.7) nm, 其原理为沉淀过程中酸碱中和反应产生的二氧化碳泡腾作用控制纳米晶体的形成与长大。

2.2 Top-down技术

Top-down技术指利用机械力如研磨或均质等使药物粒径减小的方法, 包括介质碾磨法、高压均质法等, Top-down工艺重现性好以及易于产业化, 是纳米晶体应用最广的制备技术。表 2详细列出了目前研发上市的药物纳米晶体制剂的生产企业、制备技术等相关信息, 可见目前研发上市产品中主要应用的是Top-down技术^[27]。

2.2.1 介质碾磨技术

如图 1所示, 介质研磨技术系依靠研磨介质(玻璃珠或陶瓷球等)制备药物纳米晶体的方法, 该技术由Meriskoliversidge等^{[28, 29]}发明, 是FDA批准上市药物如Rapamune、Emend、Tricor和Megace ES等的常用制备方法。该法制备过程简单, 可操作性强, 制备的纳米晶体粒径分布均一, 易于产业化, 且因制备过程可控制温度而适用于热不稳定性药物。该法制备的药物纳米晶体的粒径大小主要与研磨介质的大小及用量、研磨时间和速度、药物浓度等因素密切相关^[30]。

2.2.2 高压均质技术

高压均质技术依据均质原理不同可分为两种, 即微射流技术(IDD-P)和活塞-裂隙均质技术(Dissocubes、Nanopure)。高压微射流技术是将大颗粒药物分散于水溶液或其他溶剂中形成粗混悬液, 高压作用下使粗混悬液高速通过一个特别设计(“Z”形或“Y”形)的均化室(图 2), 利用撞击力、剪切力和空穴作用来减小药物的粒径, 在“Z”形均化室中, 混悬液在短时间内改变液流方向, 因碰撞而产生剪切力, 而在“Y”形均化室, 则是由于两个管道中的混悬液在交叉处正面高速碰撞而产生剪切力^[31]。IDD-P已被加拿大Skypharma公司成功应用于Triglide (非诺贝特)产品的生产^[11]。该技术影响药物粒径大小和粒度分布的因素主要有处理压力、循环次数及药物本身性质等, 但是该技术生产效率不高, 循环次数较多, 且不适合硬度较大的药物, 一般得到微米级粒子, 不利于生产扩大化^[32]。

活塞-裂隙均质技术是将微粉化的原料药置于含有稳定剂的溶剂中高速搅拌分散制得初混悬液, 然后利用高压均质使初混悬液通过均质阀座的狭缝, 依赖空化作用、剪切力或冲撞力制备纳米晶体, 直到符合粒度要求(图 3)。该技术的影响因素主要为均质化过程中的压力、循环次数、温度及药物的硬度^[33]。Dissocubes、Nanopure技术最初由Muller团队发明^{[12, 13]}, 均属于活塞-裂隙均质技术, Dissocubes技术现为加拿大Skyepharma公司拥有, Nanopure技术隶属于Abbott GmbH公司, 这两项技术采用的高压均质压力可达到150 MPa, 然而采用的分散介质不同, Dissocubes技术以水作为分散介质, 而Nanopure技术以非水溶剂(如油或液体聚乙二醇等)为分散介质, 用于纳米晶体生产。

2.3 组合技术

介质研磨技术、高压均质技术是制备纳米晶体的常规技术, 然而这两种技术通常要求药物初始物料必须微粉化, 而且研磨或均质时间比较长, 限制了这两种技术的广泛应用。因此, 现在常将“bottom-up”和“top-down”技术联合使用, 以提高药物粒径减小效率, 组合技术与常规的纳米晶体制备技术的对比见图 4, 相关的研究实例见表 3^{[18, 34-46]}。

2.3.1 NanoEdge技术(微量沉淀-高压均质组合技术)

该技术最初为Baxer公司发明^[34], 此法联合微量沉淀法与高压均质法, 一方面利用沉淀法获得粒径小于25 μm的初始晶体粒子, 从而减少高压均质机狭缝堵塞的风险, 提高高压均质过程中药物粒径减小的效率; 另一方面运用高压均质法的均化作用使药物晶型趋于完美, 并克服沉淀法所得的晶体粒子粒径分布不均匀、易产生奥斯瓦尔德熟化的问题, 增加纳米晶体粒子的物理稳定性。Wang等^[35]利用微量沉淀法-联合高压均质法制备光甘草定纳米晶体混悬液, 制得的纳米晶体粒径为149.2 nm, 多分散系数为0.254。Shen等^[36]利用基于酸碱中和的微量沉淀法联合高压均质法制备波棱瓜子总木脂素纳米晶体混悬液, 制得的纳米晶体粒径为243 nm, 多分散系数为0.187。

2.3.2 H69技术(高压空化沉淀-均质组合技术)

该方法类似于NanoEdge技术, 最初由Möschwitzer等^[38]发明, 该技术联合微量沉淀法与高压均质法, 与NanoEdge技术不同之处在于纳米晶体的形成发生在高压均质空化区域, 即微量沉淀的过程同时伴随着高压均质, 纳米晶体粒子一经形成便受到高压空化作用、破碎力及冲撞力等作用, 从而控制晶体的长大, 提高纳米晶体粒径的均一性。Li等^[39]运用高压空化沉淀-均质组合法制备熊去氧胆酸纳米晶体混悬液, 沉淀压力为50 MPa, 均质压力为60 MPa, 制备的纳米晶体粒径为372 nm, 显著小于普通高压均质技术制备的纳米晶体粒径大小。

2.3.3 H42技术(喷干分散-高压均质组合技术)与H96技术(冻干分散-高压均质组合技术)

该系列技术由Möschwitzer教授发明, 系指将难溶性药物与稳定剂的溶液分别经喷雾干燥或冷冻干燥, 使药物均匀分散于稳定剂骨架分子中而形成药物分散物, 然后将其重新分散到水中经高压均质而制备药物纳米晶体的方法。该法既可以使药物表面充分被稳定剂吸附修饰而减少高压均质过程中粒子的聚集, 又可以使粒子达到微米级而提高高压均质过程中药物粒径减小效率。Möschwitzer等^[41]采用H42技术制备氢化可的松纳米晶体混悬液, 结果表明喷雾干燥处理后的格列本脲在150 MPa下均质循环1次制得的纳米晶体与未处理的格列本脲于150 MPa下均质循环20次制得的纳米晶体粒径相当, 可见经喷雾干燥处理后的药物粒径减小效率显著提高。Salazar等^[42]采用H96技术制备了格列本脲纳米晶体混悬液, 经冻干处理后的格列本脲在150 MPa的压力下均质循环5次, 粒径即可减小到355 nm, 而直接高压均质法需150 MPa均质循环20次, 表明该方法明显提高了药物粒径减小的效率。

2.3.4 PLH技术(沉淀-冻干-高压均质组合技术)

PLH是将沉淀法、冻干法、均质法结合在一起的方法, 首先将药物溶解在有机溶剂中, 再加入到水相中从而沉淀形成较小晶体, 随后利用冷冻干燥对原料进行改性, 除去在沉淀步骤中所使用的有机溶剂, 最后经过高压均质使其粒径达到纳米范围。Morakul等^[43]利用PLH技术制备了粒径为(444 ± 10) nm的克拉霉素纳米晶体, 均质条件为150 MPa, 均质5次, 而直接高压均质法制备同等粒径大小的克拉霉素纳米晶体, 则需要150 MPa均质30次。

2.3.5 CT技术

该技术系联合介质研磨技术与高压均质技术制备纳米晶体, 药物首先经介质研磨技术预处理得到600~1 500 nm的纳米晶体粗混悬液, 然后再经高压均质制备稳定均一的纳米晶体混悬液, 该技术可减少高压均质的压力, 提高均质效率, 同时可显著提高纳米晶体的稳定性^[44]。Martena等^[45]运用CT技术(介质研磨3 h联合高压均质150 MPa 10次)制备麦角溴烟酯纳米晶体混悬液, 制得的纳米晶体粒径为(353 ± 17) nm, 然而直接高压均质(150 MPa均质30次)制备的纳米晶体粒径为(670 ± 55) nm, 这显著提高了麦角溴烟酯纳米晶体粒径减小的效率。

2.3.6 MRT技术(微射流反应技术)

如图 5所示, 微射流反应技术方法是将良溶剂与反溶剂物料流经单向阀后, 在高压腔内混合并被加压, 然后通过喷嘴的微孔被挤压出来, 形成高速喷射流喷入反应腔, 喷射流在反应腔内对流剪切、形成湍流并相互对撞, 通过剪切、对撞和空化效应能够达到控制晶体粒径减小的技术方法, 而良溶剂与反溶剂的混合比例、射流强度、稳定剂用量、温度等是影响微射流反应技术制备纳米晶体的关键因素。Panagiotou等^[46]运用微射流反应技术制备了诺氟沙星纳米晶体混悬液, 选用的良溶剂二甲亚砜与反溶剂水的比例为1:4, 射流压力138 MPa, 稳定剂比例为10% (w/w), 制备的纳米晶体粒径为170~350 nm。

2.3.7 ARTcrystals技术(转子-定子高速剪切-高压均质联用技术)

ART技术是联合转子-定子高速剪切技术与高压均质技术进行纳米晶体制备的方法, 首先药物混悬液经转子-定子高速剪切机(ART MICCRA, 图 6)剪切预处理, 然后再经高压均质制备稳定均一的纳米晶体混悬液, 该技术可减少高压均质的压力, 提高均质效率, 同时可显著提高纳米晶体的稳定性^[47]。Scholz等^[18]利用ARTcrystals技术制备芦丁纳米晶体混悬液, 剪切转速24 000 r·min^-1, 剪切温度为30 ℃, 剪切时间3 min, 流速600 L·h^-1, 然后经高压均质机50 MPa均质5次, 制备的芦丁纳米晶体的粒径为431 nm, 多分散系数0.27, 粒径大小与均一性较好。

3 纳米晶体技术存在的问题与展望

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3.1 加强影响纳米晶体制备的关键因素研究, 提高纳米晶体技术的粒径减小效率与稳定性

进一步缩短制备时间, 降低生产成本, 提高稳定性仍然是纳米晶体技术研究的难点。药物纳米晶体的制备难易与制备工艺方法密切有关, 此外, 还与稳定剂性质、药物的理化属性等因素有关^{[48, 49]}。药物纳米晶体混悬液容易发生聚结、晶体长大等奥斯瓦尔德熟化现象, 通常使用适量的表面活性剂或高分子聚合物稳定剂来抑制纳米晶体粒子的成长速率, 而稳定剂的表面张力、黏度、分子量、亲水与疏水基团、zeta电位及浓度等可能是影响药物纳米晶体纳米化的关键属性^[50]。此外, 药物的理化属性也是影响药物纳米晶体制备难易的重要因素, 如药物的固体形态、初始粒径、内聚能和多晶型等性质直接影响纳米晶体制备的粒径大小及其稳定性。

3.2 深入开展药物纳米晶体的体内外相关性及纳米毒理安全性评价研究

纳米晶体为改善难溶性药物的溶解度与溶出度提供了新的方法, 其作为中间制剂技术, 已被广泛应用于口服^[51]、吸入^[52]、鼻腔^[53]、经皮^[54]和靶向^[55]等给药途径制剂的制备。截至目前全球批准上市了17个产品, 其中帕利哌酮和阿立哌唑缓释注射液的上市, 为纳米晶体技术在注射液领域的应用奠定了坚实的基础。纳米晶体制剂由于药物本身为纳米状态, 具有特殊的纳米效应及性质, 能够显著改善药物的体内行为, 存在潜在的安全风险。目前, 关于药物纳米晶体制剂的体内外相关性及安全性评价的研究较少, 尤其纳米晶体注射给药与靶向给药的安全性研究更少。如何建立适合药物纳米晶体制剂特点的体内外相关性分析模型, 以及建立药物纳米晶体制剂的毒理安全性评价方法, 增强纳米晶体体内的可控性与安全性, 对药物纳米晶体制剂的发展具有重要的意义。

3.3 加强纳米晶体的基础研究, 研发纳米晶体制备相关设备, 推动我国药物纳米晶体制剂的工业化生产

纳米晶体技术发展至今已有30年, 然而我国纳米晶体技术的研究仍然处于基础研究阶段, 截止目前没有批准上市的原研产品。纳米晶体技术的应用受到设备能耗高、易磨损等因素的制约, 药物本身的性质如脆碎性和热敏感性也限制了纳米晶体技术的应用。因此, 进一步加强药物纳米晶体制备过程的放大研究及其配套设备的开发, 提高产品稳定性将是今后我国推进药物纳米晶体制备技术工业化的重要方向。

4 结语

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纳米晶体技术为改善难溶性药物的给药提供了一种可行性技术方法。过去30年纳米晶体技术在药剂学领域取得了巨大的发展, 制备技术方法不断升级更新, 纳米化效率有不同程度提升, 并实现了17个产品的批准上市, 涵盖口服、注射等给药途径, 这充分印证了纳米晶体制剂技术产业化的成熟可行与广阔前景。然而, 也必须意识到纳米晶体技术还存在一些问题, 需要进一步加强影响纳米晶体制备的关键因素研究, 提高纳米晶体技术的粒径减小效率与稳定性, 深入开展药物纳米晶体的体内外相关性及安全性评价研究等。相信伴随基础研究的不断深入, 纳米晶体技术将不断趋于完善, 并广泛应用于更多制剂领域。

基金

收起

国家自然科学基金资助项目(81560656)
国家自然科学基金资助项目(81760715)
江西省杰出青年人才资助计划(20162BCB23033)
江西省自然科学基金资助项目(20161BAB205221)

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2018年第53卷第4期

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doi: 10.16438/j.0513-4870.2017-0920

接收时间：2017-09-15
首发时间：2026-01-15
出版时间：2018-04-12

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作者

出版历史

收稿日期：2017-09-15
修回日期：2017-10-31

基金

国家自然科学基金资助项目(81560656)

国家自然科学基金资助项目(81760715)

江西省杰出青年人才资助计划(20162BCB23033)

江西省自然科学基金资助项目(20161BAB205221)

作者信息

江西中医药大学, 现代中药制剂教育部重点实验室, 创新药物与高效节能降耗制药设备国家重点实验室, 江西南昌 330004

通讯作者:

* 岳鹏飞, Tel/Fax:86-791-87118658, E-mail:ypfpharm@126.com;

杨明, E-mail:yangming16@126.com

参考文献

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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BibTeX
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RefWorks
TxT

Technology	Patent No.	Year	Inventor	Process parameter	Advantage	Ref.
Hydrosol	GB2200048	1988	Novartis	Rate of addition of solvent, solubility of drug in antisolvent, amount of stabilizer, ratio of solvent/antisolvent	Lower particle size can be obtained, amorphous character in final product, increase in solubility	[8]
NanoMorph	D19637517	2002	Soligs/Abbott			[9]
Nanocrystals	US5145684	1991	Elan Nanosystems	Milling speed, milling time, amount of milling media, drug amount, temperature	Easy industrial applicability, simple process, high drug loading, avoid use of organic solvent	[10]
IDD-P	US5091188 A	1992	Duncan H. Haynes	Homogenization cycle, homogenization temperature, hardness of drug	Suitable for all kind of drugs, easy reproducibility, less contamination as compared to media milling, high rate of production	[11]
Dissocubes	US5858410	1994	SkyePharma			[12]
Nanopure	PCT/EP00/06535	2000	PharmaSol			[13]
NANOEDGE	US 6607784	2003	Baxter International Inc.	Precipitation combined with homogenization	Less number of cycle and energy required to reduce the particle size	[14]
H42	WO2006094808 A3	2005	Pharmasol Gmbh	Spray-drying combined with homogenization	Able to produce particle size below 100 nm which is not feasible by any of the top-down technology, less cycle of high pressure homogenization required	[15]
H96	WO2006108637A2	2007	Pharmasol Gmbh	Freeze-drying combined with homogenization		[16]
CT	US20100047297	2010	Abbott Gmbh	Media milling combined with homogenization		[17]
ARTcrystal	US2013/0095198	2013	Pharmasol Gmbh	High-speed rotor-stator dispersion combined with homogenization		[18]

Technology

Patent No.

Year

Inventor

Process parameter

Advantage

Ref.

Hydrosol

GB2200048

1988

Novartis

Rate of addition of solvent, solubility of drug in antisolvent, amount of stabilizer, ratio of solvent/antisolvent

Lower particle size can be obtained, amorphous character in final product, increase in solubility

[8]

NanoMorph

D19637517

2002

Soligs/Abbott

[9]

Nanocrystals

US5145684

1991

Elan Nanosystems

Milling speed, milling time, amount of milling media, drug amount, temperature

Easy industrial applicability, simple process, high drug loading, avoid use of organic solvent

[10]

IDD-P

US5091188 A

1992

Duncan H. Haynes

Homogenization cycle, homogenization temperature, hardness of drug

Suitable for all kind of drugs, easy reproducibility, less contamination as compared to media milling, high rate of production

[11]

Dissocubes

US5858410

1994

SkyePharma

[12]

Nanopure

PCT/EP00/06535

2000

PharmaSol

[13]

NANOEDGE

US 6607784

2003

Baxter International Inc.

Precipitation combined with homogenization

Less number of cycle and energy required to reduce the particle size

[14]

H42

WO2006094808 A3

2005

Pharmasol Gmbh

Spray-drying combined with homogenization

Able to produce particle size below 100 nm which is not feasible by any of the top-down technology, less cycle of high pressure homogenization required

[15]

H96

WO2006108637A2

2007

Pharmasol Gmbh

Freeze-drying combined with homogenization

[16]

US20100047297

2010

Abbott Gmbh

Media milling combined with homogenization

[17]

ARTcrystal

US2013/0095198

2013

Pharmasol Gmbh

High-speed rotor-stator dispersion combined with homogenization

[18]

Trade name	Drug	Company	Method	Therapeutic effect	Status
Verelan PM	Verapamil	Schwarz Pharma	Top-down (WMM)	Antiarrhythmia	Approved (FDA, 1998)
Rapamune	Sirolimus	Wyeth	Top-down (WMM)	Immunosuppre-ssant	Approved (FDA, 2000)
Focalin XR	Dexmethylphenidate hydrochloride	Novartis	Top-down (WMM)	Antipsychotic	Approved (FDA, 2001)
Avinza	Morphine sulfate	King Pharm	Top-down (WMM)	Antichronic pain	Approved (FDA, 2002)
Ritalin LA	Methylphenidate hydrochloride	Novartis	Top-down (WMM)	Antipsychotic	Approved (FDA, 2002)
Herbesser	Diltiazem	Mitsubishi Tanabe Pharma	Top-down (WMM)	Antiangina	Approved (JMH, 2002)
Zanaflex	Tizanidine hydrochloride	Acorda	Top-down (WMM)	Muscle relaxant	Approved (FDA, 2002)
Emend	Aprepitant	Merck	Top-down (WMM)	Antiemetic	Approved (FDA, 2003)
Tricor	Fenofibrate	Abbott	Top-down (WMM)	Hypercholesterolemia	Approved (FDA, 2004)
Cesamet	Nabilone	Lilly	Bottom-up (CP)	Antiemetic	Approved (FDA, 2005)
Megace ES	Megestrol acetate	Par Pharma	Top-down (WMM)	Appetite stimulant	Approved (FDA, 2005)
Triglide	Fenofibrate	Skye Pharma	Top-down (HPH)	Hypercholesterolemia	Approved (FDA, 2005)
Naprelan	Naproxen sodium	Wyeth	Top-down (WMM)	Anti-inflammation	Approved (FDA, 2006)
Theodur	Theophylline	Mitsubishi Tanabe Pharma	Top-down (WMM)	Bronchial dilation	Approved (FDA, 2008)
Invega Sustenna	Paliperidone palmitate	Janssen	Top-down (HPH)	Antidepressant	Approved (FDA, 2009)
Invega Trinza	Paliperidone palmitate	Janssen	Top-down (HPH))	Antidepressant	Approved (FDA, 2015)
Aristada	Aripiprazole lauroxil	Alkermes	Top-down (HPH)	Schizophrenia	Approved (FDA, 2015)
Panzem	2-Methoxyestradiol	EntreMed	Top-down (WMM)	Anti-tumor	Phase Ⅱ (FDA)
Semapimod	Guanylhydrazone	Ferring	Top-down (WMM)	Anti-inflammation	Phase Ⅱ (FDA)
Paxceed	Paclitaxel	Angiotech Pharmaceuticals	Top-down (HPH)	Anti-tumor	Phase Ⅱ (FDA)
Theralux	Thymectacin	Celmed BioSciences	Top-down (WMM)	Anti-tumor	Phase Ⅱ (FDA)

Trade name

Drug

Company

Method

Therapeutic effect

Status

Verelan PM

Verapamil

Schwarz Pharma

Top-down (WMM)

Antiarrhythmia

Approved (FDA, 1998)

Rapamune

Sirolimus

Wyeth

Top-down (WMM)

Immunosuppre-ssant

Approved (FDA, 2000)

Focalin XR

Dexmethylphenidate hydrochloride

Novartis

Top-down (WMM)

Antipsychotic

Approved (FDA, 2001)

Avinza

Morphine sulfate

King Pharm

Top-down (WMM)

Antichronic pain

Approved (FDA, 2002)

Ritalin LA

Methylphenidate hydrochloride

Novartis

Top-down (WMM)

Antipsychotic

Approved (FDA, 2002)

Herbesser

Diltiazem

Mitsubishi Tanabe Pharma

Top-down (WMM)

Antiangina

Approved (JMH, 2002)

Zanaflex

Tizanidine hydrochloride

Acorda

Top-down (WMM)

Muscle relaxant

Approved (FDA, 2002)

Emend

Aprepitant

Merck

Top-down (WMM)

Antiemetic

Approved (FDA, 2003)

Tricor

Fenofibrate

Abbott

Top-down (WMM)

Hypercholesterolemia

Approved (FDA, 2004)

Cesamet

Nabilone

Lilly

Bottom-up (CP)

Antiemetic

Approved (FDA, 2005)

Megace ES

Megestrol acetate

Par Pharma

Top-down (WMM)

Appetite stimulant

Approved (FDA, 2005)

Triglide

Fenofibrate

Skye Pharma

Top-down (HPH)

Hypercholesterolemia

Approved (FDA, 2005)

Naprelan

Naproxen sodium

Wyeth

Top-down (WMM)

Anti-inflammation

Approved (FDA, 2006)

Theodur

Theophylline

Mitsubishi Tanabe Pharma

Top-down (WMM)

Bronchial dilation

Approved (FDA, 2008)

Invega Sustenna

Paliperidone palmitate

Janssen

Top-down (HPH)

Antidepressant

Approved (FDA, 2009)

Invega Trinza

Paliperidone palmitate

Janssen

Top-down (HPH))

Antidepressant

Approved (FDA, 2015)

Aristada

Aripiprazole lauroxil

Alkermes

Top-down (HPH)

Schizophrenia

Approved (FDA, 2015)

Panzem

2-Methoxyestradiol

EntreMed

Top-down (WMM)

Anti-tumor

Phase Ⅱ (FDA)

Semapimod

Guanylhydrazone

Ferring

Top-down (WMM)

Anti-inflammation

Phase Ⅱ (FDA)

Paxceed

Paclitaxel

Angiotech Pharmaceuticals

Top-down (HPH)

Anti-tumor

Phase Ⅱ (FDA)

Theralux

Thymectacin

Celmed BioSciences

Top-down (WMM)

Anti-tumor

Phase Ⅱ (FDA)

Combinative technology	Pretreatment (bottom-up)	Particle size reduction technology	Drug	Mean particle size/nm	Size reduction process (top-down)	Ref.
Nanoedge	Microprecipitation	HPH	Prednisolone	640	68.95 MPa for 15 min	[34]
Nanoedge	Microprecipitation	HPH	Glabridin	149.2	68.95 MPa for 30 min	[35]
Nanoedge	Microprecipitation	HPH	Herpetrione	243		[36]
Nanoedge	Microprecipitation	HPH	10-Hydroxycamptothecin	22	68.95 MPa for 30 min	[37]
H69	Cavi-precipitation	HPH	Prednisolone	787	150 MPa for 6 min	[38]
H69	Cavi-precipitation	HPH	Ursodeoxycholic acid	372	60 MPa for 10 cycles	[39]
H96	Freeze-drying	HPH	Aprepitant	35.82	150 MPa for 5 cycles	[40]
H42	Spray-drying	HPH	Hydrocortisone acetate	281	150 MPa for 20 cycles	[41]
H96	Freeze-drying	HPH	Glibenclamide	355	150 MPa for 20 cycles	[42]
PLH	Precipitation-freeze-drying	HPH	Clarithromycin	444	150 MPa for 5 cycles	[43]
CT	Pearl milling	HPH	Hesperidin	599	100 MPa for 5 cycles	[44]
CT	Pearl milling	HPH	Nicergoline	353	150 MPa for 10 cycles	[45]
MRT	Microfluids reaction	HPH	Norfloxacin	170	138 MPa	[46]
ART crystals	ART MICCRA	HPH	Rutin	431	50 MPa for 5 cycle	[18]

Combinative technology

Pretreatment (bottom-up)

Particle size reduction technology

Drug

Mean particle size/nm

Size reduction process (top-down)

Ref.

Nanoedge

Microprecipitation

HPH

Prednisolone

640

68.95 MPa for 15 min

[34]

Nanoedge

Microprecipitation

HPH

Glabridin

149.2

68.95 MPa for 30 min

[35]

Nanoedge

Microprecipitation

HPH

Herpetrione

243

[36]

Nanoedge

Microprecipitation

HPH

10-Hydroxycamptothecin

68.95 MPa for 30 min

[37]

H69

Cavi-precipitation

HPH

Prednisolone

787

150 MPa for 6 min

[38]

H69

Cavi-precipitation

HPH

Ursodeoxycholic acid

372

60 MPa for 10 cycles

[39]

H96

Freeze-drying

HPH

Aprepitant

35.82

150 MPa for 5 cycles

[40]

H42

Spray-drying

HPH

Hydrocortisone acetate

281

150 MPa for 20 cycles

[41]

H96

Freeze-drying

HPH

Glibenclamide

355

150 MPa for 20 cycles

[42]

PLH

Precipitation-freeze-drying

HPH

Clarithromycin

444

150 MPa for 5 cycles

[43]

Pearl milling

HPH

Hesperidin

599

100 MPa for 5 cycles

[44]

Pearl milling

HPH

Nicergoline

353

150 MPa for 10 cycles

[45]

MRT

Microfluids reaction

HPH

Norfloxacin

170

138 MPa

[46]

ART crystals

ART MICCRA

HPH

Rutin

431

50 MPa for 5 cycle

[18]